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High strength metastable β titanium alloys are widely employed in the aircraft industry due to their outstanding strength-to-weight ratio. While components can endure complex in-service mechanical loading, the anisotropy in tensile properties has been the subject of limited attention. In this study, its origin was investigated focusing on the role played by millimeter scale β grains as they were recently identified as a source of heterogeneous deformation. Tensile properties of Ti-10V-2Fe-3Al processed via different thermomechanical routes were assessed using multiple sampling directions. In particular, elongation values were observed to vary significantly depending on the testing direction. A combination of SEM, EBSD, µ-CT and in-situ DIC during tensile tests was employed to clarify the underlying causes of this behavior. Substantial differences in strain heterogeneity and localization were found related to features of β grains, including their crystallographic and morphologic orientations. Furthermore, multiple fracture mechanisms were observed to derive from the differences in deformation behavior, and eventually compete to trigger specimen failure. Elongation values are then determined by both the degree of strain heterogeneity and the operating fracture mechanisms. These findings provide a new understanding of the role of the microstructure in the tensile behavior of high strength metastable β titanium alloys.

Healthy aging is often associated with speech comprehension difficulties in everyday life situations despite a pure-tone hearing threshold in the normative range. Drawing on this background, we used a multidimensional approach to assess the functional and structural neural correlates underlying age-related temporal speech processing while controlling for pure-tone hearing acuity. Accordingly, we combined structural magnetic resonance imaging and electroencephalography, and collected behavioral data while younger and older adults completed a phonetic categorization and discrimination task with consonant-vowel syllables varying along a voice-onset time continuum. The behavioral results confirmed age-related temporal speech processing singularities which were reflected in a shift of the boundary of the psychometric categorization function, with older adults perceiving more syllable characterized by a short voice-onset time as /ta/ compared to younger adults. Furthermore, despite the absence of any between-group differences in phonetic discrimination abilities, older adults demonstrated longer N100/P200 latencies as well as increased P200 amplitudes while processing the consonant-vowel syllables varying in voice-onset time. Finally, older adults also exhibited a divergent anatomical gray matter infrastructure in bilateral auditory-related and frontal brain regions, as manifested in reduced cortical thickness and surface area. Notably, in the younger adults but not in the older adult cohort, cortical surface area in these two gross anatomical clusters correlated with the categorization of consonant-vowel syllables characterized by a short voice-onset time, suggesting the existence of a critical gray matter threshold that is crucial for consistent mapping of phonetic categories varying along the temporal dimension. Taken together, our results highlight the multifaceted dimensions of age-related temporal speech processing characteristics, and pave the way toward a better understanding of the relationships between hearing, speech and the brain in older age.

Learning new words in an unfamiliar language is a complex endeavor that requires the orchestration of multiple perceptual and cognitive functions. Although the neural mechanisms governing word learning are becoming better understood, little is known about the predictive value of resting-state (RS) metrics for foreign word discrimination and word learning attainment. In addition, it is still unknown which of the multistep processes involved in word learning have the potential to rapidly reconfigure RS networks. To address these research questions, we used electroencephalography (EEG), measured forty participants, and examined scalp-based power spectra, source-based spectral density maps and functional connectivity metrics before (RS1), in between (RS2) and after (RS3) a series of tasks which are known to facilitate the acquisition of new words in a foreign language, namely word discrimination, word-referent mapping and semantic generalization. Power spectra at the scalp level consistently revealed a reconfiguration of RS networks as a function of foreign word discrimination (RS1 vs. RS2) and word learning (RS1 vs. RS3) tasks in the delta, lower and upper alpha, and upper beta frequency ranges. Otherwise, functional reconfigurations at the source level were restricted to the theta (spectral density maps) and to the lower and upper alpha frequency bands (spectral density maps and functional connectivity). Notably, scalp RS changes related to the word discrimination tasks (difference between RS2 and RS1) correlated with word discrimination abilities (upper alpha band) and semantic generalization performance (theta and upper alpha bands), whereas functional changes related to the word learning tasks (difference between RS3 and RS1) correlated with word discrimination scores (lower alpha band). Taken together, these results highlight that foreign speech sound discrimination and word learning have the potential to rapidly reconfigure RS networks at multiple functional scales.

