Essential Role of the Small GTPase Ran in Postnatal Pancreatic Islet Development

The small GTPase Ran orchestrates pleiotropic cellular responses of nucleo-cytoplasmic shuttling, mitosis and subcellular trafficking, but whether deregulation of these pathways contributes to disease pathogenesis has remained elusive. Here, we generated transgenic mice expressing wild type (WT) Ran, loss-of-function Ran T24N mutant or constitutively active Ran G19V mutant in pancreatic islet β cells under the control of the rat insulin promoter. Embryonic pancreas and islet development, including emergence of insulin+ β cells, was indistinguishable in control or transgenic mice. However, by one month after birth, transgenic mice expressing any of the three Ran variants exhibited overt diabetes, with hyperglycemia, reduced insulin production, and nearly complete loss of islet number and islet mass, in vivo. Deregulated Ran signaling in transgenic mice, adenoviral over-expression of WT or mutant Ran in isolated islets, or short hairpin RNA (shRNA) silencing of endogenous Ran in model insulinoma INS-1 cells, all resulted in decreased expression of the pancreatic and duodenal homeobox transcription factor, PDX-1, and reduced β cell proliferation, in vivo. These data demonstrate that a finely-tuned balance of Ran GTPase signaling is essential for postnatal pancreatic islet development and glucose homeostasis, in vivo

Large polarization gradients and temperature-stable responses in compositionally-graded ferroelectrics

A range of modern applications require large and tunable dielectric, piezoelectric or pyroelectric response of ferroelectrics. Such effects are intimately connected to the nature of polarization and how it responds to externally applied stimuli. Ferroelectric susceptibilities are, in general, strongly temperature dependent, diminishing rapidly as one transitions away from the ferroelectric phase transition (TC). In turn, researchers seek new routes to manipulate polarization to simultaneously enhance susceptibilities and broaden operational temperature ranges. Here, we demonstrate such a capability by creating composition and strain gradients in Ba1-xSrxTiO3 films which result in spatial polarization gradients as large as 35 μC cm-2 across a 150 nm thick film. These polarization gradients allow for large dielectric permittivity with low loss (ɛr≈775, tan δ<0.05), negligible temperature-dependence (13% deviation over 500 °C) and high-dielectric tunability (greater than 70% across a 300 °C range). The role of space charges in stabilizing polarization gradients is also discussed