Reaction profiling of a set of acrylamide-based human tissue transglutaminase inhibitors

The major function of the enzyme human tissue transglutaminase (TG2) is the crosslinking of proteins via a transamidation between the γ-carboxamide of a glutamine and the ε-amino group of a lysine. Overexpression of TG2 can lead to undesirable outcomes and has been linked to conditions such as fibrosis, celiac disease and neurodegenerative diseases. Accordingly, TG2 is a tempting drug target. The most effective TG2 inhibitors to date are small-molecule peptidomimetics featuring electrophilic warheads that irreversibly modify the active site catalytic cysteine (CYS277). In an effort to facilitate the design of such TG2 inhibitors, we undertook a quantum mechanical reaction profiling of the Michael reaction between a set of six acrylamide-based known TG2 inhibitors and the TG2 CYS277. The inhibitors were docked into the active site and the coordinates were refined by MD simulations prior to modelling the covalent modification of the CYS277 thiolate. The results of QM/MM MD umbrella sampling applied to reaction coordinates driving the Michael reaction are presented for two approximations of the Michael reaction: a concerted reaction (simultaneous thiolate attack onto the acrylamide warhead and pronation from the adjacent HIS335) and a two-stage reaction (consecutive thiolate attack and protonation). The two-stage approximation of the Michael reaction gave the better results for the evaluation of acrylamide-based potential TG2 inhibitors in silico. Good correlations were observed between the experimental TG2 IC50 data and the calculated activation energies over the range 0.0061 – 6.3 µM (three orders of magnitude) and we propose that this approach may be used to evaluate acrylamide-based potential TG2 inhibitors

Measurement of the photon identification efficiencies with the ATLAS detector using LHC Run-1 data

© 2016, CERN for the benefit of the ATLAS collaboration.The algorithms used by the ATLAS Collaboration to reconstruct and identify prompt photons are described. Measurements of the photon identification efficiencies are reported, using 4.9 fb- 1 of pp collision data collected at the LHC at s=7 TeV and 20.3 fb- 1 at s=8 TeV. The efficiencies are measured separately for converted and unconverted photons, in four different pseudorapidity regions, for transverse momenta between 10 GeV and 1.5 TeV. The results from the combination of three data-driven techniques are compared to the predictions from a simulation of the detector response, after correcting the electromagnetic shower momenta in the simulation for the average differences observed with respect to data. Data-to-simulation efficiency ratios used as correction factors in physics measurements are determined to account for the small residual efficiency differences. These factors are measured with uncertainties between 0.5% and 10% in 7 TeV data and between 0.5% and 5.6% in 8 TeV data, depending on the photon transverse momentum and pseudorapidity

Performance of the ATLAS track reconstruction algorithms in dense environments in LHC Run 2

With the increase in energy of the Large Hadron Collider to a centre-of-mass energy of 13 TeV for Run 2, events with dense environments, such as in the cores of highenergy jets, became a focus for new physics searches as well as measurements of the Standard Model. These environments are characterized by charged-particle separations of the order of the tracking detectors sensor granularity. Basic track quantities are compared between 3.2 fb(-1) of data collected by the ATLAS experiment and simulation of protonproton collisions producing high-transverse-momentum jets at a centre-of-mass energy of 13 TeV. The impact of chargedparticle separations and multiplicities on the track reconstruction performance is discussed. The track reconstruction efficiency in the cores of jets with transverse momenta between 200 and 1600 GeV is quantified using a novel, datadriven, method. The method uses the energy loss, dE/ dx, to identify pixel clusters originating from two charged particles. Of the charged particles creating these clusters, themeasured fraction that fail to be reconstructed is 0.061 +/- 0.006 (stat.) +/- 0.014 (syst.) and 0.093 +/- 0.017 (stat.) +/- 0.021 (syst.) for jet transverse momenta of 200-400GeV and 1400-1600GeV, respectively

Measurements of top-quark pair differential cross-sections in the e mu channel in pp collisions at root s=13 TeV using the ATLAS detector

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