Improved flux-surface parameterization through constrained nonlinear optimization

Parameterization of magnetic flux-surfaces is often used for magnetohydrodynamic stability analysis and microturbulence modeling in tokamaks. Shape parameters for such local parameterization of a (numerical) equilibrium are traditionally computed analytically using geometrically derived quantities. However, often the shape is approximated by the average of values for different sections of the flux-surface contour or a truncated series, which does not guarantee an optimal fit. Here, instead nonlinear least squares optimization is used to compute these parameters, with a weighted sum of squared error cost function that is robust to outliers. This method results in a lower total absolute error for both the parameterization of the flux-surface contour and the poloidal magnetic field density than current methods for several parameterizations based on the well-known "Miller geometry."Furthermore, rapid convergence of shape parameters is achieved, no approximate geometric measurements of the contour are needed, and the method is applicable to any analytical shape parameterization. Validation with local, linear gyrokinetic simulations using these optimized shape parameters showed reduced root mean square errors in both the growth rate and frequency spectra when compared with simulations based on numerical equilibria. In particular, the popular Turnbull-Miller parameterization benefits from this approach, extending its usability closer toward the last-closed flux-surface for cases with minor up-down asymmetry.</p

Phosphoglycerate kinase acts as a futile cycle at high temperature

In (hyper)thermophilic organisms metabolic processes have to be adapted to function optimally at high temperature. We compared the gluconeogenic conversion of 3-phosphoglycerate via 1,3-bisphosphoglycerate to glyceraldehyde-3-phosphate at 30 C and at 70 C. At 30 C it was possible to produce 1,3-bisphosphoglycerate from 3-phosphoglycerate with phosphoglycerate kinase, but at 70 C, 1,3-bisphosphoglycerate was dephosphorylated rapidly to 3-phosphoglycerate, effectively turning the phosphoglycerate kinase into a futile cycle. When phosphoglycerate kinase was incubated together with glyceraldehyde 3-phosphate dehydrogenase it was possible to convert 3-phosphoglycerate to glyceraldehyde 3- phosphate, both at 30 C and at 70 C, however, at 70 C only low concentrations of product were observed due to thermal instability of glyceraldehyde 3-phosphate. Thus, thermolabile intermediates challenge central metabolic reactions and require special adaptation strategies for life at high temperature

Available energy of trapped electrons in Miller tokamak equilibria

Available energy (\AE{}), which quantifies the maximum amount of thermal energy that may be liberated and converted into instabilities and turbulence, has shown to be a useful metric for predicting saturated energy fluxes in trapped-electron-mode-driven turbulence. Here, we calculate and investigate the \AE{} in the analytical tokamak equilibria introduced by \citet{Miller1998NoncircularModel}. The \AE{} of trapped electrons reproduces various trends also observed in experiments; negative shear, increasing Shafranov shift, vertical elongation, and negative triangularity can all be stabilising, as indicated by a reduction in \AE{}, although it is strongly dependent on the chosen equilibrium. Comparing \AE{} with saturated energy flux estimates from the \textsc{tglf} model, we find fairly good correspondence, showcasing that \AE{} can be useful to predict trends. We go on to investigate \AE{} and find that negative triangularity is especially beneficial in vertically elongated configurations with positive shear or low gradients. We furthermore extract a gradient threshold-like quantity from \AE{} and find that it behaves similarly to gyrokinetic gradient thresholds: it tends to increase linearly with magnetic shear, and negative triangularity leads to an especially high threshold. We next optimise the device geometry for minimal \AE{} and find that the optimum is strongly dependent on equilibrium parameters, e.g. magnetic shear or pressure gradient. Investigating the competing effects of increasing the density gradient, the pressure gradient, and decreasing the shear, we find regimes that have steep gradients yet low \AE{}, and that such a regime is inaccessible in negative-triangularity tokamaks.Comment: 31 pages, 16 figure

The JWS online simulation database

Summary: JWS Online is a web-based platform for construction, simulation and exchange of models in standard formats. We have extended the platform with a database for curated simulation experiments that can be accessed directly via a URL, allowing one-click reproduction of published results. Users can modify the simulation experiments and export them in standard formats. The Simulation database thus lowers the bar on exploring computational models, helps users create valid simulation descriptions and improves the reproducibility of published simulation experiments. Availability and Implementation: The Simulation Database is available on line at https://jjj.bio.vu. nl/models/experiments/

HMG-CoA reductase inhibitors, other lipid-lowering medication, antiplatelet therapy, and the risk of venous thrombosis

