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Abstract The multivariate temporal response function (mTRF) is an effective tool for investigating the neural encoding of acoustic and complex linguistic features in natural continuous speech. In this study, we investigated how neural representations of speech features derived from natural stimuli are related to early signs of cognitive decline in older adults, taking into account the effects of hearing. Participants without ( $$n = 25$$ n = 25 ) and with ( $$n = 19$$ n = 19 ) early signs of cognitive decline listened to an audiobook while their electroencephalography responses were recorded. Using the mTRF framework, we modeled the relationship between speech input and neural response via different acoustic, segmented and linguistic encoding models and examined the response functions in terms of encoding accuracy, signal power, peak amplitudes and latencies. Our results showed no significant effect of cognitive decline or hearing ability on the neural encoding of acoustic and linguistic speech features. However, we found a significant interaction between hearing ability and the word-level segmentation model, suggesting that hearing impairment specifically affects encoding accuracy for this model, while other features were not affected by hearing ability. These results suggest that while speech processing markers remain unaffected by cognitive decline and hearing loss per se, neural encoding of word-level segmented speech features in older adults is affected by hearing loss but not by cognitive decline. This study emphasises the effectiveness of mTRF analysis in studying the neural encoding of speech and argues for an extension of research to investigate its clinical impact on hearing loss and cognition.

Abstract Root exudates contain specialised metabolites that shape the plant’s root microbiome. How host-specific microbes cope with these bioactive compounds, and how this ability affects root microbiomes, remains largely unknown. We investigated how maize root bacteria metabolise benzoxazinoids, the main specialised metabolites of maize. Diverse and abundant bacteria metabolised the major compound in the maize rhizosphere MBOA (6-methoxybenzoxazolin-2(3H)-one) and formed AMPO (2-amino-7-methoxy-phenoxazin-3-one). AMPO forming bacteria were enriched in the rhizosphere of benzoxazinoid-producing maize and could use MBOA as carbon source. We identified a gene cluster associated with AMPO formation in microbacteria. The first gene in this cluster, bxdA encodes a lactonase that converts MBOA to AMPO in vitro. A deletion mutant of the homologous bxdA genes in the genus Sphingobium, did not form AMPO nor was it able to use MBOA as a carbon source. BxdA was identified in different genera of maize root bacteria. Here we show that plant-specialised metabolites select for metabolisation-competent root bacteria. BxdA represents a benzoxazinoid metabolisation gene whose carriers successfully colonize the maize rhizosphere and thereby shape the plant’s chemical environmental footprint.

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.

Abstract Chronic hepatitis B (CHB) is a major global health challenge. CHB can be controlled by antivirals but a therapeutic cure is lacking. CHB is characterized by limited HBV-specific T cell reactivity and functionality and expression of inhibitory receptors. The mechanisms driving these T cell phenotypes are only partially understood. Here, we created a single-cell RNA-sequencing dataset of HBV immune responses in patients to contribute to a better understanding of the dysregulated immunity. Blood samples of a well-defined cohort of 21 CHB and 10 healthy controls, including a subset of 5 matched liver biopsies, were collected. scRNA-seq data of total immune cells (55,825) plus sorted HBV-specific (1,963), non-naive (32,773) and PD1+ T cells (96,631) was generated using the 10X Genomics platform (186,123 cells) or the full-length Smart-seq2 protocol (1,069 cells). The shared transcript count matrices of single-cells serve as a valuable resource describing transcriptional changes underlying dysfunctional HBV-related T cell responses in blood and liver tissue and offers the opportunity to identify targets or biomarkers for HBV-related immune exhaustion.

BackgroundMultiple Sclerosis (MS) is a common neurological disease among white populations of European origin. Frequencies among Latin Americans continue to be studied, however, epidemiologic, and clinical characterization studies lack from Central American and Caribbean countries. Ethnicity in these countries is uniformly similar with a prevalent Mestizo population.Methods and resultsData from January 2014 to December 2019 from Guatemala, El Salvador, Honduras, Nicaragua, Costa Rica, Panama, Dominican Republic, and Aruba on demographic, clinical, MRI and phenotypic traits were determined in coordinated studies: ENHANCE, a population-based, retrospective, observational study on incidence and clinical characteristics, and from the subgroup with MS national registries (Aruba, Dominican Republic, Honduras, and Panama), data on prevalence, phenotypes and demographics. Expanded Disability Status Scale (EDSS), and therapeutic schemes were included. ENHANCE data from 758 patients disclosed 79.8% of Mestizo ethnicity; 72.4% female; median age at onset 31.0 years and 33.2 at diagnosis. The highest incidence rate was from Aruba, 2.3–3.5 × 100,000 inhabitants, and the lowest, 0.07–0.15 × 100,000, from Honduras. Crude prevalence rates per 100,000 inhabitants fluctuated from 27.3 (Aruba) to 1.0 (Honduras). Relapsing MS accounted for 87.4% of cases; EDSS

