Glycine Transporter 1 Inhibitors: Predictions on Their Possible Mechanisms in the Development of Opioid Analgesic Tolerance

The development of opioid tolerance in patients on long-term opioid analgesic treatment is an unsolved matter in clinical practice thus far. Dose escalation is required to restore analgesic efficacy, but at the price of side effects. Intensive research is ongoing to elucidate the underlying mechanisms of opioid analgesic tolerance in the hope of maintaining opioid analgesic efficacy. N-Methyl-D-aspartate receptor (NMDAR) antagonists have shown promising effects regarding opioid analgesic tolerance; however, their use is limited by side effects (memory dysfunction). Nevertheless, the GluN2B receptor remains a future target for the discovery of drugs to restore opioid efficacy. Mechanistically, the long-term activation of µ-opioid receptors (MORs) initiates receptor phosphorylation, which triggers β-arrestin-MAPKs and NOS-GC-PKG pathway activation, which ultimately ends with GluN2B receptor overactivation and glutamate release. The presence of glutamate and glycine as co-agonists is a prerequisite for GluN2B receptor activation. The extrasynaptic localization of the GluN2B receptor means it is influenced by the glycine level, which is regulated by astrocytic glycine transporter 1 (GlyT1). Enhanced astrocytic glycine release by reverse transporter mechanisms as a consequence of high glutamate levels or unconventional MOR activation on astrocytes could further activate the GluN2B receptor. GlyT1 inhibitors might inhibit this condition, thereby reducing opioid tolerance

Particle identification studies with a full-size 4-GEM prototype for the ALICE TPC upgrade

A large Time Projection Chamber is the main device for tracking and charged-particle identification in the ALICE experiment at the CERN LHC. After the second long shutdown in 2019/20, the LHC will deliver Pb beams colliding at an interaction rate of about 50 kHz, which is about a factor of 50 above the present readout rate of the TPC. This will result in a significant improvement on the sensitivity to rare probes that are considered key observables to characterize the QCD matter created in such collisions. In order to make full use of this luminosity, the currently used gated Multi-Wire Proportional Chambers will be replaced. The upgrade relies on continuously operated readout detectors employing Gas Electron Multiplier technology to retain the performance in terms of particle identification via the measurement of the specific energy loss by ionization d/d. A full-size readout chamber prototype was assembled in 2014 featuring a stack of four GEM foils as an amplification stage. The performance of the prototype was evaluated in a test beam campaign at the CERN PS. The d/d resolution complies with both the performance of the currently operated MWPC-based readout chambers and the challenging requirements of the ALICE TPC upgrade program. Detailed simulations of the readout system are able to reproduce the data

Measurement of Ds + production and nuclear modification factor in Pb-Pb collisions at √sNN = 2.76 TeV

The production of prompt D s + mesons was measured for the first time in collisions of heavy nuclei with the ALICE detector at the LHC. The analysis was performed on a data sample of Pb-Pb collisions at a centre-of-mass energy per nucleon pair, sNN−−−√ , of 2.76 TeV in two different centrality classes, namely 0–10% and 20–50%. D s + mesons and their antiparticles were reconstructed at mid-rapidity from their hadronic decay channel D s +  → ϕπ +, with ϕ → K−K+, in the transverse momentum intervals 4 < p T < 12GeV/c and 6 < p T < 12 GeV/c for the 0–10% and 20–50% centrality classes, respectively. The nuclear modification factor R AA was computed by comparing the p T-differential production yields in Pb-Pb collisions to those in proton-proton (pp) collisions at the same energy. This pp reference was obtained using the cross section measured at s√=7 TeV and scaled to s√=2.76 TeV. The R AA of D s + mesons was compared to that of non-strange D mesons in the 10% most central Pb-Pb collisions. At high p T (8 < p T < 12 GeV/c) a suppression of the D s + -meson yield by a factor of about three, compatible within uncertainties with that of non-strange D mesons, is observed. At lower p T (4 < p T < 8 GeV/c) the values of the D s + -meson R AA are larger than those of non-strange D mesons, although compatible within uncertainties. The production ratios D s + /D0 and D s + /D+ were also measured in Pb-Pb collisions and compared to their values in proton-proton collisions