Over the last decade, fluctuations of retinoids (RETs), also known as vitamin A and derivatives, have proved to be useful biomarkers to assess the environmental chemical pressure on a wide variety of non-target vertebrates. This use of RET-based biomarkers is of particular interest in the non-target sentinel species Gammarus fossarum in which RETs were shown to influence crucial physiological functions. To study and probe this metabolism in this crustacean model, a UHPLC-MS/MS method was developed to 1) identify and 2) monitor several endogenous RETs in unexposed females throughout their reproductive cycle. Then, females were exposed in controlled conditions to exogenous all-trans retinoic acid (atRA) and citral (CIT), a RA synthesis inhibitor, to simulate an excess or deficiency in RA. Perturbation of vitamin A metabolism by pesticides was further studied in response to methoprene (MET), a juvenile hormone analog as well as glyphosate (GLY). The developed method allowed, for the first time in this model, the identification of RA metabolites (all-trans 4-oxo and 13-cis 4-oxo RA), RA isomers (all-trans and 13-cis RA) as well as retinaldehyde (RALD) isomers (all-trans, 11-cis, and 13-cis RALD) and showed two distinct phases in the reproductive cycle. Retinoic acid successfully increased the tissular concentration of both RA isomers and CIT proved to be efficient at perturbating the conversion from RALD to RA. Methoprene perturbed the ratios between RA isomers whereas GLY had no observed effects on the RET system of G. fossarum females. We were able to discriminate different dynamics of RET perturbations by morphogens (atRA or CIT) or MET which highlights the plausible mediation of RETs in MET-induced disorders. Ultimately, our study shows that RETs are influenced by exposure to MET and strengthen their potential to assess aquatic ecosystem chemical status.

Experimentally, it has been observed in high-confinement (H-Mode) plasmas with Edge Localised Modes (ELMs) on JET that the pressure pedestal (pe,ped) is degraded by approximately a factor of two when there is a change in electron separatrix density, ne,sep, from 1−4×1019m−3. Previous work using the pedestal stability code EUROPED, has been able to predict the degradation of pe,ped but only for ne,sep≤1.5×1019m−3. In this work, we apply a coupled code JETTO-MISHKA-FRANTIC, to self-consistently predict the transport in the pedestal region and neutral source with varying separatrix conditions. The code feeds back on the transport in the pedestal region to achieve profiles that are marginally stable to ideal MHD modes (continuous ELM model in JETTO).When accounting for the change in electron separatrix temperature (Te,sep), ion separatrix temperature (Ti,sep) and the poloidally integrated neutral flux crossing the separatrix (Γsep,neut) as it changes with ne,sep (according to a scan in ne,sep in the edge code EDGE2D-EIRENE), no degradation in pe,ped was observed in JETTO-MISHKA-FRANTIC in contrast to experiment. Instead, an increase in pe,ped with ne,sep was observed which is driven by an increasing density pedestal (ne,ped). Within the presented JETTO-MISHKA-FRANTIC simulations, changing the pedestal width by a factor of two and a half in normalised poloidal flux (ψn) resulted in an approximately 40% degradation in pe,ped for ne,sep=1−3×1019m−3. This change in pedestal width was not supported by experimental data. A scan in the ratio of particle and energy transport in the pedestal (D/χ) was found to have a negligible effect on pe,ped. Qualitative agreement between JETTO-MISHKA-FRANTIC with EUROPED was found when the input density profiles are identical.

Measurements of the ion currents to and plasma conditions at the low-field side (LFS) divertor target plate in low-confinement mode plasmas in the JET ITER-like wall materials configuration show that the core plasma density required to detach the LFS divertor plasma is independent of the hydrogenic species protium, deuterium and tritium, and a 40 %/60 % deuterium–tritium mixture. This observation applies to a divertor plasma configuration with the LFS strike line connected to the horizontal part of the LFS divertor chosen because of its superior diagnostic coverage. The finding is independent of the operational status of the JET cryogenic pump. The electron temperature (Te) at the LFS strike line was markedly reduced from 25 eV to 5 eV over a narrow range of increasing core plasma density, and observed to be between 2 eV and 3 eV at the onset of detachment. The electron density (ne) peaks across the LFS plasma when Te at the target plate is 1 eV, and spatially moves to the X-point for higher core densities. The density limit was found approximately 20 % higher in protium than in tritium and deuterium–tritium plasmas.

One of our grand challenges towards fusion energy is the achievement of a high-performance plasma core coupled to a boundary solution. The high confinement mode (H-mode) provides such a high-performance fusion core due to the build-up of an edge transport barrier leading to a pedestal. However, it usually features type-I edge localized modes (ELMs) which pose a threat for long-duration plasma operation in future fusion devices as they induce large energy fluences onto the plasma facing components and typically are projected to damage the first wall. For future fusion devices, the integration of a stationary no-ELM regime with a power exhaust solution is indispensable. Several no-ELM and small-ELM regimes have extended their operational space in the past years, with the ultimate goal of providing an alternative core–edge solution to ITER and EU-DEMO. Prominent no-ELM or small-ELM alternatives include the I-mode, QH-mode, EDA H-mode, quasi-continuous exhaust (QCE) and ‘grassy’ ELM regimes, X-point radiator scenarios and negative triangularity L-mode. The state-of-the-art, including access conditions and main signatures, of these alternative regimes is reviewed. Many of these regimes partly match the operational space of ITER and EU-DEMO, however, knowledge gaps remain. Besides compatibility with divertor detachment and a radiative mantle, these include extrapolations to high Q operations, low core collisionality, high Greenwald fractions, impurity transport, amongst others. The knowledge gaps and possible strategies to close these gaps to show their applicability to ITER and EU-DEMO are discussed.