Torpor or heterothermy is an energy‐saving mechanism used by endotherms to overcome harsh environmental conditions. During winter, the garden dormouse (Eliomys quercinus) hibernates with multiday torpor bouts and body temperatures of a few degrees Celsius, interrupted by brief euthermic phases. This study investigates gene expression within the hypothalamus, the key brain area controlling energy balance, adding information on differential gene expression potentially relevant to orchestrate torpor. A de novo assembled transcriptome of the hypothalamus was generated from garden dormice hibernating under constant darkness without food and water at 5 °C. Samples were collected during early torpor, late torpor, and interbout arousal. During early torpor, 765 genes were differentially expressed as compared with interbout arousal. Twenty‐seven pathways were over‐represented, including pathways related to hemostasis, extracellular matrix organization, and signaling of small molecules. Only 82 genes were found to be differentially expressed between early and late torpor, and no pathways were over‐represented. During late torpor, 924 genes were differentially expressed relative to interbout arousal. Despite the high number of differentially expressed genes, only 10 pathways were over‐represented. Of these, eight were also observed to be over‐represented when comparing early torpor and interbout arousal. Our results are largely consistent with previous findings in other heterotherms. The addition of a transcriptome of a novel species may help to identify species‐specific and overarching torpor mechanisms through future species comparisons.

Abstract The consensus molecular subtypes (CMS) of colorectal cancer (CRC) is the most widely-used gene expression-based classification and has contributed to a better understanding of disease heterogeneity and prognosis. Nevertheless, CMS intratumoral heterogeneity restricts its clinical application, stressing the necessity of further characterizing the composition and architecture of CRC. Here, we used Spatial Transcriptomics (ST) in combination with single-cell RNA sequencing (scRNA-seq) to decipher the spatially resolved cellular and molecular composition of CRC. In addition to mapping the intratumoral heterogeneity of CMS and their microenvironment, we identified cell communication events in the tumor-stroma interface of CMS2 carcinomas. This includes tumor growth-inhibiting as well as -activating signals, such as the potential regulation of the ETV4 transcriptional activity by DCN or the PLAU-PLAUR ligand-receptor interaction. Our study illustrates the potential of ST to resolve CRC molecular heterogeneity and thereby help advance personalized therapy.

Problems in understanding speech in noisy environments are characteristic for age-related hearing loss. Since hearing aids do not mitigate these communication problems in every case, potential alternatives in a clinical rehabilitation plan need to be explored. This study investigates whether a computer-based speechreading training improves audiovisual speech perception in noise in a sample of middle-aged and older adults (N = 62, 47-83 years) with 32 participants completing a speechreading training and 30 participants of an active control group completing a foreign language training. Before and after training participants performed a speech-in-noise task mimicking real-life communication settings with participants being required to answer a speaker's questions. Using generalized linear mixed-effects models we found a significant improvement in audiovisual speech perception in noise in the speechreading training group. This is of great relevance as these results highlight the potential of a low-cost and easy-to-implement intervention for a profound and widespread problem as speech-in-noise comprehension impairment.

