Free Energy Simulations of a GTPase: GTP and GDP Binding to Archaeal Initiation Factor 2

International audienceArchaeal initiation factor 2 (aIF2) is a protein involved in the initiation of protein biosynthesis. In its GTP-bound, "ON" conformation, aIF2 binds an initiator tRNA and carries it to the ribosome. In its GDP-bound, "OFF" conformation, it dissociates from tRNA. To understand the specific binding of GTP and GDP and its dependence on the ON or OFF conformational state of aIF2, molecular dynamics free energy simulations (MDFE) are a tool of choice. However, the validity of the computed free energies depends on the simulation model, including the force field and the boundary conditions, and on the extent of conformational sampling in the simulations. aIF2 and other GTPases present specific difficulties; in particular, the nucleotide ligand coordinates a divalent Mg(2+) ion, which can polarize the electronic distribution of its environment. Thus, a force field with an explicit treatment of electronic polarizability could be necessary, rather than a simpler, fixed charge force field. Here, we begin by comparing a fixed charge force field to quantum chemical calculations and experiment for Mg(2+):phosphate binding in solution, with the force field giving large errors. Next, we consider GTP and GDP bound to aIF2 and we compare two fixed charge force fields to the recent, polarizable, AMOEBA force field, extended here in a simple, approximate manner to include GTP. We focus on a quantity that approximates the free energy to change GTP into GDP. Despite the errors seen for Mg(2+):phosphate binding in solution, we observe a substantial cancellation of errors when we compare the free energy change in the protein to that in solution, or when we compare the protein ON and OFF states. Finally, we have used the fixed charge force field to perform MDFE simulations and alchemically transform GTP into GDP in the protein and in solution. With a total of about 200 ns of molecular dynamics, we obtain good convergence and a reasonable statistical uncertainty, comparable to the force field uncertainty, and somewhat lower than the predicted GTP/GDP binding free energy differences. The sign and magnitudes of the differences can thus be interpreted at a semiquantitative level, and are found to be consistent with the experimental binding preferences of ON- and OFF-aIF2

Caractérisation de la stabilité d'un élément piézoélectrique du type PZT sous compression uniaxiale rapide

The purpose of this paper is the characterization of lead zirconate titanate piezoelectric ceramics suitable for reversible impact-striking applications. Energy-measurements and stability tests under various pulse-width impacts were achieved ; it is found that the main parameters are the following : the stability is a decreasingfunction of this pulse-width ; both efficiency and stability of material depends on the vacancy-state and electric balance of this composition, as also on the Zr/Ti ratio.Le présent article concerne la caractérisation de céramiques piézoélectriques au zirconotitanate de plomb destinées à l'allumage réversible par impact. Les mesures d'énergie complétées par des tests de stabilité sous 400 impacts de durée différente font apparaître les paramètres essentiels suivants : la stabilité est une fonction décroissante de cette durée ; la qualité du matériau dépend de l'état lacunaire et de l'équilibre électrique de sa composition ainsi que du rapport des concentrations en zirconium et en titane

USE of A THRESHOLD of INTERLEUKIN-10 and IL-10/IL-6 RATIO in OCULAR SAMPLES for the SCREENING of VITREORETINAL LYMPHOMA

cited By 2International audiencePurpose: To determine a threshold for interleukin (IL)-10 and IL-10/IL-6 ratio in the aqueous humor (AH) and the vitreous for the screening of vitreoretinal lymphoma (VRL). Methods: One hundred nineteen patients for whom IL-10 and IL-6 in the AH and/or vitreous had been measured were included: 16 patients with a final diagnosis of VRL and 103 patients with final diagnosis of uveitis. Groups were compared according to IL-10 and IL-6 levels and demographic data. Results: In patients with VRL (Group 1), mean IL-10 values were 5,636 pg/mL, and in patients with uveitis (Group 2), 6.7 pg/mL in the vitreous and 190 pg/mL in Group 1 and 8.6 pg/mL in the AH. In Group 1, the mean IL-10/IL-6 ratio was 29.02 in the vitreous and 10.9 in the AH; in Group 2, ratio was 0.1 in both humors. These values were significantly different between patients with VRL and with uveitis (P < 0.001). A cutoff of 65 pg/mL and 30 pg/mL IL-10 in the vitreous and AH, respectively, was associated with sensitivity of 93% and 78%, respectively, and specificity of 100% and 97%, respectively. A ratio higher than 1 in the vitreous had sensitivity of 93% and specificity of 100%. Conclusion: Vitreoretinal lymphoma diagnosis is difficult, and tools like interleukin measurements in AH and vitreous can make it easier. The use of a cutoff for IL-10 and IL-10/IL-6 ratio could allow for an earlier diagnosis that may improve prognosis. © 2018 Lippincott Williams and Wilkins. All rights reserved

Patterns of practice survey for brachytherapy for cervix cancer in Australia and New Zealand

Introduction: The purpose of this survey was to explore the current patterns of practice for brachytherapy in cervix cancer in Australia and New Zealand. The survey was also intended to explore clinician attitudes towards image-guided adaptive brachytherapy (IGABT) and identify barriers to the implementation of IGABT. Methods: Electronic surveys were sent to all radiotherapy centres in Australia and New Zealand under collaboration with Australia New Zealand Gynaecology and Oncology Group (ANZGOG), in order to identify patterns of radiotherapy practice. The survey was sent out in December 2013, with a reminder in February 2014. Results: Of the 75 radiotherapy centres in Australia and New Zealand, 23 centres replied (31% response rate). Twenty-two responding departments treat cervix cancer with external beam radiation (EBRT) (22/23; 96%). Fourteen responses were from departments that also use intracavitary brachytherapy (14/22; 64%). The remaining eight departments who do not offer intracavitary brachytherapy referred their patients on to other centres for brachytherapy. Ultrasound was used by 86% for applicator guidance. CT and MRI were used by 79%, and 50% respectively for planning. Optimisation was based on organs at risk (93%) and target volumes (64%). Conclusions: Brachytherapy remains an integral component of definitive treatment for cervix cancer in Australia and New Zealand. There was increased use of soft tissue imaging modalities with emphasis on verification; high rates of volumetric planning, and adherence to a defined overall treatment period. Brachytherapy was not substituted with other EBRT modalities. Despite this, there remain barriers to implementation of image-guided brachytherapy