Background: Statins [3-hydroxymethyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors] and antiplatelet therapy reduce the risk of atherosclerotic disease. Besides a reduction of lipid levels, statins might also have antithrombotic and anti-inflammatory properties, and anti-platelet therapy reduces clot formation. We have studied the risk of venous thrombosis with use of statins, other lipid-lowering medication, and antiplatelet therapy. Materials and methods: Patients with a first episode of deep vein thrombosis in the leg or pulmonary embolism between March 1999 and September 2004 were included in a large population-based case–control study (MEGA study). Control subjects were partners of patients (53%) or recruited via a random-digit-dialing method (47%). Participants reported different all-medication use in a questionnaire. Results: Of 4538 patients, 154 used statins (3.3%), as did 354 of 5914 control subjects (5.7%). The use of statins [odds ratio (OR) 0.45; 95% confidence interval (CI) 0.36–0.56] but not other lipid-lowering medications (OR 1.22; 95% CI 0.62–2.43), was associated with a reduced venous thrombosis risk as compared with individuals who did not use any lipid-lowering medication, after adjustment for age, sex, body mass index, atherosclerotic disease, antiplatelet therapy and use of vitamin K antagonists. Different types and various durations of statin therapy were all associated with a decreased venous thrombosis risk. Antiplatelet therapy also reduced venous thrombosis risk (OR 0.56; 95% CI 0.42–0.74). However, sensitivity analyses suggested that this effect is most likely explained by a so-called ‘healthy user effect’. Simultaneous use of medication most strongly reduced venous thrombosis risk. Conclusion: These results suggest that the use of various types of statins is associated with a reduced risk of venous thrombosis, whereas antiplatelet therapy and other lipid-lowering medications are not.\u

The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1

Testosterone and its 5α-reduced form, 5α-dihydrotestosterone, were previously thought to represent the only active androgens in humans. However, recent studies have shown that the potent androgen, 11-ketotestosterone, derived from the adrenal androgen precursor, 11β-hydroxyandrostenedione, may in fact serve as the primary androgen in healthy women. Yet, despite recent renewed interest in these steroids, their downstream metabolism has remained undetermined. We therefore set out to investigate the metabolism of 11-ketotestosterone by characterising the 5α- or 5β-reduction commitment step. We show that inactivation of 11-ketotestosterone is predominantly driven by AKR1D1, which efficiently catalyses the 5β-reduction of 11-ketotestosterone, committing it to a metabolic pathway that terminates in 11-ketoetiocholanolone. We demonstrate that 5α-reduction of 11-ketotestosterone is catalysed by SRD5A2, but not SRD5A1, and terminates in 11-ketoandrosterone, but is only responsible for a minority of 11-ketotestosterone inactivation. However, as 11-ketoetiocholanolone is also generated by the metabolism of the glucocorticoid cortisone, 11-ketoandrosterone should be considered a more specific urinary marker of 11-ketotestosterone production

Inhibition of the glucocorticoid‐activating enzyme 11β‐hydroxysteroid dehydrogenase type 1 drives concurrent 11‐oxygenated androgen excess

Aldo‐keto reductase 1C3 (AKR1C3) is a key enzyme in the activation of both classic and 11‐oxygenated androgens. In adipose tissue, AKR1C3 is co‐expressed with 11β‐hydroxysteroid dehydrogenase type 1 (HSD11B1), which catalyzes not only the local activation of glucocorticoids but also the inactivation of 11‐oxygenated androgens, and thus has the potential to counteract AKR1C3. Using a combination of in vitro assays and in silico modeling we show that HSD11B1 attenuates the biosynthesis of the potent 11‐oxygenated androgen, 11‐ketotestosterone (11KT), by AKR1C3. Employing ex vivo incubations of human female adipose tissue samples we show that inhibition of HSD11B1 results in the increased peripheral biosynthesis of 11KT. Moreover, circulating 11KT increased 2–3 fold in individuals with type 2 diabetes after receiving the selective oral HSD11B1 inhibitor AZD4017 for 35 days, thus confirming that HSD11B1 inhibition results in systemic increases in 11KT concentrations. Our findings show that HSD11B1 protects against excess 11KT production by adipose tissue, a finding of particular significance when considering the evidence for adverse metabolic effects of androgens in women. Therefore, when targeting glucocorticoid activation by HSD11B1 inhibitor treatment in women, the consequently increased generation of 11KT may offset beneficial effects of decreased glucocorticoid activation