Hibernation is a period of metabolic suppression utilized by many small and large mammal species to survive during winter periods. As the underlying cellular and molecular mechanisms remain incompletely understood, our study aimed to determine whether skeletal muscle myosin and its metabolic efficiency undergo alterations during hibernation to optimize energy utilization. We isolated muscle fibers from small hibernators, Ictidomys tridecemlineatus and Eliomys quercinus and larger hibernators, Ursus arctos and Ursus americanus. We then conducted loaded Mant-ATP chase experiments alongside X-ray diffraction to measure resting myosin dynamics and its ATP demand. In parallel, we performed multiple proteomics analyses. Our results showed a preservation of myosin structure in U. arctos and U. americanus during hibernation, whilst in I. tridecemlineatus and E. quercinus, changes in myosin metabolic states during torpor unexpectedly led to higher levels in energy expenditure of type II, fast-twitch muscle fibers at ambient lab temperatures (20 °C). Upon repeating loaded Mant-ATP chase experiments at 8 °C (near the body temperature of torpid animals), we found that myosin ATP consumption in type II muscle fibers was reduced by 77–107% during torpor compared to active periods. Additionally, we observed Myh2 hyper-phosphorylation during torpor in I. tridecemilineatus, which was predicted to stabilize the myosin molecule. This may act as a potential molecular mechanism mitigating myosin-associated increases in skeletal muscle energy expenditure during periods of torpor in response to cold exposure. Altogether, we demonstrate that resting myosin is altered in hibernating mammals, contributing to significant changes to the ATP consumption of skeletal muscle. Additionally, we observe that it is further altered in response to cold exposure and highlight myosin as a potentially contributor to skeletal muscle non-shivering thermogenesis.

Seasonal animal dormancy is widely interpreted as a physiological response for surviving energetic challenges during the harshest times of the year (the physiological constraint hypothesis). However, there are other mutually non-exclusive hypotheses to explain the timing of animal dormancy, that is, entry into and emergence from hibernation (i.e. dormancy phenology). Survival advantages of dormancy that have been proposed are reduced risks of predation and competition (the ‘life-history’ hypothesis), but comparative tests across animal species are few. Using the phylogenetic comparative method applied to more than 20 hibernating mammalian species, we found support for both hypotheses as explanations for the phenology of dormancy. In accordance with the life-history hypotheses, sex differences in hibernation emergence and immergence were favored by the sex difference in reproductive effort. In addition, physiological constraint may influence the trade-off between survival and reproduction such that low temperatures and precipitation, as well as smaller body mass, influence sex differences in phenology. We also compiled initial evidence that ectotherm dormancy may be (1) less temperature dependent than previously thought and (2) associated with trade-offs consistent with the life-history hypothesis. Thus, dormancy during non-life-threatening periods that are unfavorable for reproduction may be more widespread than previously thought.

The increasing use of chemicals requires a better understanding of their presence and dynamics in the environment, as well as their impact on ecosystems. The aim of this study was to validate the first steps of an innovative multi-omics approach based on metabolomics and 16S metabarcoding data for analyses of the fate and impact of contaminants in Mediterranean lagoons. Semi-targeted analytical procedures for water and sediment matrices were implemented to assess chemical contamination of the lagoon: forty-six compounds were detected, 28 of which could be quantified in water (between 0.09 and 47.4 ng/L) and sediment (between 0.008 and 26.3 ng/g) samples using the UHPLC-MS/MS instrument. In addition, a non-targeted approach (UHPLC-HRMS) using four different sample preparation protocols based on solid/liquid extractions or an automated pressurized fluid extraction system (EDGE®) was carried out to determine the protocol with the best metabolome coverage, efficiency and reproducibility. Solid/liquid extraction using the solvent mixture acetonitrile/methanol (50/50) was evaluated as the best protocol. Microbial diversity in lagoon sediment was also measured after DNA extraction using five commercial extraction kits. Our study showed that the DNeasy PowerSoil Pro Qiagen kit (Promega, USA) was the most suitable for assessing microbial diversity in fresh sediment.

Abstract Background Despite centuries of research, debate remains on the scaling of metabolic rate to mass especially for intraspecific cases. The high variation of body mass within brown bears presents a unique opportunity to study the intraspecific effects of body mass on physiological variables. The amplitude of metabolic rate reduction in hibernators is dependent on body mass of the species. Small hibernators have high metabolic rates when euthermic but experience a drastic decrease in body temperature during torpor, which is necessary to reach a very low metabolic rate. Conversely, large hibernators, such as the brown bear (Ursus arctos), show a moderate decrease in temperature during hibernation, thought to be related to the bear’s large size. We studied body mass, abdominal body temperature, heart rate, and accelerometer-derived activity from 63 free-ranging brown bears (1–15 years old, 15–233 kg). We tested for relationships between body mass and body temperature, heart rate, and hibernation duration. Results The smallest individuals maintained lower body temperatures during hibernation, hibernated longer, and ended hibernation later than large bears. Unlike body temperature, winter heart rates were not associated with body mass. In summer, the opposite pattern was found, with smaller individuals having higher body temperature and daytime heart rates. Body mass was associated with body temperature in the winter hypometabolic state, even in a large hibernating mammal. Smaller bears, which are known to have higher thermal conductance, reached lower body temperatures during hibernation. During summer, smaller bears had higher body temperatures and daytime heart rates, a phenomenon not previously documented within a single mammalian species. Conclusion We conclude that the smallest bears hibernated more deeply and longer than large bears, likely from a combined effect of basic thermodynamics, the higher need for energy savings, and a lower cost of warming up a smaller body.