Objective: Disturbances in NAD+ metabolism have been described as a hallmark for multiple metabolic and age-related diseases, including type 2 diabetes. While alterations in pancreatic β-cell function are critical determinants of whole-body glucose homeostasis, the role of NAD+ metabolism in the endocrine pancreas remains poorly explored. Here, we aimed to evaluate the role of nicotinamide riboside (NR) metabolism in maintaining NAD+ levels and pancreatic β-cell function in pathophysiological conditions. Methods: Whole body and pancreatic β-cell-specific NRK1 knockout (KO) mice were metabolically phenotyped in situations of high-fat feeding and aging. We also analyzed pancreatic β-cell function, β-cell mass and gene expression. Results: We first demonstrate that NRK1, the essential enzyme for the utilization of NR, is abundantly expressed in pancreatic β-cells. While NR treatment did not alter glucose-stimulated insulin secretion in pancreatic islets from young healthy mice, NRK1 knockout mice displayed glucose intolerance and compromised β-cells response to a glucose challenge upon high-fat feeding or aging. Interestingly, β cell dysfunction stemmed from the functional failure of other organs, such as liver and kidney, and the associated changes in circulating peptides and hormones, as mice lacking NRK1 exclusively in β-cells did not show altered glucose homeostasis. Conclusions: This work unveils a new physiological role for NR metabolism in the maintenance of glucose tolerance and pancreatic β-cell function in high-fat feeding or aging conditions.

Age-related hearing loss is a highly prevalent condition, which manifests at both the auditory periphery and the brain. It leads to degraded auditory input, which needs to be repaired in order to achieve understanding of spoken language. It is still unclear how older adults with this condition draw on their neural resources to optimally process speech. By presenting interrupted speech to 26 healthy older adults with normal-for-age audiograms, this study investigated neural tracking of degraded auditory input. The electroencephalograms of the participants were recorded while they first listened to and then verbally repeated sentences interrupted by silence in varying interruption rates. Speech tracking was measured by inter-trial phase coherence in response to the stimuli. In interruption rates that corresponded to the theta frequency band, speech tracking was highly specific to the interruption rate and positively related to the understanding of interrupted speech. These results suggest that older adults’ brain activity optimizes through the tracking of stimulus characteristics, and that this tracking aids in processing an incomplete auditory stimulus. Further investigation of speech tracking as a candidate training mechanism to alleviate age-related hearing loss is thus encouraged.

The total radiated fraction is examined in high density H-mode plasmas (Greenwald fraction of about 85 %) in JET by the variation of the auxiliary heating power of Pheat = 14 MW-29 MW. An achieved radiation fraction of about 75 % at most has been observed in JET-ILW, which is less than the highest achievable (≈90 %) fraction in JET-C during the high radiative power scenarios with N2 seeding. It is shown that the maximal achievable total radiation fraction averaged over ELM cycles has a strong dependence on the radiation efficiency of the ELM energy, θrad: γrad,totalmax=1-fELM×ΔWELMPheat1-θrad. About 50 % and 16 % of the ELM induced diamagnetic energy drop (ΔWELM) radiates during the ELM in JET-C and JET-ILW, respectively, which corresponds to the maximum total radiated powers of γrad,JET-Cmax=0.87 and γrad,JET-ILWmax=0.77. These values of the maximum of the radiative power fractions are in good agreement with γradmax experimentally observed in JET-C (90 %) and JET-ILW (75 %).

Objective: A decay in intracellular NAD+ levels is one of the hallmarks of physiological decline in normal tissue functions. Accordingly, dietary supplementation with NAD+ precursors can prevent, alleviate, or even reverse multiple metabolic complications and age-related disorders in diverse model organisms. Within the constellation of NAD+ precursors, nicotinamide riboside (NR) has gained attention due to its potent NAD+ biosynthetic effects in vivo while lacking adverse clinical effects. Nevertheless, NR is not stable in circulation, and its utilization is rate-limited by the expression of nicotinamide riboside kinases (NRKs). Therefore, there is a strong interest in identifying new effective NAD+ precursors that can overcome these limitations. Methods: Through a combination of metabolomics and pharmacological approaches, we describe how NRH, a reduced form of NR, serves as a potent NAD+ precursor in mammalian cells and mice. Results: NRH acts as a more potent and faster NAD+ precursor than NR in mammalian cells and tissues. Despite the minor structural difference, we found that NRH uses different steps and enzymes to synthesize NAD+, thus revealing a new NRK1-independent pathway for NAD+ synthesis. Finally, we provide evidence that NRH is orally bioavailable in mice and prevents cisplatin-induced acute kidney injury. Conclusions: Our data identify a new pathway for NAD+ synthesis and classify NRH as a promising new therapeutic strategy to enhance NAD+ levels. Keywords: NAD+, Nicotinamide riboside, Metabolism

