The Endoplasmic Reticulum Stress Response in Neuroprogressive Diseases: Emerging Pathophysiological Role and Translational Implications

The endoplasmic reticulum (ER) is the main cellular organelle involved in protein synthesis, assembly and secretion. Accumulating evidence shows that across several neurodegenerative and neuroprogressive diseases, ER stress ensues, which is accompanied by over-activation of the unfolded protein response (UPR). Although the UPR could initially serve adaptive purposes in conditions associated with higher cellular demands and after exposure to a range of pathophysiological insults, over time the UPR may become detrimental, thus contributing to neuroprogression. Herein, we propose that immune-inflammatory, neuro-oxidative, neuro-nitrosative, as well as mitochondrial pathways may reciprocally interact with aberrations in UPR pathways. Furthermore, ER stress may contribute to a deregulation in calcium homoeostasis. The common denominator of these pathways is a decrease in neuronal resilience, synaptic dysfunction and even cell death. This review also discusses how mechanisms related to ER stress could be explored as a source for novel therapeutic targets for neurodegenerative and neuroprogressive diseases. The design of randomised controlled trials testing compounds that target aberrant UPR-related pathways within the emerging framework of precision psychiatry is warranted

Measurement of the tt̄W and tt̄Z production cross sections in pp collisions at √s = 8 TeV with the ATLAS detector

The production cross sections of top-quark pairs in association with massive vector bosons have been measured using data from pp collisions at s√ = 8 TeV. The dataset corresponds to an integrated luminosity of 20.3 fb−¹ collected by the ATLAS detector in 2012 at the LHC. Final states with two, three or four leptons are considered. A fit to the data considering the tt̄W and tt̄Z processes simultaneously yields a significance of 5.0σ (4.2σ) over the background-only hypothesis for tt¯Wtt¯W (tt̄Z) production. The measured cross sections are σtt̄W = 369 + 100−91 fb and σtt̄Z = 176 + 58−52 fb. The background-only hypothesis with neither tt̄W nor tt̄Z production is excluded at 7.1σ. All measurements are consistent with next-to-leading-order calculations for the tt̄W and tt̄Z processes

Design and performance of a custom ASIC digitizer for wire chamber readout in 65 nm CMOS technology

We present the design and performance of a prototype ASIC digitizer for integrated wire chamber readout, implemented in 65 nm commercial CMOS technology. Each channel of the 4-channel prototype is composed of two 16-bit Time-to-Digital Converters (TDCs), one 8-bit Analog-to-Digital Converter (ADC), a front-end preamplifier and shaper, plus digital and analog buffers that support a variety of digitization chains. The prototype has a multiplexed digital backend that executes a state machine, distributes control and timing signals, and buffers data for serial output. Laboratory bench tests measure the absolute TDC resolution between 74 ps and 480 ps, growing with the absolute delay, and a relative time resolution of 19 ps. Resolution outliers due to cross-talk between clock signals and supply or reference voltages are seen. After calibration, the ADC displays good linearity and noise performance, with an effective number of bits of 6.9. Under normal operating conditions the circuit consumes 32 mW per channel. Potential design improvements to address the resolution drift and tails are discussed