Abstract Background Torpor is an energy saving strategy achieved by substantial reductions of metabolic rate and body temperature that enables animals to survive periods of low resource availability. During hibernation (multiday torpor), the frequency of periodic rewarming—characterised by high levels of oxidative stress—is associated with shortening of telomeres, a marker of somatic maintenance. Objectives In this study, we determined the impact of ambient temperature on feeding behaviour and telomere dynamics in hibernating garden dormice (Eliomys quercinus) over winter. This obligate hibernator prepares for hibernation by accumulating fat stores but can also feed during hibernation. Methodology Food intake, torpor pattern, changes in telomere length, and body mass change were assessed in animals housed at experimentally controlled temperatures of either 14 °C (i.e., a mild winter) or 3 °C (i.e., a cold winter) over 6 months. Results When hibernating at 14 °C, dormice experienced 1.7-fold more frequent and 2.4-fold longer inter-bout euthermia, and spent significantly less time torpid, compared to animals hibernating at 3 °C. Higher food intake enabled individuals to compensate for increased energetic costs when hibernating at milder temperatures (14 °C vs. 3 °C), to buffer body mass loss and thus increase winter survival. Interestingly, we observed a significant increase of telomere length over the entire hibernation period, irrespective of temperature treatment. Conclusion We conclude that higher temperatures during winter, if associated with sufficient food availability, can have a positive effect on the individual’s energy balance and somatic maintenance. These results suggest that winter food availability might be a crucial determinant for the survival of the garden dormouse in the context of ever-increasing environmental temperatures.

Telomere dynamics in hibernating species are known to reflect seasonal changes in somatic maintenance. Throughout hibernation, the periodic states of rewarming, known as inter-bout euthermia or arousals, are associated with high metabolic costs including shortening of telomeres. In the active season, if high energetic resources are available, telomere length can be restored in preparation for the upcoming winter. The mechanism for telomere elongation has not been clearly demonstrated, although the action of the ribonucleoprotein complex, telomerase, has been implicated in many species. Here we tested for levels of telomerase activity in the garden dormouse (Eliomys quercinus) at different seasonal time points throughout the year and across ages from liver tissues of male juveniles to adults. We found that telomerase is active at high levels across seasons (during torpor and inter-bout euthermia, plus in the active season) but that there was a substantial decrease in activity in the month prior to hibernation. Telomerase levels were consistent across age groups and were independent of feeding regime and time of birth (early or late born). The changes in activity levels that we detected were broadly associated with changes in telomere lengths measured in the same tissues. We hypothesise that i) telomerase is the mechanism used by garden dormice for maintenance of telomeres and that ii) activity is kept at high levels throughout the year until pre-hibernation when resources are diverted to increasing fat reserves for overwintering. We found no evidence for a decrease in telomerase activity with age or a final increase in telomere length which has been detected in other hibernating rodents.

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.