Accurate detection and quantification of unruptured intracranial aneurysms (UIAs) is important for rupture risk assessment and to allow an informed treatment decision to be made. Currently, 2D manual measures used to assess UIAs on Time-of-Flight magnetic resonance angiographies (TOF-MRAs) lack 3D information and there is substantial inter-observer variability for both aneurysm detection and assessment of aneurysm size and growth. 3D measures could be helpful to improve aneurysm detection and quantification but are time-consuming and would therefore benefit from a reliable automatic UIA detection and segmentation method. The Aneurysm Detection and segMentation (ADAM) challenge was organised in which methods for automatic UIA detection and segmentation were developed and submitted to be evaluated on a diverse clinical TOF-MRA dataset.A training set (113 cases with a total of 129 UIAs) was released, each case including a TOF-MRA, a structural MR image (T1, T2 or FLAIR), annotation of any present UIA(s) and the centre voxel of the UIA(s). A test set of 141 cases (with 153 UIAs) was used for evaluation. Two tasks were proposed: (1) detection and (2) segmentation of UIAs on TOF-MRAs. Teams developed and submitted containerised methods to be evaluated on the test set. Task 1 was evaluated using metrics of sensitivity and false positive count. Task 2 was evaluated using dice similarity coefficient, modified hausdorff distance (95th percentile) and volumetric similarity. For each task, a ranking was made based on the average of the metrics.In total, eleven teams participated in task 1 and nine of those teams participated in task 2. Task 1 was won by a method specifically designed for the detection task (i.e. not participating in task 2). Based on segmentation metrics, the top two methods for task 2 performed statistically significantly better than all other methods. The detection performance of the top-ranking methods was comparable to visual inspection for larger aneurysms. Segmentation performance of the top ranking method, after selection of true UIAs, was similar to interobserver performance. The ADAM challenge remains open for future submissions and improved submissions, with a live leaderboard to provide benchmarking for method developments at https://adam.isi.uu.nl/.

While current tokamak experiments are beginning to use real-time feedback control systems to manage the plasma exhaust, future tokamaks still require validation of theoretical models used to predict the threshold impurity concentration required to sufficiently reduce the power and particle fluxes to the divertor. This work exploits new spectroscopic measurements of the divertor nitrogen concentration, cN, in partially detached N2-seeded H-mode plasmas on ASDEX Upgrade (AUG) and JET with the ITER-Like Wall (JET-ILW) to test the parameter dependencies of the power flowing to the outer divertor, Pdiv,outer, and the separatrix electron density, ne,sep. A least-squares regression of the AUG measurements demonstrates that the threshold cN required for detachment scales as cN∝Pdiv,outer1.19±0.32ne,sep-2.77±0.36. This scaling of ne,sep is also consistent with the measurements from JET which, at constant Pdiv,outer, show cN∝ne,sep-2.43±0.27. The dependencies of Pdiv,outer and ne,sep is demonstrated over at least a factor of two change in both parameters and indicates a stronger dependence on ne,sep in comparison to the Lengyel model, which could be due to the assumption in this model that the heat flux channel width is independent of density. This first assessment of detachment scaling with impurity seeding highlights the need for further analysis of the systematic uncertainties of the measurement and more consistent scenarios from more tokamaks to investigate the machine size scaling.

A numerical study is presented, using the SOLPS-ITER plasma boundary code with full drifts and currents activated, of impurity seeded JET discharges in support of high power H-mode experimental campaigns designed to compare two ITER candidate seeding species, nitrogen (N) and neon (Ne). Fluid-kinetic edge plasma simulations are first performed at lower levels of power into the scrape-off layer (SOL) and benchmarked against existing JET experimental data. Calculations are then performed for higher levels of SOL power to examine the impact of this key parameter on the efficiency of both radiators. From the code point of view, for the chosen JET parameters, Ne can be as efficient a divertor radiator as N at the same level of upstream separatrix Zeff

The core transport code, JETTO, coupled to the neutral Monte Carlo code, EIRENE, has been used to examine the sensitivity of the JET H-mode pedestal to the neutral flux crossing the separatrix. The Neutral Penetration Model (NPM) [Groebner et. al., Physics of Plasmas 9, 2134 (2002)] predicts the width of the density pedestal along the neutral path to scale with the inverse of its height: 1/ne,ped. By keeping the same physics assumptions in the NPM, and setting the deuterium atoms to cross the separatrix at the same location as the synthetic diagnostic line of sight (i.e. at the outer mid-plane, OMP), we were able to reproduce this scaling in JETTO-EIRENE. However, when the atoms were set to cross the separatrix at the X-point (more consistent with EDGE2D-EIRENE simulations of JET H-modes), the density width at the OMP was found to be much more sensitive to the pedestal height (approximately proportional to 1/ne,ped2). This is attributed to a radial variation in the poloidal flux expansion from OMP to X-point, over the range of ionisation mean free path lengths explored in the scan. Accounting for this variation allowed the expected scaling at the OMP to be recovered. Implications are discussed for experimental comparisons to the NPM and its application to pedestal prediction models.

