Effect of copper deficiency on the concentrations of catecholamines and related enzyme activities in the rat brain.

Immature rats were made copper deficient by feeding them a low (< 1 p. p. m.) copper diet. During the gestation and lactation periods their dams consumed the same diet. Controls received a dietary supplement of 10 p. p. m. copper. At approx 7 weeks of age, the deficient animals exhibited signs of neurological dysfunction and gross lesions of the brain. Cytochrome oxidase activity and copper content of the liver and brain were used as criteria of copper status and confirmed the existence of severe deficiency. The whole brains minus cerebella of the deficient animals contained approx 30% less dopamine and norepinephrine than those of the controls. The tyrosine hydroxylase activity was depressed more than 25% in the copper deficient brains while the superoxide dismutase activity was lowered more than 35%. There was a high correlation between the chief criterion of copper status, liver cytochrome oxidase activity, and the brain concentrations of dopamine, norepinephrine and tyrosine hydroxylase activity. The decrease in activity of tyrosine hydroxylase was sufficient to account for the lowered concentrations of the catecholamines.     

Common STAT3 variants are not associated with obesity or insulin resistance in female twins

In animal models, STAT3 action in the hypothalamus and liver appears essential for normal body weight and glucose homeostasis in response to insulin. We hypothesized that variation in the STAT3 gene may be associated with body fat and/or insulin resistance in the general population. Five tagging SNPs spanning the STAT3 gene, rs8074524, rs2293152, rs2306580, rs6503695, and rs7211777 were genotyped in 2776 white female twins (mean age, 47.4+/-12.5 yrs) from the St Thomas' United Kingdom Adult Twin Registry (Twins UK). Minor allele frequencies were as follows: rs8074524 (0.19), rs2293152 (0.37), rs2306580 (0.06), rs6503695 (0.35), and rs7211777 (0.34). The minor allele of rs2293152 was associated with higher homeostasis model assessment index of insulin resistance (p=0.013) in the full cohort and confirmed in sib-transmission/disequilibrium test (TDT): (p=0.015; n=60). However, there were no associations with fasting serum insulin or glucose or with obesity variables. Although defective STAT3 action results in obesity and insulin resistance in animal models, we failed to establish any indicative associations with common SNPs in this human study.     

ApoE and clusterin cooperatively suppress Abeta levels and deposition: evidence that ApoE regulates extracellular Abeta metabolism in vivo

Apolipoprotein E (apoE) and clusterin can influence structure, toxicity, and accumulation of the amyloid-beta (Abeta) peptide in brain. Both molecules may also be involved in Abeta metabolism prior to its deposition. To assess this possibility, we compared PDAPP transgenic mice that develop age-dependent Abeta accumulation in the absence of apoE or clusterin as well as in the absence of both proteins. apoE(-/-) and clusterin(-/-) mice accumulated similar Abeta levels but much less fibrillar Abeta. In contrast, apoE(-/-)/clusterin(-/-) mice had both earlier onset and markedly increased Abeta and amyloid deposition. Both apoE(-/-) and apoE(-/-)/clusterin(-/-) mice had elevated CSF and brain interstitial fluid Abeta, as well as significant differences in the elimination half-life of interstitial fluid Abeta measured by in vivo microdialysis. These findings demonstrate additive effects of apoE and clusterin on influencing Abeta deposition and that apoE plays an important role in regulating extracellular CNS Abeta metabolism independent of Abeta synthesis.     

Characterization of the region containing the jcpk PKD gene on mouse Chromosome 10

The jcpk gene on mouse Chromosome 10 causes a severe, early onset form of polycystic kidney disease (PKD) when inherited in an autosomal recessive manner. In order to positionally clone this gene, high resolution genetic and radiation hybrid maps were generated along with a detailed physical map of the approximately 500-kb region containing the jcpk gene. Additionally, sixty-nine kidney-specific ESTs were evaluated as candidates for jcpk and subsequently localized throughout the mouse genome by radiation hybrid mapping analysis. Previous studies indicating non-complementation of the jcpk mutation and 67Gso, a new PKD translocation mutant had suggested that 67Gso represents a new allele of jcpk. Fluorescence in situ hybridization (FISH) analysis using key bacterial artificial chromosome clones from the jcpk critical region, refined the 67Gso breakpoint and provided support for the allelism of jcpk and 67Gso.     

Gene dosage and selective expression modify phenotype in a Drosophila model of human mitochondrial disease

Human mitochondrial disease manifests with a wide range of clinical phenotypes of varying severity. To create a model for these disorders, we have manipulated the Drosophila gene technical knockout, encoding mitoribosomal protein S12. Various permutations of endogenous and transgenic alleles create a range of phenotypes, varying from larval developmental arrest through to mild neurological defects in the adult, and also mimic threshold effects associated with human mtDNA disease. Nuclear genetic background influences mutant phenotype by a compensatory mechanism affecting mitochondrial RNA levels. Selective expression of the wild-type allele indicates critical times and cell-types in development, in which mitochondrial protein synthesis deficiency leads to specific phenotypic outcomes.     

Spatial analysis of within-population microsatellite variability reveals restricted gene flow in the Pacific golden chanterelle (Cantharellus formosus)

We examined the within-population genetic structure of the Pacific golden chanterelle (Cantharellus formosus) in a 50 y old forest stand dominated by Douglas-fir (Pseudotsuga menziesii) and western hemlock (Tsuga heterophylla) with spatial autocorrelation analysis. We tested the null hypothesis that multilocus genotypes possessed by chanterelle genets were randomly distributed within the study area. Fruit bodies from 203 C. formosus genets were collected from a 50 ha study plot. One hundred six unique multilocus genotypes were identified after scoring these collections at five microsatellite loci. Statistically significant positive spatial autocorrelation was detected indicating the presence of fine-scale genetic structure within the area. Repeated autocorrelation analyses with varied minimum distance classes (50-500 m) detected positive spatial genetic structure up to 400 m. Therefore nonrandom evolutionary processes (e.g., isolation by distance) can cause fine-scale genetic structure in C. formosus. The implications of this research for future broad-scale population studies of this species are that population samples should be separated by at least 400 m to be considered statistically independent. Sampling designs that account for fine-scale genetic structure will better characterize heterogeneity distributed across the landscape by avoiding the effects of pseudo replication.