We attempted to produce a rat model of brain aluminum toxicity in order to explore whether or not aluminum accumulation produces the neurochemical changes observed in brains of patients who die with dialysis encephalopathy. Daily subcutaneous injection of Al(OH)3 caused marked elevation of serum aluminum concentrations, but did not increase brain aluminum contents, either in rats with normal renal function, or in rats with unilateral or 5/6 nephrectomies. LiCl pretreatment, which has been reported to cause irreversible renal failure, did not impair renal function nor aid in achieving elevated brain aluminum contents. No reductions in brain contents of -aminobutyric acid (GABA) or in glutamic acid decarboxylase (GAD, E.C.4.1.1.15) and choline acetyltransferase (ChAT, E.C.2.3.1.6) activities were observed in aluminum-treated rats. We conclude that the rat is not a suitable laboratory animal to explore the role of aluminum toxicity in causing the GABA and ChAT deficits present in brains of hemodialyzed human patients. 相似文献
Rats were fed maximally tolerated doses of L-3,4-Dihydroxyphenylalanine (L-DOPA) and carbidopa daily for 120 days in order to achieve a sustained elevation in brain dopamine levels. Some animals were also given buthionine sulfoximine, a gamma-glutamylcysteine synthetase inhibitor, in an unsuccessful effort to reduce brain glutathione contents. L-DOPA- and carbidopa-treated animals displayed no behavioral changes suggestive of nigrostriatal dopaminergic neuronal loss. When sacrificed 60 days after L-DOPA treatment ended, all rats had normal tyrosine hydroxylase activities and dopamine contents in their striata, and cell counts were normal in the substantia nigra. It therefore seems unlikely that a model of Parkinson's disease, suitable for exploring the etiological importance of glutathione deficiency, can be produced in rats merely by administering the largest tolerable doses of L-DOPA. 相似文献
Fishes represent the stem vertebrate condition and have maintained several
gene arrangements common to mammalian genomes throughout the 450 Myr of
divergence from a common ancestor. One such syntenic arrangement includes
the GPI-PEPD enzyme association on Xiphophorus linkage group IV and human
chromosome 19. Previously we assigned the Xiphophorus homologue of the
human ERCC2 gene to linkage group U5 in tight association with the CKM
locus. CKM is also tightly linked to the ERCC2 locus on human chromosome
19, leading to speculation that human chromosome 19 may have arisen by
fusion of two ancestral linkage groups which have been maintained in
fishes. To investigate this hypothesis further, we isolated and sequenced
Xiphophorus fish genomic regions exhibiting considerable sequence
similarity to the human DNA ligase 1 amino acid sequence. Comparison of the
fish DNA ligase sequence with those of other species suggests several modes
of amino acid conservation in this gene. A 2.2-kb restriction fragment
containing part of an X. maculatus DNA ligase 1 exon was used in backcross
hybrid mapping with 12 enzyme or RFLP loci. Significant linkage was
observed between the nucleoside phosphorylase (NP2) and the DNA ligase
(LIG1) loci on Xiphophorus linkage group VI. This assignment suggests that
the association of four DNA repair-related genes on human chromosome 19 may
be the result of chance chromosomal rearrangements.
相似文献
Abstract Two chronosequences of unsaturated, buried loess sediments, ranging in age from <10,000 years to >1 million years, were investigated to reconstruct patterns of microbial ecological succession that have occurred since sediment burial. The relative importance of microbial transport and survival to succession was inferred from sediment ages, porewater ages, patterns of abundance (measured by direct counts, counts of culturable cells, and total phospholipid fatty acids), activities (measured by radiotracer and enzyme assays), and community composition (measured by phospholipid fatty acid patterns and Biolog substrate usage). Core samples were collected at two sites 40 km apart in the Palouse region of eastern Washington State, near the towns of Washtucna and Winona. The Washtucna site was flooded multiple times during the Pleistocene by glacial outburst floods; the Winona site elevation is above flood stage. Sediments at the Washtucna site were collected from near surface to 14.9 m depth, where the sediment age was approximately 250 ka and the porewater age was 3700 years; sample intervals at the Winona site ranged from near surface to 38 m (sediment age: approximately 1 Ma; porewater age: 1200 years). Microbial abundance and activities declined with depth at both sites; however, even the deepest, oldest sediments showed evidence of viable microorganisms. Same-age sediments had equal quantities of microorganisms, but different community types. Differences in community makeup between the two sites can be attributed to differences in groundwater recharge and paleoflooding. Estimates of the microbial community age can be constrained by porewater and sediment ages. In the shallower sediments (<9 m at Washtucna, <12 m at Winona), the microbial communities are likely similar in age to the groundwater; thus, microbial succession has been influenced by recent transport of microorganisms from the surface. In the deeper sediments, the populations may be considerably older than the porewater ages, since microbial transport is severely restricted in unsaturated sediments. This is particularly true at the Winona site, which was never flooded. 相似文献
Restriction mapping and sequencing have shown that humans have
substantially lower levels of mitochondrial genome diversity (d) than
chimpanzees. In contrast, humans have substantially higher levels of
heterozygosity (H) at protein-coding loci, suggesting a higher level of
diversity in the nuclear genome. To investigate the discrepancy further, we
sequenced a segment of the mitochondrial genome control region (CR) from 49
chimpanzees. The majority of these were from the Pan troglodytes versus
subspecies, which was underrepresented in previous studies. We also
estimated the average heterozygosity at 60 short tandem repeat (STR) loci
in both species. For a total sample of 115 chimpanzees, d = 0.075 +/0
0.037, compared to 0.020 +/- 0.011 for a sample of 1,554 humans. The
heterozygosity of human STR loci is significantly higher than that of
chimpanzees. Thus, the higher level of nuclear genome diversity relative to
mitochondrial genome diversity in humans is not restricted to
protein-coding loci. It seems that humans, not chimpanzees, have an unusual
d/H ratio, since the ratio in chimpanzees is similar to that in other
catarrhines. This discrepancy in the relative levels of nuclear and
mitochondrial genome diversity in the two species cannot be explained by
differences in mutation rate. However, it may result from a combination of
factors such as a difference in the extent of sex ratio disparity, the
greater effect of population subdivision on mitochondrial than on nuclear
genome diversity, a difference in the relative levels of male and female
migration among subpopulations, diversifying selection acting to increase
variation in the nuclear genome, and/or directional selection acting to
reduce variation in the mitochondrial genome.
