Abstract-Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), encoded by the OLR1 gene, is a scavenger receptor that plays a fundamental role in the pathogenesis of atherosclerosis. LOX-1 activation is associated with apoptosis of endothelial cells, smooth muscle cells (SMCs), and macrophages. This process is an important underlying mechanism that contributes to plaque instability and subsequent development of acute coronary syndromes. Independent association genetic studies have implicated OLR1 gene variants in myocardial infarction (MI) susceptibility. Because single nucleotide polymorphisms (SNPs) linked to MI are located in intronic sequences of the gene, it remains unclear as to how they determine their biological effects. Using quantitative real-time PCR and minigene approach, we show that intronic SNPs, linked to MI, regulate the expression of a new functional splicing isoform of the OLR1 gene, LOXIN, which lacks exon 5. Macrophages from subjects carrying the "non-risk" disease haplotype at OLR1 gene have an increased expression of LOXIN at mRNA and protein level, which results in a significant reduction of apoptosis in response to oxLDL. Expression of LOXIN in different cell types results in loss of surface staining, indicating that truncation of the C-terminal portion of the protein has a profound effect on its cellular trafficking. Furthermore, the proapoptotic effect of LOX-1 receptor in cell culture is specifically rescued by the coexpression of LOXIN in a dose-dependent manner. The demonstration that increasing levels of LOXIN protect cells from LOX-1 induced apoptosis sets a groundwork for developing therapeutic approaches for prevention of plaque instability.
Sequence comparisons of multiple acyltransferase (AT) domains from modular polyketide synthases (PKSs) have highlighted a correlation between a short sequence motif and the nature of the extender unit selected. When this motif was specifically altered in the bimodular model PKS DEBS1-TE of Saccharopolyspora erythraea, the products included triketide lactones in which acetate extension units had been incorporated instead of propionate units at the predicted positions. We also describe a cassette system for convenient construction of hybrid modular PKSs based on the tylosin PKS in Streptomyces fradiae and demonstrate its use in domain and module swaps.
A comparison was made of the type and frequency of mutational events found in the progeny of tomato plants regenerated after one passage in vitro with those induced by chemical mutagenesis with ethyl methane sulphonate. Several mutants were recovered in the progeny of regenerated and mutagenized plants of two cultivars of tomato. They can be grouped into the following categories: seedling lethality, male sterility, resistance to Verticillium, short stature, change in number of lateral shoots or in leaf shape. The results indicate that the two sources of variability differ in their effect, changing the spectrum and frequency of the mutants as well as, at least in some cases, their pattern of segregation.
The lamin A/C (LMNA) are nuclear intermediate filament proteins composing the nuclear lamina. Mutations in LMNA are associated with a broad range of tissue‐specific laminopathies. In particular, dilated cardiomyopathy (DCM) with conduction system disease and sudden death is frequently caused by a premature termination codon mutation in LMNA resulting in an aberrant expression of a truncated LMNA on the nuclear envelope. In this study, we used a known LMNA nonsense mutation, R321X, to gain more insight into the pathophysiological mechanisms induced by LMNA‐R321X in human embryonic kidney (HEK293) cells.Western blot analysis of homogenate from HEK293 cells transfected with LMNA‐R321X showed a 65kDa band corresponding to the truncated LMNA. Also, immunofluorescence confocal analysis demonstrated that expression of GFP‐tagged LMNA‐R321X, but not GFP‐tagged LMNA‐WT, caused (I) loss of nuclear envelope shape and integrity (II) retention of lamin A in the endoplasmic reticulum (ER) and (III) dramatic reorganization of the ER. Interestingly, LMNA‐R321X‐induced ER reorganization dramatically perturbed Ca2+ homeostasis since both cyclopiazonic acid (CPA)‐induced Ca2+ release and capacitative Ca2+ entry were perturbed in HEK293 cells loaded with the Ca2+ dye Rhod‐2.Here, we proposed for the first time that the aberrant geometry of the ER induced by the expression of truncated LMNA may potentially lead to the development of DCM, rhythm disturbances and cardiac sudden death also via perturbance of Ca2+ homeostasis.
When planning an osteotomy reproduction of a biodimensional radiographical femoral image is fundamental. The authors show that radiographical measurement of the inclination angle on x-ray (ß1 and on segment (ß) differs according to the correlation between ß, ß1 and the anteversion angle (a) and thus an osteotomy plan must be rigorously mathematical.
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