Tokamak à configuration variable (TCV), recently celebrating 30 years of near-continual operation, continues in its missions to advance outstanding key physics and operational scenario issues for ITER and the design of future power plants such as DEMO. The main machine heating systems and operational changes are first described. Then follow five sections: plasma scenarios. ITER Base-Line (IBL) discharges, triangularity studies together with X3 heating and N2 seeding. Edge localised mode suppression, with a high radiation region near the X-point is reported with N _2 injection with and without divertor baffles in a snowflake configuration. Negative triangularity (NT) discharges attained record, albeit transient, β _N ∼ 3 with lower turbulence, higher low-Z impurity transport, vertical stability and density limits and core transport better than the IBL. Positive triangularity L-Mode linear and saturated ohmic confinement confinement saturation, often-correlated with intrinsic toroidal rotation reversals, was probed for D, H and He working gases. H-mode confinement and pedestal studies were extended to low collisionality with electron cyclotron heating obtaining steady state electron iternal transport barrier with neutral beam heating (NBH), and NBH driven H-mode configurations with off-axis co-electron cyclotron current drive. Fast particle physics. The physics of disruptions, runaway electrons and fast ions (FIs) was developed using near-full current conversion at disruption with recombination thresholds characterised for impurity species (Ne, Ar, Kr). Different flushing gases (D2, H2) and pathways to trigger a benign disruption were explored. The 55 kV NBH II generated a rich Alfvénic spectrum modulating the FI fas ion loss detector signal. NT configurations showed less toroidal Alfvén excitation activity preferentially affecting higher FI pitch angles. Scrape-off layer and edge physics. gas puff imaging systems characterised turbulent plasma ejection for several advanced divertor configurations, including NT. Combined diagnostic array divertor state analysis in detachment conditions was compared to modelling revealing an importance for molecular processes. Divertor physics. Internal gas baffles diversified to include shorter/longer structures on the high and/or low field side to probe compressive efficiency. Divertor studies concentrated upon mitigating target power, facilitating detachment and increasing the radiated power fraction employing alternative divertor geometries, optimised X-point radiator regimes and long-legged configurations. Smaller-than-expected improvements with total flux expansion were better modelled when including parallel flows. Peak outer target heat flux reduction was achieved (>50%) for high flux-expansion geometries, maintaining core performance ( H _98 > 1). A reduction in target heat loads and facilitated detachment access at lower core densities is reported. Real-time control. TCV’s real-time control upgrades employed MIMO gas injector control of stable, robust, partial detachment and plasma β feedback control avoiding neoclassical tearing modes with plasma confinement changes. Machine-learning enhancements include trajectory tracking disruption proximity and avoidance as well as a first-of-its-kind reinforcement learning-based controller for the plasma equilibrium trained entirely on a free-boundary simulator. Finally, a short description of TCV’s immediate future plans will be given.

Within the 9th European Framework programme, since 2021 EUROfusion is operating five tokamaks under the auspices of a single Task Force called ‘Tokamak Exploitation’. The goal is to benefit from the complementary capabilities of each machine in a coordinated way and help in developing a scientific output scalable to future largre machines. The programme of this Task Force ensures that ASDEX Upgrade, MAST-U, TCV, WEST and JET (since 2022) work together to achieve the objectives of Missions 1 and 2 of the EUROfusion Roadmap: i) demonstrate plasma scenarios that increase the success margin of ITER and satisfy the requirements of DEMO and, ii) demonstrate an integrated approach that can handle the large power leaving ITER and DEMO plasmas. The Tokamak Exploitation task force has therefore organized experiments on these two missions with the goal to strengthen the physics and operational basis for the ITER baseline scenario and for exploiting the recent plasma exhaust enhancements in all four devices (PEX: Plasma EXhaust) for exploring the solution for handling heat and particle exhaust in ITER and develop the conceptual solutions for DEMO. The ITER Baseline scenario has been developed in a similar way in ASDEX Upgrade, TCV and JET. Key risks for ITER such as disruptions and run-aways have been also investigated in TCV, ASDEX Upgrade and JET. Experiments have explored successfully different divertor configurations (standard, super-X, snowflakes) in MAST-U and TCV and studied tungsten melting in WEST and ASDEX Upgrade. The input from the smaller devices to JET has also been proven successful to set-up novel control schemes on disruption avoidance and detachment.

