Priming nonlinear searches for pathway identification

BACKGROUND: Dense time series of metabolite concentrations or of the expression patterns of proteins may be available in the near future as a result of the rapid development of novel, high-throughput experimental techniques. Such time series implicitly contain valuable information about the connectivity and regulatory structure of the underlying metabolic or proteomic networks. The extraction of this information is a challenging task because it usually requires nonlinear estimation methods that involve iterative search algorithms. Priming these algorithms with high-quality initial guesses can greatly accelerate the search process. In this article, we propose to obtain such guesses by preprocessing the temporal profile data and fitting them preliminarily by multivariate linear regression. RESULTS: The results of a small-scale analysis indicate that the regression coefficients reflect the connectivity of the network quite well. Using the mathematical modeling framework of Biochemical Systems Theory (BST), we also show that the regression coefficients may be translated into constraints on the parameter values of the nonlinear BST model, thereby reducing the parameter search space considerably. CONCLUSION: The proposed method provides a good approach for obtaining a preliminary network structure from dense time series. This will be more valuable as the systems become larger, because preprocessing and effective priming can significantly limit the search space of parameters defining the network connectivity, thereby facilitating the nonlinear estimation task

Cardiac steatosis associates with visceral obesity in nondiabetic obese men.

Background: Liver fat and visceral adiposity are involved in the development of the metabolic syndrome (MetS). Ectopic fat accumulation within and around the heart has been related to increased risk of heart disease. The aim of this study was to explore components of cardiac steatosis and their relationship to intra-abdominal ectopic fat deposits and cardiometabolic risk factors in nondiabetic obese men. Methods: Myocardial and hepatic triglyceride (TG) contents were measured with 1.5 T magnetic resonance spectroscopy, and visceral adipose (VAT), abdominal subcutaneous tissue (SAT), epicardial and pericardial fat by magnetic resonance imaging in 37 men with the MetS and in 40 men without the MetS. Results: Myocardial and hepatic TG contents, VAT, SAT, epicardial fat volumes, and pericardial fat volumes were higher in men with the MetS compared with subjects without the MetS (P < .001). All components of cardiac steatosis correlated with SAT, VAT, and hepatic TG content and the correlations seemed to be strongest with VAT. Myocardial TG content, epicardial fat, pericardial fat, VAT, and hepatic TG content correlated with waist circumference, body mass index, high-density lipoprotein cholesterol TGs, very low-density lipoprotein-1 TGs, and the insulin-resistance homeostasis model assessment index. VAT was a predictor of TGs, high-density lipoprotein cholesterol, and measures of glucose metabolism, whereas age and SAT were determinants of blood pressure parameters. Conclusions: We suggest that visceral obesity is the best predictor of epicardial and pericardial fat in abdominally obese subjects. Myocardial TG content may present a separate entity that is influenced by factors beyond visceral adiposity

Biomarkers and prediction of myocardial triglyceride content in non-diabetic men

Background and aims: Lipid oversupply to cardiomyocytes or decreased utilization of lipids leads to cardiac steatosis. We aimed to examine the role of different circulating metabolic biomarkers as predictors of myocardial triglyceride (TG) content in non-diabetic men. Methods and results: Myocardial and hepatic TG contents were measured with 1.5 T magnetic resonance (MR) spectroscopy, and LV function, visceral adipose tissue (VAT), abdominal subcutaneous tissue (SAT), epicardial and pericardial fat by MR imaging in 76 non-diabetic men. Serum concentration of circulating metabolic biomarkers [adiponectin, leptin, adipocyte-fatty acid binding protein 4 (A-FABP 4), resistin, and lipocalin-2] including beta-hydroxybuturate (beta-OHB) were measured. Subjects were stratified by tertiles of myocardial TG into low, moderate, and high myocardial TG content groups. Concentrations of beta-OHB were lower (p = 0.003) and serum levels of A-FABP 4 were higher (p <0.001) in the group with high myocardial TG content compared with the group with low myocardial TG content. beta-OHB was negatively correlated with myocardial TG content (r = -0.316, p = 0.006), whereas A-FABP 4 was not correlated with myocardial TG content (r = 0.192, p = 0.103). In multivariable analyses beta-OHB and plasma glucose levels were the best predictors of myocardial TG content independently of VAT and hepatic TG content. The model explained 58.8% of the variance in myocardial TG content. Conclusion: Our data showed that beta-OHB and fasting glucose were the best predictors of myocardial TG content in non-diabetic men. These data suggest that hyperglycemia and alterations in lipid oxidation may be associated with cardiac steatosis in humans. (C) 2015 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.Peer reviewe

Characterization of different fat depots in NAFLD using inflammation-associated proteome, lipidome and metabolome