相似文献
Cytochrome P450 (CYP) 2C19 is essential for the metabolism of clinically used drugs including omeprazole, proguanil, and S-mephenytoin. This hepatic enzyme exhibits genetic polymorphism with inter-individual variability in catalytic activity. This study aimed to characterise the functional consequences of CYP2C19*23 (271 G>C, 991 A>G) and CYP2C19*24 (991 A>G, 1004 G>A) in vitro. Mutations in CYP2C19 cDNA were introduced by site-directed mutagenesis, and the CYP2C19 wild type (WT) as well as variants proteins were subsequently expressed using Escherichia coli cells. Catalytic activities of CYP2C19 WT and those of variants were determined by high performance liquid chromatography-based essay employing S-mephenytoin and omeprazole as probe substrates. Results showed that the level of S-mephenytoin 4′-hydroxylation activity of CYP2C19*23 (Vmax 111.5 ± 16.0 pmol/min/mg, Km 158.3 ± 88.0 μM) protein relative to CYP2C19 WT (Vmax 101.6 + 12.4 pmol/min/mg, Km 123.0 ± 19.2 μM) protein had no significant difference. In contrast, the Km of CYP2C19*24 (270.1 ± 57.2 μM) increased significantly as compared to CYP2C19 WT (123.0 ± 19.2 μM) and Vmax of CYP2C19*24 (23.6 ± 2.6 pmol/min/mg) protein was significantly lower than that of the WT protein (101.6 ± 12.4 pmol/min/mg). In vitro intrinsic clearance (CLint = Vmax/Km) for CYP2C19*23 protein was 85.4 % of that of CYP2C19 WT protein. The corresponding CLint value for CYP2C19*24 protein reduced to 11.0 % of that of WT protein. These findings suggested that catalytic activity of CYP2C19 was not affected by the corresponding amino acid substitutions in CYP2C19*23 protein; and the reverse was true for CYP2C19*24 protein. When omeprazole was employed as the substrate, Km of CYP2C19*23 (1911 ± 244.73 μM) was at least 100 times higher than that of CYP2C19 WT (18.37 ± 1.64 μM) and Vmax of CYP2C19*23 (3.87 ± 0.74 pmol/min/mg) dropped to 13.4 % of the CYP2C19 WT (28.84 ± 0.61 pmol/min/mg) level. Derived from Vmax/Km, the CLint value of CYP2C19 WT was 785 folds of CYP2C19*23. Km and Vmax values could not be determined for CYP2C19*24 due to its low catalytic activity towards omeprazole 5′-hydroxylation. Therefore, both CYP2C19*23 and CYP2C19*24 showed marked reduced activities of metabolising omeprazole to 5-hydroxyomeprazole. Hence, carriers of CYP2C19*23 and CYP2C19*24 allele are potentially poor metabolisers of CYP2C19-mediated substrates. 相似文献
This study investigated the effects of temperature (20 and 30 °C) and pH (pH 3.1, 3.9) on kinetic changes of chemical constituents of the durian wine fermented with Saccharomyces cerevisiae. Temperature significantly affected growth of S. cerevisiae EC-1118 regardless of pH with a higher temperature leading to a faster cell death. The pH had a more significant effect on ethanol production than temperature with higher production at 20 °C (5.95%, v/v) and 30 °C (5.56%, v/v) at pH 3.9, relative to that at pH 3.1 (5.25 and 5.01%, v/v). However, relatively higher levels of isobutyl alcohol and isoamyl alcohol up to 64.52 ± 6.39 and 56.27 ± 3.00 mg/L, respectively, were produced at pH 3.1 than at pH 3.9 regardless of temperature. In contrast, production of esters was more affected by temperature than pH, where levels of ethyl esters (ethyl esters of octanoate, nonanoate, and decanoate) and acetate esters (ethyl acetate and isoamyl acetate) were significantly higher up to 2.13 ± 0.23 and 4.61 ± 0.22 mg/L, respectively, at 20 °C than at 30 °C. On the other hand, higher temperature improved the reduction of volatile sulfur compounds. This study illustrated that temperature control would be a more effective tool than pH in modulating the resulting aroma compound profile of durian wine.