Protein palmitoylation has emerged as an important mechanism for regulating protein trafficking, stability, and protein–protein interactions; however, its relevance to disease processes is not clear. Using a genome-wide, phenotype driven N-ethyl-N-nitrosourea–mediated mutagenesis screen, we identified mice with failure to thrive, shortened life span, skin and hair abnormalities including alopecia, severe osteoporosis, and systemic amyloidosis (both AA and AL amyloids depositions). Whole-genome homozygosity mapping with 295 SNP markers and fine mapping with an additional 50 SNPs localized the disease gene to chromosome 7 between 53.9 and 56.3 Mb. A nonsense mutation (c.1273A>T) was located in exon 12 of the Zdhhc13 gene (Zinc finger, DHHC domain containing 13), a gene coding for palmitoyl transferase. The mutation predicted a truncated protein (R425X), and real-time PCR showed markedly reduced Zdhhc13 mRNA. A second gene trap allele of Zdhhc13 has the same phenotypes, suggesting that this is a loss of function allele. This is the first report that palmitoyl transferase deficiency causes a severe phenotype, and it establishes a direct link between protein palmitoylation and regulation of diverse physiologic functions where its absence can result in profound disease pathology. This mouse model can be used to investigate mechanisms where improper palmitoylation leads to disease processes and to understand molecular mechanisms underlying human alopecia, osteoporosis, and amyloidosis and many other neurodegenerative diseases caused by protein misfolding and amyloidosis.
Polymorphisms in the VKORC1 gene have the strongest effects on warfarin dose, followed by CYP2C9*3. In addition, our results showed that CYP2C18, PROC and EPHX1 have small but significant associations with warfarin dose. In multiple regression analysis, PROC and EPHX1 explained 3% of the dose variation. The incorporation of these two genes into warfarin dosing algorithms could improve the accuracy of prediction in the Han-Chinese population.
The activity of a single subcutaneous injection of ivermectin at dose of 200 mcg/kg of body weight was evaluated against naturally acquired gastro-intestinal parasites in mules. Faecal samples were examined at the time of treatment and weekly thereafter up to 4 weeks. Results indicated that invrmectin was highly effective (100%) against Oxyuries equi, Strongyloides westeri, Tristostronglus axei, Trichhonema spp., and Strongylus spp. as judged one week after ivermectin administration.
Complete elimination of Parascaris equorum eggs occurred two weeks after treatment. In contrast, ivermectin was not effective against the tape worms, Anoplocephala spp.. Infected animals had low levels of haemoglobin and red blood cells counts and an elevated packed cell volume, white blood cells and erythrocyte sedimentation rate.
These values returned to normal values 21 days post treatment. No adverse reaction was recorded in the treated animals.
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