Non-alcoholic fatty liver disease (NAFLD) is recognized as a liver manifestation of metabolic syndrome, accompanied with excessive fat accumulation in the liver and other vital organs. Ectopic fat accumulation was previously associated with negative effects at the systemic and local level in the human body. Thus, we aimed to identify and assess the predictive capability of novel potential metabolic biomarkers for ectopic fat depots in non-diabetic men with NAFLD, using the inflammation-associated proteome, lipidome and metabolome. Myocardial and hepatic triglycerides were measured with magnetic spectroscopy while function of left ventricle, pericardial and epicardial fat, subcutaneous and visceral adipose tissue were measured with magnetic resonance imaging. Measured ectopic fat depots were profiled and predicted using a Random Forest algorithm, and by estimating the Area Under the Receiver Operating Characteristic curves. We have identified distinct metabolic signatures of fat depots in the liver (TAG50:1, glutamate, diSM18:0 and CE20:3), pericardium (N-palmitoyl-sphinganine, HGF, diSM18:0, glutamate, and TNFSF14), epicardium (sphingomyelin, CE20:3, PC38:3 and TNFSF14), and myocardium (CE20:3, LAPTGF-beta 1, glutamate and glucose). Our analyses highlighted non-invasive biomarkers that accurately predict ectopic fat depots, and reflect their distinct metabolic signatures in subjects with NAFLD.Peer reviewe

A machine learning approach based on generative topographic mapping for disruption prevention and avoidance at JET

The need for predictive capabilities greater than 95% with very limited false alarms are demanding requirements for reliable disruption prediction systems in tokamaks such as JET or, in the near future, ITER. The prediction of an upcoming disruption must be provided sufficiently in advance in order to apply effective disruption avoidance or mitigation actions to prevent the machine from being damaged. In this paper, following the typical machine learning workflow, a generative topographic mapping (GTM) of the operational space of JET has been built using a set of disrupted and regularly terminated discharges. In order to build the predictive model, a suitable set of dimensionless, machine-independent, physics-based features have been synthesized, which make use of 1D plasma profile information, rather than simple zero-D time series. The use of such predicting features, together with the power of the GTM in fitting the model to the data, obtains, in an unsupervised way, a 2D map of the multi-dimensional parameter space of JET, where it is possible to identify a boundary separating the region free from disruption from the disruption region. In addition to helping in operational boundaries studies, the GTM map can also be used for disruption prediction exploiting the potential of the developed GTM toolbox to monitor the discharge dynamics. Following the trajectory of a discharge on the map throughout the different regions, an alarm is triggered depending on the disruption risk of these regions. The proposed approach to predict disruptions has been evaluated on a training and an independent test set and achieves very good performance with only one tardive detection and a limited number of false detections. The warning times are suitable for avoidance purposes and, more important, the detections are consistent with physical causes and mechanisms that destabilize the plasma leading to disruptions.Peer reviewe

RF sheath modeling of experimentally observed plasma surface interactions with the JET ITER-Like Antenna

Waves in the Ion Cyclotron Range of Frequencies (ICRF) enhance local Plasma-Surface Interactions (PSI) near the wave launchers and magnetically-connected objects via Radio-Frequency (RF) sheath rectification. ITER will use 20MW of ICRF power over long pulses, questioning the long-term impact of RF-enhanced localized erosion on the lifetime of its Beryllium (Be) wall. Recent dedicated ICRF-heated L-mode discharges documented this process on JET for different types of ICRF antennas. Using visible spectroscopy in JET ICRF-heated L-mode discharges, poloidally-localized regions of enhanced (by similar to 2-4x) Be I and Be II light emission were observed on two outboard limiters magnetically connected to the bottom of the active ITER-Like Antenna (ILA). The observed RF-PSI induced by the ILA was qualitatively comparable to that induced by the JET standard, type-A2 antennas, for similar strap toroidal phasing and connection geometries. The Be II line emission was found more intense when powering the bottom half of the ILA rather than its top half. Conversely, more pronounced SOL density modifications were observed with only top array operation, on field lines connected to the top half of the ILA. So far the near-field modeling of the ILA with antenna code TOPICA (Torino Polytechnic Ion Cyclotron Antenna), using curved antenna model, was partially able to reproduce qualitatively the observed phenomena. A quantitative discrepancy persisted between the observed Be source amplification and the calculated, corresponding increases in E-// field at the magnetically connected locations to the ILA when changing from only top to only bottom half antenna operation. This paper revisits these current drive phased and half-ILA powered cases using for the new simulations flat model of the ILA and more realistic antenna feeding to calculate the E-// field maps with TOPICA code. Further, the Self-consistent Sheaths and Waves for Ion Cyclotron Heating Slow Wave (SSWICH-SW) code, which couples slow wave evanescence with DC Scrape-Off Layer (SOL) biasing, is used to estimate the poloidal distribution of rectified RF-sheath Direct Current (DC) potential V-DC in the private SOL between the ILA poloidal limiters. The approach so far was limited to correlating the observed, enhanced emission regions at the remote limiters to the antenna near-electric fields, as calculated by TOPICA. The present approach includes also a model for the rectification of these near-fields in the private SOL of the ILA. With the improved approach, when comparing only top and only bottom half antenna feeding, we obtained good qualitative correlation between all experimental measurements and the calculated local variations in the E-// field and V-DC potential.Peer reviewe