In 2021 JET exploited its unique capabilities to operate with T and D–T fuel with an ITER-like Be/W wall (JET-ILW). This second major JET D–T campaign (DTE2), after DTE1 in 1997, represented the culmination of a series of JET enhancements—new fusion diagnostics, new T injection capabilities, refurbishment of the T plant, increased auxiliary heating, in-vessel calibration of 14 MeV neutron yield monitors—as well as significant advances in plasma theory and modelling in the fusion community. DTE2 was complemented by a sequence of isotope physics campaigns encompassing operation in pure tritium at high T-NBI power. Carefully conducted for safe operation with tritium, the new T and D–T experiments used 1 kg of T (vs 100 g in DTE1), yielding the most fusion reactor relevant D–T plasmas to date and expanding our understanding of isotopes and D–T mixture physics. Furthermore, since the JET T and DTE2 campaigns occurred almost 25 years after the last major D–T tokamak experiment, it was also a strategic goal of the European fusion programme to refresh operational experience of a nuclear tokamak to prepare staff for ITER operation. The key physics results of the JET T and DTE2 experiments, carried out within the EUROfusion JET1 work package, are reported in this paper. Progress in the technological exploitation of JET D–T operations, development and validation of nuclear codes, neutronic tools and techniques for ITER operations carried out by EUROfusion (started within the Horizon 2020 Framework Programme and continuing under the Horizon Europe FP) are reported in (Litaudon et al Nucl. Fusion accepted), while JET experience on T and D–T operations is presented in (King et al Nucl. Fusion submitted).

Recent results from MAST Upgrade are presented, emphasising understanding the capabilities of this new device and deepening understanding of key physics issues for the operation of ITER and the design of future fusion power plants. The impact of MHD instabilities on fast ion confinement have been studied, including the first observation of fast ion losses correlated with Compressional and Global Alfvén Eigenmodes. High-performance plasma scenarios have been developed by tailoring the early plasma current ramp phase to avoid internal reconnection events, resulting in a more monotonic q profile with low central shear. The impact of m / n = 3/2, 2/1 and 1/1 modes on thermal plasma confinement and rotation profiles has been quantified, and scenarios optimised to avoid them have transiently reached values of normalised beta approaching 4.2. In pedestal and ELM physics, a maximum pedestal top temperature of ∼350 eV has been achieved, exceeding the value achieved on MAST at similar heating power. Mitigation of type-I ELMs with n = 1 RMPs has been observed. Studies of plasma exhaust have concentrated on comparing conventional and Super-X divertor configurations, while X-point target, X-divertor and snowflake configurations have been developed and studied in parallel. In L-mode discharges, the separatrix density required to detach the outer divertors is approximately a factor 2 lower in the Super-X than the conventional configuration, in agreement with simulations. Detailed analysis of spectroscopy data from studies of the Super-X configuration reveal the importance of including plasma-molecule interactions and D _2 Fulcher band emission to properly quantify the rates of ionisation, plasma-molecule interactions and volumetric recombination processes governing divertor detachment. In H-mode with conventional and Super-X configurations, the outer divertors are attached in the former and detached in the latter with no impact on core or pedestal confinement.

JET, the world’s largest operating tokamak with unique Be/W wall and tritium handling capability, completed a Deuterium-Tritium (D-T) campaign in 2021 (Maggi et al 29th Fusion Energy Conf. ) following a decade of preparatory experiments, dedicated enhancements, technical rehearsals and training (Horton et al 2016 Fusion Eng. Des. 109–111 925). Operation with tritium raises significant technical, safety and scientific challenges not encountered in standard protium or deuterium operation. This contribution describes the tritium operational requirements, pulses and technical preparations, new operating procedures, lessons learned and details on the achieved operational availability and performance. The preparation and execution of the recent JET tritium experiments benefitted from the previous experience in 1991 (Preliminary Tritium Experiment), 1997 (DTE1 campaign) and 2003 (Trace Tritium Campaigns) and consisted of the following five phases: technical rehearsals and scenario preparation, tritium commissioning, 100% tritium campaign, D-T campaign (DTE2), tritium clean-up. Following the clean-up JET resumed normal operation and is currently undertaking a further D-T campaign (DTE3).

This paper reports the first experiment carried out in deuterium–tritium addressing the integration of a radiative divertor for heat-load control with good confinement. Neon seeding was carried out for the first time in a D–T plasma as part of the second D–T campaign of JET with its Be/W wall environment. The technical difficulties linked to the re-ionisation heat load are reported in T and D–T. This paper compares the impact of neon seeding on D–T plasmas and their D counterpart on the divertor detachment, localisation of the radiation, scrape-off profiles, pedestal structure, edge localised modes and global confinement.

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.

