Paradoxical dominant negative activity of an immunodeficiency-associated activating variant.

encodes three regulatory subunits of class IA phosphoinositide 3-kinase (PI3K), each associating with any of three catalytic subunits, namely p110α, p110β, or p110δ. Constitutional mutations cause diseases with a genotype-phenotype relationship not yet fully explained: heterozygous loss-of-function mutations cause SHORT syndrome, featuring insulin resistance and short stature attributed to reduced p110α function, while heterozygous activating mutations cause immunodeficiency, attributed to p110δ activation and known as APDS2. Surprisingly, APDS2 patients do not show features of p110α hyperactivation, but do commonly have SHORT syndrome-like features, suggesting p110α hypofunction.

Mapping domain structures near a grain boundary in a lead zirconate titanate ferroelectric film using X-ray nanodiffraction.

The effect of an electric field on local domain structure near a 24° tilt grain boundary in a 200 nm-thick Pb(ZrTi)O bi-crystal ferroelectric film was probed using synchrotron nanodiffraction. The bi-crystal film was grown epitaxially on SrRuO-coated (001) SrTiO 24° tilt bi-crystal substrates. From the nanodiffraction data, real-space maps of the ferroelectric domain structure around the grain boundary prior to and during application of a 200 kV cm electric field were reconstructed.

Biosimilar approval pathways: comparing the roles of five medicines regulators.

Biologics are playing an increasingly important role in health care globally but are placing a substantial burden on payers. The development of biosimilars-drugs that are highly similar to and have no clinically meaningful differences from originator biologics-is critical to improving the affordability and accessibility of these medications. Medicines regulators, however, have had varied success with biosimilars to date.

Future climate doubles the risk of hydraulic failure in a wet tropical forest.

Future climate presents conflicting implications for forest biomass. We evaluate how plant hydraulic traits, elevated CO levels, warming, and changes in precipitation affect forest primary productivity, evapotranspiration, and the risk of hydraulic failure. We used a dynamic vegetation model with plant hydrodynamics (FATES-HYDRO) to simulate the stand-level responses to future climate changes in a wet tropical forest in Barro Colorado Island, Panama.