ITPKC functional polymorphism associated with Kawasaki disease susceptibility and formation of coronary artery aneurysms

Kawasaki disease is a pediatric systemic vasculitis of unknown etiology for which a genetic influence is suspected. We identified a functional SNP (itpkc_3) in the inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) gene on chromosome 19q13.2 that is significantly associated with Kawasaki disease susceptibility and also with an increased risk of coronary artery lesions in both Japanese and US children. Transfection experiments showed that the C allele of itpkc_3 reduces splicing efficiency of the ITPKC mRNA. ITPKC acts as a negative regulator of T-cell activation through the Ca2+/NFAT signaling pathway, and the C allele may contribute to immune hyper-reactivity in Kawasaki disease. This finding provides new insights into the mechanisms of immune activation in Kawasaki disease and emphasizes the importance of activated T cells in the pathogenesis of this vasculitis.     

The essential light chains constitute part of the active site of smooth muscle myosin

Myosin, a major contractile protein, characteristically possesses a long coiled-coil alpha-helical tail and two heads. Each head contains both an actin binding site and an ATPase site and is formed from the NH2-terminal half of one of the two heavy chains (relative molecular mass, Mr, 200,000) and a pair of light chains; the so-called regulatory and essential light chains of approximately Mr 20,000 each. Recently we have identified Trp 130 of the myosin heavy chain from rabbit skeletal muscle as an active-site amino-acid residue after labelling with a new photoaffinity analogue of ADP, N-(4-azido-2-nitrophenyl)-2-aminoethyl diphosphate (NANDP). Nonspecific labelling was eliminated by first trapping NANDP at the active site with thiol crosslinking agents. Exclusive labelling of the heavy chains with no labelling of the light chains agreed with previous findings that the heavy chains alone contain the actin-activated Mg-ATPase activity of rabbit skeletal myosin. Here we report similar photolabelling experiments with smooth muscle myosin (chicken gizzard) in which 3H-NANDP is trapped at the active site with vanadate and which show that both the heavy chains and the essential light chains are labelled. The results indicate that both chains contribute to the ATP binding site and represent the first direct evidence for participation of the essential light chains in the active site of any type of myosin.     

A functional variant in FCRL3, encoding Fc receptor-like 3, is associated with rheumatoid arthritis and several autoimmunities

Rheumatoid arthritis is a common autoimmune disease with a complex genetic etiology. Here we identify a SNP in the promoter region of FCRL3, a member of the Fc receptor-like family, that is associated with susceptibility to rheumatoid arthritis (odds ratio = 2.15, P = 0.00000085). This polymorphism alters the binding affinity of nuclear factor-kappaB and regulates FCRL3 expression. We observed high FCRL3 expression on B cells and augmented autoantibody production in individuals with the disease-susceptible genotype. We also found associations between the SNP and susceptibility to autoimmune thyroid disease and systemic lupus erythematosus. FCRL3 may therefore have a pivotal role in autoimmunity.     

Glycerol-3-phosphate is a critical mobile inducer of systemic immunity in plants

Glycerol-3-phosphate (G3P) is an important metabolite that contributes to the growth and disease-related physiologies of prokaryotes, plants, animals and humans alike. Here we show that G3P serves as the inducer of an important form of broad-spectrum immunity in plants, termed systemic acquired resistance (SAR). SAR is induced upon primary infection and protects distal tissues from secondary infections. Genetic mutants defective in G3P biosynthesis cannot induce SAR but can be rescued when G3P is supplied exogenously. Radioactive tracer experiments show that a G3P derivative is translocated to distal tissues, and this requires the lipid transfer protein, DIR1. Conversely, G3P is required for the translocation of DIR1 to distal tissues, which occurs through the symplast. These observations, along with the fact that dir1 plants accumulate reduced levels of G3P in their petiole exudates, suggest that the cooperative interaction of DIR1 and G3P orchestrates the induction of SAR in plants.     

Interplanetary dust from the explosive dispersal of hydrated asteroids by impacts

The Earth accretes about 30,000 tons of dust particles per year, with sizes in the range of 20-400 microm (refs 1, 2). Those particles collected at the Earth's surface--termed micrometeorites--are similar in chemistry and mineralogy to hydrated, porous meteorites, but such meteorites comprise only 2.8% of recovered falls. This large difference in relative abundances has been attributed to 'filtering' by the Earth's atmosphere, that is, the porous meteorites are considered to be so friable that they do not survive the impact with the atmosphere. Here we report shock-recovery experiments on two porous meteorites, one of which is hydrated and the other is anhydrous. The application of shock to the hydrated meteorite reduces it to minute particles and explosive expansion results upon release of the pressure, through a much broader range of pressures than for the anhydrous meteorite. Our results indicate that hydrated asteroids will produce dust particles during collisions at a much higher rate than anhydrous asteroids, which explains the different relative abundances of the hydrated material in micrometeorites and meteorites: the abundances are established before contact with the Earth's atmosphere.