Construction of 3D models of the CYP11B family as a tool to predict ligand binding characteristics

Aldosterone is synthesised by aldosterone synthase (CYP11B2). CYP11B2 has a highly homologous isoform, steroid 11β-hydroxylase (CYP11B1), which is responsible for the biosynthesis of aldosterone precursors and glucocorticoids. To investigate aldosterone biosynthesis and facilitate the search for selective CYP11B2 inhibitors, we constructed three-dimensional models for CYP11B1 and CYP11B2 for both human and rat. The models were constructed based on the crystal structure of Pseudomonas Putida CYP101 and Oryctolagus Cuniculus CYP2C5. Small steric active site differences between the isoforms were found to be the most important determinants for the regioselective steroid synthesis. A possible explanation for these steric differences for the selective synthesis of aldosterone by CYP11B2 is presented. The activities of the known CYP11B inhibitors metyrapone, R-etomidate, R-fadrazole and S-fadrazole were determined using assays of V79MZ cells that express human CYP11B1 and CYP11B2, respectively. By investigating the inhibitors in the human CYP11B models using molecular docking and molecular dynamics simulations we were able to predict a similar trend in potency for the inhibitors as found in the in vitro assays. Importantly, based on the docking and dynamics simulations it is possible to understand the enantioselectivity of the human enzymes for the inhibitor fadrazole, the R-enantiomer being selective for CYP11B2 and the S-enantiomer being selective for CYP11B1

Micro ion beam analysis for the erosion of beryllium marker tiles in a tokamak limiter

Beryllium limiter marker tiles were exposed to plasma in the Joint European Torus to diagnose the erosion of main chamber wall materials. A limiter marker tile consists of a beryllium coating layer (7-9 mu m) on the top of bulk beryllium, with a nickel interlayer (2-3 mu m) between them. The thickness variation of the beryllium coating layer, after exposure to plasma, could indicate the erosion measured by ion beam analysis with backscattering spectrometry. However, interpretations from broad beam backscattering spectra were limited by the non-uniform surface structures. Therefore, micro-ion beam analysis (mu-IBA) with 3 MeV proton beam for Elastic back scattering spectrometry (EBS) and PIXE was used to scan samples. The spot size was in the range of 3-10 mu m. Scanned areas were analysed with scanning electron microscopy (SEM) as well. Combining results from mu-IBA and SEM, we obtained local spectra from carefully chosen areas on which the surface structures were relatively uniform. Local spectra suggested that the scanned area (approximate to 600 mu m x 1200 mu m) contained regions with serious erosion with only 2-3 mu m coating beryllium left, regions with intact marker tile, and droplets with 90% beryllium. The nonuniform erosion, droplets mainly formed by beryllium, and the possible mixture of beryllium and nickel were the major reasons that confused interpretation from broad beam EBS

First principles and integrated modelling achievements towards trustful fusion power predictions for JET and ITER

Predictability of burning plasmas is a key issue for designing and building credible future fusion devices. In this context, an important effort of physics understanding and guidance is being carried out in parallel to JET experimental campaigns in H and D by performing analyses and modelling towards an improvement of the understanding of DT physics for the optimization of the JET-DT neutron yield and fusion born alpha particle physics. Extrapolations to JET-DT from recent experiments using the maximum power available have been performed including some of the most sophisticated codes and a broad selection of models. There is a general agreement that 11-15 MW of fusion power can be expected in DT for the hybrid and baseline scenarios. On the other hand, in high beta, torque and fast ion fraction conditions, isotope effects could be favourable leading to higher fusion yield. It is shown that alpha particles related physics, such as TAE destabilization or fusion power electron heating, could be studied in ITER relevant JET-DT plasmas

Radial variation of heat transport in L-mode JET discharges

In this paper, we analyze heat transport in the JET tokamak using data from its high resolution ECE diagnostic and analyses based on the transfer entropy (TE). The analysis reveals that heat transport is not smooth and continuous, but is characterized by 'trapping regions' separated by `minor transport barriers'. Meat may 'jump over' these barriers and when the heating power is raised, this 'jumping' behavior becomes more prominent. To check that our results are relevant for global heat transport, we deduced an effective diffusion coefficient from the TE results. Both its value and overall radial variation are consistent with heat diffusivities reported in literature. The detailed radial structure of the effective diffusion coefficient was shown to be linked to the mentioned minor transport barriers

14 MeV calibration of JET neutron detectors-phase 1: Calibration and characterization of the neutron source

In view of the planned DT operations at JET, a calibration of the JET neutron monitors at 14 MeV neutron energy is needed using a 14 MeV neutron generator deployed inside the vacuum vessel by the JET remote handling system. The target accuracy of this calibration is 10% as also required by ITER, where a precise neutron yield measurement is important, e.g. for tritium accountancy. To achieve this accuracy, the 14 MeV neutron generator selected as the calibration source has been fully characterised and calibrated prior to the in-vessel calibration of the JET monitors. This paper describes the measurements performed using different types of neutron detectors, spectrometers, calibrated long counters and activation foils which allowed us to obtain the neutron emission rate and the anisotropy of the neutron generator, i.e.The neutron flux and energy spectrum dependence on emission angle, and to derive the absolute emission rate in 4π sr. The use of high resolution diamond spectrometers made it possible to resolve the complex features of the neutron energy spectra resulting from the mixed D/T beam ions reacting with the D/T nuclei present in the neutron generator target. As the neutron generator is not a stable neutron source, several monitoring detectors were attached to it by means of an ad hoc mechanical structure to continuously monitor the neutron emission rate during the in-vessel calibration. These monitoring detectors, two diamond diodes and activation foils, have been calibrated in terms of neutrons/counts within ± 5% total uncertainty. A neutron source routine has been developed, able to produce the neutron spectra resulting from all possible reactions occurring with the D/T ions in the beam impinging on the Ti D/T target. The neutron energy spectra calculated by combining the source routine with a MCNP model of the neutron generator have been validated by the measurements. These numerical tools will be key in analysing the results from the in-vessel calibration and to derive the response of the JET neutron detectors to DT plasma neutrons starting from the response to the generator neutrons, and taking into account all the calibration circumstances

Investigation of deuterium trapping and release in the JET divertor during the third ILW campaign using TDS

Selected set of samples from JET ITER-Like Wall (JET-ILW) divertor tiles exposed in 2015-2016 has been analysed using Thermal Desorption Spectrometry (TDS). The deuterium (D) amounts obtained with TDS were compared with Nuclear Reaction Analysis (NRA). The highest amount of D was found on the top part of inner divertor which has regions with the thickest deposited layers as for divertor tiles removed in 2014. This area resides deep in the scrape-off layer and plasma configurations for the second (ILW-2, 2013-2014) and the third (ILW-3, 2015-2016) JET-ILW campaigns were similar. Agreement between TDS and NRA is good on the apron of Tile 1 and on the upper vertical region whereas on the lower vertical region of Tile 1 the NRA results are clearly smaller than the TDS results. Inner divertor Tile 3 has somewhat less D than Tiles 0 and 1, and the D amount decreases towards the lower part of the tile. The D retention at the divertor inner and outer corner regions is not symmetric as there is more D retention poloidally at the inner than at the outer divertor corner. In most cases the TDS spectra for the ILW-3 samples are different from the corresponding ILW-2 spectra because HD and D-2 release occurs at higher temperatures than from the ILW-2 samples indicating that the low energy traps have been emptied during the plasma operations and that D is either in the energetically deep traps or located deeper in the sample