Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile osteolysis

Familial expansile osteolysis (FEO, MIM 174810) is a rare, autosomal dominant bone disorder characterized by focal areas of increased bone remodelling. The osteolytic lesions, which develop usually in the long bones during early adulthood, show increased osteoblast and osteoclast activity. Our previous linkage studies mapped the gene responsible for FEO to an interval of less than 5 cM between D18S64 and D18S51 on chromosome 18q21.2-21.3 in a large Northern Irish family. The gene encoding receptor activator of nuclear factor-kappa B (RANK; ref. 5), TNFRSF11A, maps to this region. RANK is essential in osteoclast formation. We identified two heterozygous insertion mutations in exon 1 of TNFRSF11A in affected members of four families with FEO or familial Paget disease of bone (PDB). One was a duplication of 18 bases and the other a duplication of 27 bases, both of which affected the signal peptide region of the RANK molecule. Expression of recombinant forms of the mutant RANK proteins revealed perturbations in expression levels and lack of normal cleavage of the signal peptide. Both mutations caused an increase in RANK-mediated nuclear factor-kappaB (NF-kappaB) signalling in vitro, consistent with the presence of an activating mutation.     

Chronology of the early Solar System from chondrule-bearing calcium-aluminium-rich inclusions

Chondrules and Ca-Al-rich inclusions (CAIs) are high-temperature components of meteorites that formed during transient heating events in the early Solar System. A major unresolved issue is the relative timing of CAI and chondrule formation. From the presence of chondrule fragments in an igneous CAI, it was concluded that some chondrules formed before CAIs (ref. 5). This conclusion is contrary to the presence of relict CAIs inside chondrules, as well as to the higher abundance of 26Al in CAIs; both observations indicate that CAIs pre-date chondrules by 1-3 million years (Myr). Here we report that relict chondrule material in the Allende meteorite, composed of olivine and low-calcium pyroxene, occurs in the outer portions of two CAIs and is 16O-poor (Delta17O approximately -1 per thousand to -5 per thousand). Spinel and diopside in the CAI cores are 16O-rich (Delta17O up to -20 per thousand), whereas diopside in their outer zones, as well as melilite and anorthite, are 16O-depleted (Delta17O = -8 per thousand to 2 per thousand). Both chondrule-bearing CAIs are 26Al-poor with initial 26Al/27Al ratios of (4.7 +/- 1.4) x 10(-6) and <1.2 x 10(-6). We conclude that these CAIs had chondrule material added to them during a re-melting episode approximately 2 Myr after formation of CAIs with the canonical 26Al/27Al ratio of 5 x 10(-5).     

Type-2 copper-containing enzymes

Type-2 Cu sites are found in all the major branches of life and are often involved in the catalysis of oxygen species. Four type-2 Cu protein families are selected as model systems for review: amine oxidases, Cu monooxygenases, nitrite reductase/multicopper oxidase, and CuZn superoxide dismutase. For each model protein, the availability of multiple crystal structures and detailed enzymological studies provides a detailed molecular view of the type-2 Cu site and delineation of the mechanistic role of the Cu in biological function. Comparison of these model proteins leads to the identification of common properties of the Cu sites and insight into the evolution of the trinuclear active site found in multicopper oxidases. Received 6 July 2007; accepted 18 July 2007     

The von Neumann relation generalized to coarsening of three-dimensional microstructures

Cellular structures or tessellations are ubiquitous in nature. Metals and ceramics commonly consist of space-filling arrays of single-crystal grains separated by a network of grain boundaries, and foams (froths) are networks of gas-filled bubbles separated by liquid walls. Cellular structures also occur in biological tissue, and in magnetic, ferroelectric and complex fluid contexts. In many situations, the cell/grain/bubble walls move under the influence of their surface tension (capillarity), with a velocity proportional to their mean curvature. As a result, the cells evolve and the structure coarsens. Over 50 years ago, von Neumann derived an exact formula for the growth rate of a cell in a two-dimensional cellular structure (using the relation between wall velocity and mean curvature, the fact that three domain walls meet at 120 degrees and basic topology). This forms the basis of modern grain growth theory. Here we present an exact and much-sought extension of this result into three (and higher) dimensions. The present results may lead to the development of predictive models for capillarity-driven microstructure evolution in a wide range of industrial and commercial processing scenarios--such as the heat treatment of metals, or even controlling the 'head' on a pint of beer.