Pharmacologic IRE1/XBP1s Activation Confers Targeted ER Proteostasis Reprogramming

Activation of the IRE1/XBP1s signaling arm of the unfolded protein response (UPR) is a promising strategy to correct defects in endoplasmic reticulum (ER) proteostasis implicated in diverse diseases. However, no pharmacologic activators of this pathway identified to date are suitable for ER proteostasis remodeling through selective activation of IRE1/XBP1s signaling. Here, we use high-throughput screening to identify non-toxic compounds that induce ER proteostasis remodeling through IRE1/XBP1s activation. We employ transcriptional profiling to stringently confirm that our prioritized compounds selectively activate IRE1/XBP1s signaling without activating other cellular stress-responsive signaling pathways. Furthermore, we demonstrate that our compounds improve ER proteostasis of destabilized variants of amyloid precursor protein (APP) through an IRE1-dependent mechanism and reduce APP-associated mitochondrial toxicity in cellular models. These results establish highly selective IRE1/XBP1s activating compounds that can be widely employed to define the functional importance of IRE1/XBP1s activity for ER proteostasis regulation in the context of health and disease. [Figure not available: see fulltext.]

The HERMES Dual-Radiator Ring Imaging Cerenkov Detector

The construction and use of a dual radiator Ring Imaging Cerenkov(RICH) detector is described. This instrument was developed for the HERMES experiment at DESY which emphasizes measurements of semi-inclusive deep-inelastic scattering. It provides particle identification for pions, kaons, and protons in the momentum range from 2 to 15 GeV, which is essential to these studies. The instrument uses two radiators, C4F10, a heavy fluorocarbon gas, and a wall of silica aerogel tiles. The use of aerogel in a RICH detector has only recently become possible with the development of clear, large homogeneous and hydrophobic aerogel. A lightweight mirror was constructed using a newly perfected technique to make resin-coated carbon-fiber surfaces of optical quality. The photon detector consists of 1934 photomultiplier tubes for each detector half, held in a soft steel matrix to provide shielding against the residual field of the main spectrometer magnet.Comment: 25 pages, 23 figure

Species diversification – which species should we use?

Large detector systems for particle and astroparticle physics; Particle tracking detectors; Gaseous detectors; Calorimeters; Cherenkov detectors; Particle identification methods; Photon detectors for UV. visible and IR photons; Detector alignment and calibration methods; Detector cooling and thermo-stabilization; Detector design and construction technologies and materials. The LHCb experiment is dedicated to precision measurements of CP violation and rare decays of B hadrons at the Large Hadron Collider (LHC) at CERN (Geneva). The initial configuration and expected performance of the detector and associated systems. as established by test beam measurements and simulation studies. is described. © 2008 IOP Publishing Ltd and SISSA