Introduction The ongoing ageing population is associated with an increase in the number of patients suffering a stroke, transient ischaemic attack (TIA) or myocardial infarction (MI). In these patients, implementing secondary prevention is a critical challenge and new strategies need to be developed to close the gap between clinical practice and evidence-based recommendations. We describe the protocol of a randomised clinical trial that aims to evaluate the efficiency and effectiveness of an intensive multidisciplinary follow-up of patients compared with standard care.Methods and analysis The DiVa study is a randomised, prospective, controlled, multicentre trial including patients >18 years old with a first or recurrent stroke (ischaemic or haemorrhagic) or TIA, or a type I or II MI, managed in one of the participating hospitals of the study area, with a survival expectancy >12 months. Patients will be randomised with an allocation ratio of 1:1 in two parallel groups: one group assigned to a multidisciplinary, nurse-based and pharmacist-based 2-year follow-up in association with general practitioners, neurologists and cardiologists versus one group with usual follow-up. In each group for each disease (stroke/TIA or MI), 430 patients will be enrolled (total of 1720 patients) over 3 years. The primary outcome will be the incremental cost–utility ratio at 24 months between intensive and standard follow-up in a society perspective. Secondary outcomes will include the incremental cost–utility ratio at 6 and 12 months, the incremental cost-effectiveness ratio at 24 months, reduction at 6, 12 and 24 months of the rates of death, unscheduled rehospitalisation and iatrogenic complications, changes in quality of life, net budgetary impact at 5 years of the intensive follow-up on the national health insurance perspective and analysis of factors having positive or negative effects on the implementation of the project in the study area.Ethics and dissemination Ethical approval was obtained and all patients receive information about the study and give their consent to participate before randomisation. Results of the main trial and each of the secondary analyses will be submitted for publication in a peer-reviewed journal.Trial registration number ClinicalTrials.gov Identifier: NCT04188457. Registered on 6 December 2019.

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.

Abstract The causes of the neurodegenerative processes in Alzheimer's disease (AD) are not completely known. Recent studies have shown that white matter (WM) damage could be more severe and widespread than whole‐brain cortical atrophy and that such damage may appear even before the damage to the gray matter (GM). In AD, Amyloid‐beta (Aβ42) and tau proteins could directly affect WM, spreading across brain networks. Since hippocampal atrophy is common in the early phase of disease, it is reasonable to expect that hippocampal volume (HV) might be also related to WM integrity. Our study aimed to evaluate the integrity of the whole‐brain WM, through diffusion tensor imaging (DTI) parameters, in mild AD and amnestic mild cognitive impairment (aMCI) due to AD (with Aβ42 alteration in cerebrospinal fluid [CSF]) in relation to controls; and possible correlations between those measures and the CSF levels of Aβ42, phosphorylated tau protein (p‐Tau) and total tau (t‐Tau). We found a widespread WM alteration in the groups, and we also observed correlations between p‐Tau and t‐Tau with tracts directly linked to mesial temporal lobe (MTL) structures (fornix and hippocampal cingulum). However, linear regressions showed that the HV better explained the variation found in the DTI measures (with weak to moderate effect sizes, explaining from 9% to 31%) than did CSF proteins. In conclusion, we found widespread alterations in WM integrity, particularly in regions commonly affected by the disease in our group of early‐stage disease and patients with Alzheimer's disease. Nonetheless, in the statistical models, the HV better predicted the integrity of the MTL tracts than the biomarkers in CSF.

Hot thermal fluids flow through the Earth's crust and carry valuable information about the deep subsurface. The monitoring of natural tracers transported in geothermal fluids, such as gases or ions, are relevant to better understand the geological processes in the Earth's subsurface and their relation to deep fluid dynamics. Recently developed technologies (e.g., portable gas-equilibrium membrane-inlet mass spectrometry) allow for the continuous monitoring of gas species at a much higher temporal resolution than the sampling procedures commonly used, based on a few individual samples. However, the monitoring of gas species from hot thermal fluids still poses experimental challenges tied to unwanted water vapor condensation in the headspace of the separation module, which irremediably leads to clogging (e.g., of the connecting capillaries) and failure of the detection device. In this contribution, we present two new experimental methods that provide suitable technical conditions to measure gases, even in high temperature geothermal fluids, using a portable gas analyzer. Two sites with different thermal water temperatures (first one ranging from 50 °C to 65 °C and second one close to boiling temperature) were selected. The first method was deployed on the thermal waters of Lavey-les-Bains (Vaud, Switzerland), for which we report results from October 2021. The second method was used in Beppu (Oita Prefecture, Japan), for which we report results from April 2018. Our results show that at both sites, our methods allow for continuous measurements of gas species (N2, Ar, O2, Kr, He, CH4, CO2 and H2) in thermal waters. Furthermore, they show that the variability of gas emanation from the two sites can only be adequately described by measurements with high temporal resolution, which both methods allow.