The modelling of JET corner configurations, in which the strike points are positioned deep in the corners of the divertor, is extremely challenging for edge plasma fluid modelling tools. To circumvent this technical limitation, a geometrical approximation has been proposed, consisting in considering an artificial minor modification of the geometry of the divertor targets plates. In this paper, we investigate how significantly this approximation impacts the output of transport simulations. Using the SOLEDGE2D-EIRENE transport code which has the unique capability to be able to cope with both the full and the approximated geometry, we have performed a density scan in H-mode for pulses in which the outer strike-point lies in the corner of the divertor. We report here how simulations in the artificial geometry differ from the ones in unaltered geometry. At the exception of low density cases, mid-plane profiles in the closed field lines region and the near scrape-off layer are little impacted. Further out however, in flux-surfaces that are concerned by the geometrical modification, we find that modifying the geometry leads to a strong overestimate of the plasma density. The density perturbation is not local and concerns the whole flux surfaces. Although the divertor geometry is modified only on the outer side, the largest impact is found at the inner divertor where densities are systematically overestimated by a factor that can exceed 10 in low density cases in the far Scrape-Off Layer (SOL) and temperature underestimated by 10 to 20 eV in most of the studied density range. The near SOL and strike point peak values are also impacted in the same direction with density changes by a factor of 2. As a consequence, the threshold to detachment of the inner divertor is found lower in the approximate geometry than in the unaltered one. Due to the large flux expansion between the outer and the inner target, the difference in plasma is especially sensitive at the top of the inner divertor baffle, which could have consequence on the evaluation of physical sputtering at that critical location.

Superficial Siderosis of the Central Nervous System (SSCNS) is a condition secondary to the deposition of hemosiderin within the subpial layers of central nervous system leading to its progressive degeneration, clinically responsible for hearing impairment, cerebellar ataxia and pyramidal syndrome. Here we report the case of a 61-year-old man with medical history of congenital hemophilia A presenting with typical clinical features of SSCNS associated with extensive hypo-intensity on fast 2D gradient-echo-weighted sequences, along the spinal cord, posterior fossa's structures and cerebral cortex. Interestingly, although his disorder was revealed by a lumbar spinal stenosis, presurgical imaging and subclinical hearing impairment preceding the surgery suggest another underlying cause. As a comprehensive work-up performed in our department ruled-out usual causes of SSCNS, this case reinforces the question of the ability for hemophilia A to generate SSCNS on its own.

The fabrication of bioelectrocatalytic protein electrodes by the simple compression of carbon nanotube and protein powders was investigated using a series of proteins including bilirubin oxidase (BOx), bovine serum albumin (BSA), catalase, cytochrome C (Cyt C), diaphorase, FAD-dependent glucose dehydrogenase (FAD-GDH), galactose oxidase (GAOx), glucose oxidase (GOx), horseradish peroxidase (HRP), laccase and urease. The isoelectric points (pI) of the proteins ranged from 3.5 to 12 and the molecular weights ranged from 12.4 to 480 kDa. The compression of diaphorase, laccase, BOx, FAD-GDH, catalase and urease gave mechanically stable biopellets in 0.1 M phosphate buffer pH 7.4. For Cyt C, BSA, GAOx, GOx, and HRP, contact with buffer destabilised the biopellet and induced a fast destruction of the composite. In parallel, stable redox pellets were obtained with differently charged redox mediators: hexaammineruthenium (III) chloride, potassium hexacyanoferrate or 1,4-naphthoquinone. Several parameters were explored to shed new light on the factors that determine biopellet stability. Stable biopellets capable of direct and mediated electron transfer were subsequently elaborated, for O2 reduction and glucose oxidation, respectively, based on the simplified procedure that does not require stabilising protection membranes or holders on the contrary to existing methods.

Using data from the COMPASS-ND study we investigated associations between hearing loss and hippocampal volume as well as cortical thickness in older adults with subjective cognitive decline (SCD), mild cognitive impairment (MCI), and Alzheimer’s dementia (AD). SCD participants with greater pure-tone hearing loss exhibited lower hippocampal volume, but more cortical thickness in the left superior temporal gyrus and right pars opercularis. Greater speech-in-noise reception thresholds were associated with lower cortical thickness bilaterally across much of the cortex in AD. The AD group also showed a trend towards worse speech-in-noise thresholds compared to the SCD group.

