Metabolomics-Driven Elucidation of Cellular Nitrate Tolerance Reveals Ascorbic Acid Prevents Nitroglycerin-Induced Inactivation of Xanthine Oxidase

Glyceryl trinitrate (GTN) has found widespread use for the treatment of angina pectoris, a pathological condition manifested by chest pain resulting from insufficient blood supply to the heart. Metabolic conversion of GTN, a nitric oxide (NO) pro-drug, into NO induces vasodilation and improves blood flow. Patients develop tolerance to GTN after several weeks of continuous use, limiting the potential for long-term therapy. The mechanistic cause of nitrate tolerance is relatively unknown. We developed a cell culture model of nitrate tolerance that utilizes stable isotopes to measure metabolism of 15N3-GTN into 15N-nitrite. We performed global metabolomics to identify the mechanism of GTN-induced nitrate tolerance and to elucidate the protective role of vitamin C (ascorbic acid). Metabolomics analyses revealed that GTN impaired purine metabolism and depleted intracellular ATP and GTP. GTN inactivated xanthine oxidase (XO), an enzyme that is critical for the metabolic bioactivation of GTN into NO. Ascorbic acid prevented inactivation of XO, resulting in increased NO production from GTN. Our studies suggest that ascorbic acid has the ability to prevent nitrate tolerance by protecting XO, but not aldehyde dehydrogenase (another GTN bioactivating enzyme), from GTN-induced inactivation. Our findings provide a mechanistic explanation for the previously observed beneficial effects of ascorbic acid in nitrate therapy

Molecular Evolution of Phosphoprotein Phosphatases in Drosophila

Phosphoprotein phosphatases (PPP), these ancient and important regulatory enzymes are present in all eukaryotic organisms. Based on the genome sequences of 12 Drosophila species we traced the evolution of the PPP catalytic subunits and noted a substantial expansion of the gene family. We concluded that the 18–22 PPP genes of Drosophilidae were generated from a core set of 8 indispensable phosphatases that are present in most of the insects. Retropositons followed by tandem gene duplications extended the phosphatase repertoire, and sporadic gene losses contributed to the species specific variations in the PPP complement. During the course of these studies we identified 5, up till now uncharacterized phosphatase retrogenes: PpY+, PpD5+, PpD6+, Pp4+, and Pp6+ which are found only in some ancient Drosophila. We demonstrated that all of these new PPP genes exhibit a distinct male specific expression. In addition to the changes in gene numbers, the intron-exon structure and the chromosomal localization of several PPP genes was also altered during evolution. The G−C content of the coding regions decreased when a gene moved into the heterochromatic region of chromosome Y. Thus the PPP enzymes exemplify the various types of dynamic rearrangements that accompany the molecular evolution of a gene family in Drosophilidae

Model for screening of resonant magnetic perturbations by plasma in a realistic tokamak geometry and its impact on divertor strike points

This work addresses the question of the relation between strike-point splitting and magnetic stochasticity at the edge of a poloidally diverted tokamak in the presence of externally imposed magnetic perturbations. More specifically, ad-hoc helical current sheets are introduced in order to mimic a hypothetical screening of the external resonant magnetic perturbations by the plasma. These current sheets, which suppress magnetic islands, are found to reduce the amount of splitting expected at the target, which suggests that screening effects should be observable experimentally. Multiple screening current sheets reinforce each other, i.e. less current relative to the case of only one current sheet is required to screen the perturbation.Comment: Accepted in the Proceedings of the 19th International Conference on Plasma Surface Interactions, to be published in Journal of Nuclear Materials. Version 2: minor formatting and text improvements, more results mentioned in the conclusion and abstrac

On the mechanisms governing gas penetration into a tokamak plasma during a massive gas injection

A new 1D radial fluid code, IMAGINE, is used to simulate the penetration of gas into a tokamak plasma during a massive gas injection (MGI). The main result is that the gas is in general strongly braked as it reaches the plasma, due to mechanisms related to charge exchange and (to a smaller extent) recombination. As a result, only a fraction of the gas penetrates into the plasma. Also, a shock wave is created in the gas which propagates away from the plasma, braking and compressing the incoming gas. Simulation results are quantitatively consistent, at least in terms of orders of magnitude, with experimental data for a D 2 MGI into a JET Ohmic plasma. Simulations of MGI into the background plasma surrounding a runaway electron beam show that if the background electron density is too high, the gas may not penetrate, suggesting a possible explanation for the recent results of Reux et al in JET (2015 Nucl. Fusion 55 093013)

Modelling of the effect of ELMs on fuel retention at the bulk W divertor of JET

Effect of ELMs on fuel retention at the bulk W target of JET ITER-Like Wall was studied with multi-scale calculations. Plasma input parameters were taken from ELMy H-mode plasma experiment. The energetic intra-ELM fuel particles get implanted and create near-surface defects up to depths of few tens of nm, which act as the main fuel trapping sites during ELMs. Clustering of implantation-induced vacancies were found to take place. The incoming flux of inter-ELM plasma particles increases the different filling levels of trapped fuel in defects. The temperature increase of the W target during the pulse increases the fuel detrapping rate. The inter-ELM fuel particle flux refills the partially emptied trapping sites and fills new sites. This leads to a competing effect on the retention and release rates of the implanted particles. At high temperatures the main retention appeared in larger vacancy clusters due to increased clustering rate

Velocity-space sensitivity of the time-of-flight neutron spectrometer at JET

The velocity-space sensitivities of fast-ion diagnostics are often described by so-called weight functions. Recently, we formulated weight functions showing the velocity-space sensitivity of the often dominant beam-target part of neutron energy spectra. These weight functions for neutron emission spectrometry (NES) are independent of the particular NES diagnostic. Here we apply these NES weight functions to the time-of-flight spectrometer TOFOR at JET. By taking the instrumental response function of TOFOR into account, we calculate time-of-flight NES weight functions that enable us to directly determine the velocity-space sensitivity of a given part of a measured time-of-flight spectrum from TOFOR