We report two crystal structures of the wild-type phosphatidylinositol 3-kinase α (PI3Kα) heterodimer refined to 2.9 Å and 3.4 Å resolution: the first as the free enzyme, the second in complex with the lipid substrate, diC4-PIP2, respectively. The first structure shows key interactions of the N-terminal SH2 domain (nSH2) and iSH2 with the activation loop that suggest a mechanism by which the enzyme is inhibited in its basal state. In the second structure, the lipid substrate binds in a positively charged pocket adjacent to the ATP-binding site, bordered by the P-loop, the activation loop and the iSH2 domain. An additional lipid-binding site was identified at the interface of the ABD, iSH2 and kinase domains. The ability of PI3Kα to bind an additional PIP2 molecule was confirmed in vitro by fluorescence quenching experiments. The crystal structures reveal key differences in the way the nSH2 domain interacts with wild-type p110α and with the oncogenic mutant p110αH1047R. Increased buried surface area and two unique salt-bridges observed only in the wild-type structure suggest tighter inhibition in the wild-type PI3Kα than in the oncogenic mutant. These differences may be partially responsible for the increased basal lipid kinase activity and increased membrane binding of the oncogenic mutant.

We have developed a model that estimates the risk of respiratory hospitalisation and death in patients with COPD.

We have developed a kinetic model to describe the oxidation behavior of Si1−xGex alloys during Ge segregation, which compares the Deal–Grove flux of oxidant diffusing through the oxide to the maximum flux of Si diffusing through the Ge-rich layer. This is motivated by thermal oxidation experiments on Si1−xGex alloys (x<0.17) using a fluorine-containing ambient (O2 and 200 ppm of NF3). The fluorine is known to modify point defect generation during oxidation of pure Si toward vacancy production, which is also the case for Ge in Si. We demonstrate that fluorinated oxidation of Si1−xGex enhances the oxidation rate by 25%–40% in the temperature range of 700–800 °C. Oxides formed at these temperatures were SiO2, while those formed at 600 °C exhibited a transition from SiO2 to mixed oxide growth at some point during the very early phase of oxidation, depending on the alloy composition. Consideration of these data suggests that other factors in addition to oxidation temperature must be considered in predicting which oxide type will be produced, in contrast to most previous reports. Our model, indeed, shows that alloy composition, oxide thickness, and oxidant partial pressure are also important parameters. We believe that the model is very useful in predicting the oxide type that should result from a given set of growth conditions, and in particular, it suggests that a changeover from SiO2 to mixed oxide formation is likely at some point during the oxidation process, particularly if carried to larger thicknesses.

Multidrug-resistant Gram-negative bacteria have been an urgent threat to global public health. Novel antibiotics are desperately needed to combat these 'superbugs'.