The recent characterization of functional brown adipose tissue in adult humans has opened new perspectives for regulation of energy expenditure with respect to obesity and diabetes. Furthermore, dietary recommendations have taken into account the insufficient dietary intake of ω3 PUFAs and the concomitant excessive intake of ω6 PUFA associated with the occurrence of overweight/obesity. We aimed to study whether ω3 PUFAs could play a role in the recruitment and function of energy-dissipating brown/brite adipocytes. We show that ω3 PUFA supplementation has a beneficial effect on the thermogenic function of adipocytes. In vivo, a low dietary ω6:ω3 ratio improved the thermogenic response of brown and white adipose tissues to β3-adrenergic stimulation. This effect was recapitulated in vitro by PUFA treatment of hMADS adipocytes. We pinpointed the ω6-derived eicosanoid prostaglandin (PG)F2α as the molecular origin because the effects were mimicked with a specific PGF2α receptor agonist. PGF2α level in hMADS adipocytes was reduced in response to ω3 PUFA supplementation. The recruitment of thermogenic adipocytes is influenced by the local quantity of individual oxylipins, which is controlled by the ω6:ω3 ratio of available lipids. In human nutrition, energy homeostasis may thus benefit from the implementation of a more balanced dietary ω6:ω3 ratio.

Objective: Thermogenic adipocytes (i.e. brown or brite/beige adipocytes) are able to burn large amounts of lipids and carbohydrates as a result of highly active mitochondria and enhanced uncoupled respiration, due to UCP1 activity. Although mitochondria are the key organelles for this thermogenic function, limited human data are available. Methods/results: We characterized changes in the mitochondrial function of human brite adipocytes, using hMADS cells as a model of white- to brite-adipocyte conversion. We found that profound molecular modifications were associated with morphological changes in mitochondria. The fission process was partly driven by the DRP1 protein, which also promoted mitochondrial uncoupling. Conclusion: Our data demonstrate that white-to-brite conversion of human adipocytes relies on molecular, morphological and functional changes in mitochondria, which enable brite/beige cells to carry out thermogenesis. Keywords: hMADS, UCP1, DRP1, Brite/beige adipocyte, Mitochondria

A series of neon seeded JET ELMy H-mode pulses is considered from the modeling as well as from the experimental point of view. For two different Ne seeding rates and two different D puffing gas levels the heating power, Pheat, is in the range 22–29.5 MW. The main focus is on the numerical reconstruction of the total radiated power (which mostly depends on the W concentration) and its distribution between core and divertor and of Zeff (which mostly depends on the Ne concentration). To model self-consistently the core and the SOL two input parameters had to be adjusted case by case: the SOL diffusivity, DSOL, and the core impurity inward pinch, vpinch. DSOL had to be increased with increasing ΓNe and the level of vpinch had to be changed, for any given ΓNe, according to the level of Pheat: it decreases with increasing Pheat. Since the ELM frequency, fELM, is experimentally correlated with Pheat, (it increases with Pheat) the impurity inward pinch can be seen as to depend on fELM. Therefore, to maintain a low vpinch level (i.e. high fELM) ΓNe/Pheat should not exceed a certain threshold, which slightly increases with the ΓD puffing rate. This might lead to a limitation in the viability of reducing the target heat load by Ne seeding at moderate ΓD, while keeping Zeff at acceptably low level. Keywords: Tokamak, Integrated modeling, Core plasma, Edge plasma

Use of new 3-strap ICRF antennas with all-tungsten (W) limiters in ASDEX Upgrade results in a reduction of the W sources at the antenna limiters and of the W content in the confined plasma by at least a factor of 2 compared to the W-limiter 2-strap antennas used in the past. The reduction is observed with a broad range of plasma shapes. In multiple locations of antenna frame, the limiter W source has a minimum when RF image currents are decreased by cancellation of the RF current contributions of the central and the outer straps. In JET with ITER-like wall, ITER-like antenna produces about 20% less of main chamber radiation and of W content compared to the old A2 antennas. However the effect of the A2 antennas on W content is scattered depending on which antennas are powered. Experiments in JET with trace nitrogen (N2) injection show that a presence of active ICRF antenna close to the midplane injection valve has little effect on the core N content, both in dipole and in -90° phasing. This indicates that the effect of ICRF on impurity transport across the scape-off-layer is small in JET compared to the dominant effect on impurity sources leading to increased impurity levels during ICRF operation. Keywords: ICRF, RF sheath, Three-strap, 3-strap, ASDEX Upgrade, JET, ILW, A2 antenna, ILA, Sputtering