Comparison of the structure of the plasma-facing surface and tritium accumulation in beryllium tiles from JET ILW campaigns 2011-2012 and 2013-2014

In this study, beryllium tiles from Joint European Torus (JET) vacuum vessel wall were analysed and compared regarding their position in the vacuum vessel and differences in the exploitation conditions during two campaigns of ITER-Like-Wall (ILW) in 2011-2012 (ILW1) and 2013-2014 (ILW2) Tritium content in beryllium samples were assessed. Two methods were used to measure tritium content in the samples - dissolution under controlled conditions and tritium thermal desorption. Prior to desorption and dissolution experiments, scanning electron microscopy and energy dispersive x-ray spectroscopy were used to study structure and chemical composition of plasma-facing-surfaces of the beryllium samples. Experimental results revealed that tritium content in the samples is in range of 2.10(11)-2.10(13) tritium atoms per square centimetre of the surface area with its highest content in the samples from the outer wall of the vacuum vessel (up to 1.9.10(13) atoms/cm(2) in ILW1 campaign and 2.4.10(13) atoms/cm(2) in ILW2). The lowest content of tritium was found in the upper part of the vacuum vessel (2.0.10(12) atoms/cm(2) and 2.0.10(11) atoms/cm(2) in ILW1 and ILW2, respectively). Results obtained from scanning electron microscopy has shown that surface morphology is different within single tile, however if to compare two campaigns main tendencies remains similar.Peer reviewe

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.Peer reviewe

Modelling of tungsten erosion and deposition in the divertor of JET-ILW in comparison to experimental findings

The erosion, transport and deposition of tungsten in the outer divertor of JET-ILW has been studied for an H-Mode discharge with low frequency ELMs. For this specific case with an inter-ELM electron temperature at the strike point of about 20 eV, tungsten sputtering between ELMs is almost exclusively due to beryllium impurity and self-sputtering. However, during ELMs tungsten sputtering due to deuterium becomes important and even dominates. The amount of simulated local deposition of tungsten relative to the amount of sputtered tungsten in between ELMs is very high and reaches values of 99% for an electron density of 5E13 cm(-3) at the strike point and electron temperatures between 10 and 30 eV. Smaller deposition values are simulated with reduced electron density. The direction of the B-field significantly influences the local deposition and leads to a reduction if the E x B drift directs towards the scrape-off-layer. Also, the thermal force can reduce the tungsten deposition, however, an ion temperature gradient of about 0.1 eV/mm or larger is needed for a significant effect. The tungsten deposition simulated during ELMs reaches values of about 98% assuming ELM parameters according to free-streaming model. The measured WI emission profiles in between and within ELMs have been reproduced by the simulation. The contribution to the overall net tungsten erosion during ELMs is about 5 times larger than the one in between ELMs for the studied case. However, this is due to the rather low electron temperature in between ELMs, which leads to deuterium impact energies below the sputtering threshold for tungsten.Peer reviewe

Dynamic modelling of local fuel inventory and desorption in the whole tokamak vacuum vessel for auto-consistent plasma-wall interaction simulations

An extension of the SolEdge2D-EIRENE code package, named D-WEE, has been developed to add the dynamics of thermal desorption of hydrogen isotopes from the surface of plasma facing materials. To achieve this purpose, D-WEE models hydrogen isotopes implantation, transport and retention in those materials. Before launching autoconsistent simulation (with feedback of D-WEE on SolEdge2D-EIRENE), D-WEE has to be initialised to ensure a realistic wall behaviour in terms of dynamics (pumping or fuelling areas) and fuel content. A methodology based on modelling is introduced to perform such initialisation. A synthetic plasma pulse is built from consecutive SolEdge2D-EIRENE simulations. This synthetic pulse is used as a plasma background for the D-WEE module. A sequence of plasma pulses is simulated with D-WEE to model a tokamak operation. This simulation enables to extract at a desired time during a pulse the local fuel inventory and the local desorption flux density which could be used as initial condition for coupled plasma-wall simulations. To assess the relevance of the dynamic retention behaviour obtained in the simulation, a confrontation to post-pulse experimental pressure measurement is performed. Such confrontation reveals a qualitative agreement between the temporal pressure drop obtained in the simulation and the one observed experimentally. The simulated dynamic retention during the consecutive pulses is also studied.Peer reviewe