The distribution of major histocompatibility complex class I polymorphic Alu insertions and their associations with HLA alleles in a Chinese population from Malaysia

The frequency and association of polymorphic Alu insertions (POALINs) with human leucocyte antigen (HLA) class I genes within the class I genomic region of the major histocompatibility complex (MHC) have been reported previously for three populations: the Australian Caucasian, Japanese and north-eastern Thai populations. Here, we report on the individual insertion frequency of the five POALINs within the MHC class I region, their HLA-A and HLA-B associations, the POALIN haplotype frequencies and the HLA-A/POALIN four-loci haplotype frequencies in the Malaysian Chinese population. The phylogenetic relationship of the four populations based on the five POALIN allele frequencies was also examined. In the Malaysian Chinese population, the POALIN AluyHG was present at the highest frequency (0.560), followed by AluyHJ (0.300), AluyMICB (0.170), AluyTF (0.040) and AluyHF (0.030). The most frequent five-loci POALIN haplotype of the 16 inferred haplotypes was the AluyHG single insertion haplotype at a frequency of 0.489. Strong associations were present between AluyHJ and HLA-A24, HLA-A33 and HLA-A11 and between AluyHG and HLA-A2, HLA-A24 and HLA-A11, and these were reflected by the inferred haplotype frequencies constructed from the combination of the HLA-A locus and the AluyHG, AluyHJ and AluyHF loci. The strongest association of AluyMICB was with the HLA-B54 allele (five of five), whereas the associations with the other 17 HLA-B alleles were weak, moderate or undetermined. Phylogenetic analysis of the five POALIN allele frequencies places the Malaysian Chinese closest to the Japanese and north-eastern Thai populations in the same cluster and separate to the Australian Caucasian population. The MHC POALINs are confirmed in this study to be informative genetic markers in lineage (haplotype) analysis, population genetics and evolutionary relationships, especially in studying the MHC genomic region

Probucol inhibits in-stent thrombosis and neointimal hyperplasia by promoting re-endothelialization

BACKGROUND: Evidence suggests that delayed re-endothelialization is responsible for in-stent thrombosis. Probucol inhibits neointimal thickening in animals via enhanced re-endothelialization and is the only oral drug that consistently inhibits restenosis after coronary angioplasty in humans. Here, we examined the effects of probucol on re-endothelialization and neointimal formation in a stent model. METHODS AND RESULTS: New Zealand White rabbits were fed a hypercholesterolemic diet with probucol (1%) or without (control) (n=11 each) for 6 weeks. At 2 weeks, endothelial denudation and stenting of the iliac artery was performed. Iliac arteries were harvested at week 6, and stented segments sectioned and analyzed. Compared with control, probucol increased in-stent re-endothelialization (74+/-6% in controls versus 93+/-3% in probucol-treated; P=0.008), and decreased average luminal stenosis (58+/-27 versus 31+/-16%; P=0.01) and stent depth (619+/-310 versus 314+/-158mum; P=0.009). Compared with control, probucol also decreased accumulation of macrophages in the neointima. Furthermore, none of the probucol-treated rabbits had in-stent thrombosis, whereas four of eleven control rabbits showed thrombosis (P=0.04). CONCLUSIONS: Probucol demonstrates anti-restenotic and appears to have anti-thrombotic properties that are likely related to its ability to promote in-stent re-endothelialization

Membrane Trafficking of Heterotrimeric G Proteins via the Endoplasmic Reticulum and Golgi

Membrane targeting of G-protein αβγ heterotrimers was investigated in live cells by use of Gα and Gγ subunits tagged with spectral mutants of green fluorescent protein. Unlike Ras proteins, Gβγ contains a single targeting signal, the CAAX motif, which directed the dimer to the endoplasmic reticulum. Endomembrane localization of farnesylated Gγ(1), but not geranylgeranylated Gγ(2), required carboxyl methylation. Targeting of the heterotrimer to the plasma membrane (PM) required coexpression of all three subunits, combining the CAAX motif of Gγ with the fatty acyl modifications of Gα. Gα associated with Gβγ on the Golgi and palmitoylation of Gα was required for translocation of the heterotrimer to the PM. Thus, two separate signals, analogous to the dual-signal targeting mechanism of Ras proteins, cooperate to target heterotrimeric G proteins to the PM via the endomembrane