Future tokamak reactors of conventional design will require high levels of exhaust power dissipation (more than 90% of the input power) if power densities at the divertor targets are to remain compatible with active cooling. Impurity seeded H-mode discharges in JET-ITER-like Wall (ILW) have reached a maximum radiative fraction (Frad) of ∼75%. Divertor Langmuir probe (LP) measurements in these discharges indicate, however, that less than ∼3% of the thermal plasma power reaches the targets, suggesting a missing channel for power loss. This paper presents experimental evidence from limiter LP for enhanced cross-field particle fluxes on the main chamber walls at high Frad. In H-mode nitrogen-seeded discharges with Frad increasing from ∼30% to up to ∼75%, the main chamber wall particle fluence rises by a factor ∼3 while the divertor plasma fluence drops by one order of magnitude. Contribution of main chamber wall particle losses to detachment, as suggested by EDGE2D-EIRENE modeling, is not sufficient to explain the magnitude of the observed divertor fluence reduction. An intermediate detached case obtained at Frad ∼ 60% with neon seeding is also presented. Heat loads were measured using the main chamber wall thermocouples. Comparison between thermocouple and bolometry measurements shows that the fraction of the input power transported to the main chamber wall remains below ∼5%, whatever the divertor detachment state is. Main chamber sputtering of beryllium by deuterium is reduced in detached conditions only on the low field side. If the fraction of power exhaust dissipated to the main chamber wall by cross-field transport in future reactors is similar to the JET-ILW levels, wall plasma power loading should not be an issue. However, other contributions such as charge exchange may be a problem.

For simulation of plasma-facing component erosion in fusion experiments, an analytical expression for the ion velocity just before the surface impact including the local electric field and an optional surface biasing effect is suggested. Energy and angular impact distributions and the resulting effective sputtering yields were produced for several experimental scenarios at JET ILW mostly involving PFCs exposed to an oblique magnetic field. The analytic solution has been applied as an improvement to earlier ERO modelling of localized, Be outer limiter, RF-enhanced erosion, modulated by toggling of a remote, however magnetically connected ICRH antenna. The effective W sputtering yields due to D and Be ion impact in Type-I and Type-III ELMs and inter-ELM conditions were also estimated using the analytical approach and benchmarked by spectroscopy. The intra-ELM W sputtering flux increases almost 10 times in comparison to the inter-ELM flux. Keywords: Plasma-surface interaction, JET, ITER-like wall, Beryllium, Erosion, Oblique magnetic field, Electric field, ELM

Plasmas in machines with all metal plasma facing components have a lower Zeff, less radiation cooling in the scrape-off layer and divertor regions and are prone to impurity accumulation in the core. Higher gas puff and the seeding of low-Z impurities are applied to prevent impurity accumulation, to increase the frequency of edge localised modes and to cool the divertor. A lower power threshold for the transition from low-confinement mode to high confinement mode has been found in all metal wall machines when compared to carbon wall machines. The application of lithium before or during discharges can lead to ELM free H-modes. The seeding of high-Z impurities increases core radiation, reduces the power flux across the separatrix and, if applied in the right amount, does not lead to deterioration of the confinement. All these effects have in common that they can often be explained by the shape or position of the density profile. Not only the peakedness of the density profile in the core but also the position of the edge pressure gradient influences global confinement. It is shown how (i) ionisation in the pedestal region due to higher reflection of deuterium from high-Z walls, (ii) reduced recycling in consequence of lithium wall conditioning, (iii) the fostering of edge modes with lithium dropping, (iv) increased gas puff and (v) the cooling of the scrape-off layer by medium-Z impurities such as nitrogen affect the edge density profile. The consequence is a shift in the pressure profile relative to the separatrix, leading to improved pedestal stability of H-mode plasmas when the direction is inwards. Keywords: Plasma, Pedestal, Confinement, Wall material, Reflection, Lithium, Edge localised modes, Impurities, Stability