Animal models are a key component of translational medicine, helping transfer scientific findings into practical applications for human health. A fundamental principle of research ethics involves weighing the benefits of the research to society against the burden imposed on the animals used for scientific purposes. The utilisation of wild animals for research requires evaluation of the effects of capture and invasive sampling. Determining the severity and duration of these interventions on the animal’s physiology and behaviour allows for refining study methodology and for excluding or accounting for biased data. In this study, 39 Scandinavian brown bears (Ursus arctos) captured either while hibernating in winter or via helicopter in summer and that underwent surgery as part of a human health project had their movement, body temperature and timing of onset of hibernation compared with those of 14 control bears that had not been captured during the same period. Bears captured in winter and summer showed decreased movement from den exit until late summer, compared to those in the control group. Bears captured in summer showed reduced movement and body temperature for at least, respectively, 14 and 3 days, with an 11% decrease in hourly distance, compared to pre-capture levels, but did not differ in the timing of hibernation onset. We reveal that brown bear behaviour and physiology can be altered in response to capture and surgery for days to months, post-capture. This has broad implications for the conclusions of wildlife studies that rely upon invasive sampling.

Factors for initiating hibernation are unknown, but the condition shares some metabolic similarities with consciousness/sleep, which has been associated with n-3 fatty acids in humans. We investigated plasma phospholipid fatty acid profiles during hibernation and summer in free-ranging brown bears (Ursus arctos) and in captive garden dormice (Eliomys quercinus) contrasting in their hibernation patterns. The dormice received three different dietary fatty acid concentrations of linoleic acid (LA) (19%, 36% and 53%), with correspondingly decreased alpha-linolenic acid (ALA) (32%, 17% and 1.4%). Saturated and monounsaturated fatty acids showed small differences between summer and hibernation in both species. The dormice diet influenced n-6 fatty acids and eicosapentaenoic acid (EPA) concentrations in plasma phospholipids. Consistent differences between summer and hibernation in bears and dormice were decreased ALA and EPA and marked increase of n-3 docosapentaenoic acid and a minor increase of docosahexaenoic acid in parallel with several hundred percent increase of the activity index of elongase ELOVL2 transforming C20-22 fatty acids. The highest LA supply was unexpectantly associated with the highest transformation of the n-3 fatty acids. Similar fatty acid patterns in two contrasting hibernating species indicates a link to the hibernation phenotype and requires further studies in relation to consciousness and metabolism.

Abstract Introduction The paper examines the discrimination of lexical stress contrasts in a foreign language from a neural perspective. The aim of the study was to identify the areas associated with word stress processing (in comparison with vowel processing), when listeners of a fixed‐stress language have to process stress in a foreign free‐stress language. Methods We asked French‐speaking participants to process stress and vowel contrasts in Spanish, a foreign language that the participants did not know. Participants performed a discrimination task on Spanish word pairs differing either with respect to word stress (penultimate or final stressed word) or with respect to the final vowel while functional magnetic resonance imaging data was acquired. Results Behavioral results showed lower accuracy and longer reaction times for discriminating stress contrasts than vowel contrasts. The contrast Stress > Vowel revealed an increased bilateral activation of regions shown to be associated with stress processing (i.e., supplementary motor area, insula, middle/superior temporal gyrus), as well as a stronger involvement of areas related to more domain‐general cognitive control functions (i.e., bilateral inferior frontal gyrus). The contrast Vowel > Stress showed an increased activation in regions typically associated with the default mode network (known for decreasing its activity during attentionally more demanding tasks). Conclusion When processing Spanish stress contrasts as compared to processing vowel contrasts, native listeners of French activated to a higher degree anterior networks including regions related to cognitive control. They also show a decrease in regions related to the default mode network. These findings, together with the behavioral results, reflect the higher cognitive demand, and therefore, the larger difficulties, for French‐speaking listeners during stress processing as compared to vowel processing.

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.