The edge fluid code EDGE2D-EIRENE was used to compare the calculated low field side mid-plane separatrix temperature (Teu, sep) in the presence of seeding impurities with the two point model. The value of Teu, sep and scalings of Teu, sep with the power crossing the separatrix (Psep) are studied. Two scalings of Teu, sep with Psep can be derived from two point model; (1) Teu,sep∝Psep27 which assumes that the power decay length λq is constant and; (2) Teu,sep∝Psep49 which accounts for the λq dependence on Psep and the presence of prescribed diffusive radial transport. A linear scaling between Teu, sep and Psep is observed in the EDGE2D simulations, although the Teu,sep∝Psep49 scaling captures the variation in Teu, sep (in the simulations) for all but highly seeded simulations. This linear dependence (between Teu, sep and Psep) is due to a stronger than linear dependence on the parallel heat flux entering the divertor (q∥, u, sep) on Psep (for a doubling of Psep a factor six variation in q∥, u, sep is observed). Psep is reduced by a factor of two due to the varying impurity radiation inside the separatrix. However, q∥, u, sep reduces more than a factor two because (i) impurity radiation preferentially removes heat flux above the x-point and near the separatrix and (ii) the variation in λq with Psep due to increasing radial diffusive heat flux (Eq. (5.77) Stangeby 2000). The largely varying q∥, u, sep, interestingly, is successfully captured by the power decay length (λq, Eich) calculated by fitting to the target heat flux density. Accounting for the q∥, u, sep variation by using λq, Eich and Psep (both experimentally measurable quantities), an agreement between the two point model equation and the predicted Teu, sep from EDGE2D-EIRENE was obtained. A variation of Teu, sep from approximately 60 eV to 120 eV, for electron separatrix density range of 2−3×1019m−3, was observed. This separatrix temperature variation from EDGE2D is in contrast to a routinely assumed separatrix temperature of 100 eV used for pedestal stability analysis at JET. Keywords: Separatrix temperature, EDGE2D-EIRENE

Objective: In rodents and humans, besides brown adipose tissue (BAT), islands of thermogenic adipocytes, termed “brite” (brown-in-white) or beige adipocytes, emerge within white adipose tissue (WAT) after cold exposure or β3-adrenoceptor stimulation, which may protect from obesity and associated diseases. microRNAs are novel modulators of adipose tissue development and function. The purpose of this work was to characterize the role of microRNAs in the control of brite adipocyte formation. Methods/Results: Using human multipotent adipose derived stem cells, we identified miR-125b-5p as downregulated upon brite adipocyte formation. In humans and rodents, miR-125b-5p expression was lower in BAT than in WAT. In vitro, overexpression and knockdown of miR-125b-5p decreased and increased mitochondrial biogenesis, respectively. In vivo, miR-125b-5p levels were downregulated in subcutaneous WAT and interscapular BAT upon β3-adrenergic receptor stimulation. Injections of an miR-125b-5p mimic and LNA inhibitor directly into WAT inhibited and increased β3-adrenoceptor-mediated induction of UCP1, respectively, and mitochondrial brite adipocyte marker expression and mitochondriogenesis. Conclusion: Collectively, our results demonstrate that miR-125b-5p plays an important role in the repression of brite adipocyte function by modulating oxygen consumption and mitochondrial gene expression. Author Video: Author Video Watch what authors say about their articles Keywords: miR-125b-5p, White adipocyte, Brite adipocyte, Mitochondriogenesis

Objective: Brite adipocytes are inducible energy-dissipating cells expressing UCP1 which appear within white adipose tissue of healthy adult individuals. Recruitment of these cells represents a potential strategy to fight obesity and associated diseases. Methods/Results: Using human Multipotent Adipose-Derived Stem cells, able to convert into brite adipocytes, we show that arachidonic acid strongly inhibits brite adipocyte formation via a cyclooxygenase pathway leading to secretion of PGE2 and PGF2α. Both prostaglandins induce an oscillatory Ca++ signaling coupled to ERK pathway and trigger a decrease in UCP1 expression and in oxygen consumption without altering mitochondriogenesis. In mice fed a standard diet supplemented with ω6 arachidonic acid, PGF2α and PGE2 amounts are increased in subcutaneous white adipose tissue and associated with a decrease in the recruitment of brite adipocytes. Conclusion: Our results suggest that dietary excess of ω6 polyunsaturated fatty acids present in Western diets, may also favor obesity by preventing the “browning” process to take place.

Objective: To evaluate the nationwide implementation of the "Living well with COPD" program by the Swiss Lung Association in various cantons in Switzerland., Methods: For the process evaluation, we used qualitative (interview, focus group) and quantitative (questionnaires, documentation analysis) methods to assess the implementation outcomes reach, dose, fidelity and acceptability. For the effectiveness, we performed a pre-post analysis of patient data collected at baseline and program end (after 14 months)., Results: Seven Cantonal Lung Associations implemented the program into their services according to plan, conducted it 13 times and included 122 COPD patients. Patients' attendance rate was 81% and coaches' fidelity to protocol 94%. Acceptance and satisfaction of all involved persons was high. Integration of the coaches' additional workload, uncertainties regarding roles and responsibilities and sustainable reimbursement were major challenges. Patients significantly improved in COPD specific quality of life and increased exercise capacity with on average 3.2 more repetitions in the 1-minute sit-to-stand test., Conclusion: The program was successfully implemented throughout Switzerland with high acceptability and positive association with patients' quality of life., Practice Implications: Our findings support the broader multiplication throughout Switzerland and serves the international community since it is one of the first nationwide implementations beyond study settings., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)