Strongly driven ion-scale turbulence in tokamak plasmas is shown to be regulated by a new propagating zonal flow mode, the toroidal secondary mode, which is nonlinearly supported by the turbulence. The mode grows and propagates due to the combined effects of zonal flow shearing and advection by the magnetic drift. Above a threshold in the turbulence level, small-scale toroidal secondary modes become unstable and shear apart turbulent eddies, forcing the turbulence level to remain near the threshold. This threshold condition is used to derive scaling laws for the turbulent heat flux, fluctuation spectra, and zonal flow amplitude, which are validated in nonlinear gyrokinetic simulations and explain previous experimental observations.

Starting from the assumption that saturation of plasma turbulence driven by temperature-gradient instabilities in fusion plasmas is achieved by a local energy cascade between a long-wavelength outer scale, where energy is injected into the fluctuations, and a small-wavelength dissipation scale, where fluctuation energy is thermalised by particle collisions, we formulate a detailed phenomenological theory for the influence of perpendicular flow shear on magnetised-plasma turbulence. Our theory introduces two distinct regimes, called the weak-shear and strong-shear regimes, each with its own set of scaling laws for the scale and amplitude of the fluctuations and for the level of turbulent heat transport. We discover that the ratio of the typical radial and poloidal wavenumbers of the fluctuations (i.e., their aspect ratio) at the outer scale plays a central role in determining the dependence of the turbulent transport on the imposed flow shear. Our theoretical predictions are found to be in excellent agreement with numerical simulations of two paradigmatic models of fusion-relevant plasma turbulence: (i) an electrostatic fluid model of slab electron-scale turbulence, and (ii) Cyclone-base-case gyrokinetic ion-scale turbulence. Additionally, our theory envisions a potential mechanism for the suppression of electron-scale turbulence by perpendicular ion-scale flows based on the role of the aforementioned aspect ratio of the electron-scale fluctuations.

Collisions between particles in a low density plasma are described by the Fokker-Planck collision operator. In applications, this nonlinear integro-differential operator is often approximated by linearised or ad-hoc model operators due to computational cost and complexity. In this work, we present an implementation of the nonlinear Fokker-Planck collision operator written in terms of Rosenbluth potentials in the Rosenbluth-MacDonald-Judd (RMJ) form. The Rosenbluth potentials may be obtained either by direct integration or by solving partial differential equations (PDEs) similar to Poisson's equation: we optimise for performance and scalability by using sparse matrices to solve the relevant PDEs. We represent the distribution function using a tensor-product continuous-Galerkin finite-element representation and we derive and describe the implementation of the weak form of the collision operator. We present tests demonstrating a successful implementation using an explicit time integrator and we comment on the speed and accuracy of the operator. Finally, we speculate on the potential for applications in the current and next generation of kinetic plasma models.

Efficient control of turbulent heat transport is crucial for magnetic confinement fusion reactors. This work discusses the complex interplay between density gradients and micro-instabilities, shedding light on their impact on turbulent heat transport in different fusion devices. In particular, the influence of density gradients on turbulent heat transport is investigated through an extensive inter-machine study, including various stellarators such as W7-X, LHD, TJ-II and NCSX, along with the Asdex-Upgrade tokamak and the tokamak geometry of the Cyclone Base Case (CBC). Linear and nonlinear simulations are performed employing the $\delta$f-gyrokinetic code stella across a wide range of parameters to explore the effects of density gradients, temperature gradients, and kinetic electrons. A strong reduction in ion heat flux with increasing density gradients is found in NCSX and W7-X due to the stabilization of temperature-gradient-driven modes without significantly destabilizing density-gradient-driven modes. In contrast, the tokamaks exhibit an increase in ion heat flux with density gradients. Notably, the behavior of ion heat fluxes in stellarators does not align with that of linear growth rates. Additionally, this study provides physical insights into the micro-instabilities, emphasizing the dominance of trapped-electron-modes in CBC, AUG, TJ-II, LHD and NCSX, while both the trapped-electron-mode and the passing-particle-driven universal instability contribute significantly in W7-X.

OBJECTIVES:Sjögren's disease (SjD) is clinically and biologically heterogeneous, and no immunomodulatory drug has yet demonstrated efficacy in phase 3 trials. We previously identified 4 transcriptomic endotypes in SjD patients using whole-blood RNA sequencing. We hypothesised that these endotypes may predict differential therapeutic responses. METHODS:We analysed clinical, biological, and transcriptomic data from 3 randomised controlled trials evaluating hydroxychloroquine-leflunomide (HCQ-LEF; n = 18; RepurpSS-I trial), rituximab (RTX; n = 56; TRACTISS trial), and abatacept (n = 117). Patients were assigned to the 4 endotypes using semisupervised uniform manifold approximation and projection combined with a support vector machine model. Demographics, disease activity, and therapeutic response, as defined by the Sjögren Tool for Assessing Response index, were compared across clusters in both pooled and individual trial analyses. RESULTS:Of 170 patients, 81, 24, 80, and 6 were classified into clusters 1 to 4, respectively. European Alliance of Associations for Rheumatology (EULAR) Sjögren's Syndrome Patient Reported Index scores were comparable across clusters, while the EULAR Sjögren's Syndrome Disease Activity Index was significantly higher in clusters 3 and 4 vs clusters 1 and 2 (P = .003). In pooled analyses, patients in cluster 1 had significantly greater response rates with active treatment vs placebo (61.5% vs 32.6%: P = .016), with a similar trend in the RTX trial. In contrast, patients in cluster 3 benefitted from HCQ-LEF, whereas cluster 2 (healthy-like patients) showed no significant response to any therapy. CONCLUSIONS:Transcriptomic stratification of SjD patients revealed differential responses to HCQ-LEF and RTX. Notably, healthy-like patients exhibited minimal treatment response, suggesting they may be unsuitable candidates for future therapeutic trials.

The thermal fluctuation spectrum of the electric field arising due to particle noise in a quiescent Vlasov-Poisson plasma was derived in the 1960s. Here, we derive the universal fluctuation spectrum of the electric field, at Debye and sub-Debye scales, for a turbulent Vlasov-Poisson plasma. This spectrum arises from what is likely to be the final cascade - a universal regime to be encountered at the extreme small-scale end of any turbulent cascade in a nearly collisionless plasma. The cascaded invariant is $C_2$, the quadratic Casimir invariant of the particle distribution function. $C_2$ cascades to small scales in position and velocity space via linear and nonlinear phase mixing, in such a way that the time scales of the two processes are critically balanced at every scale. We construct a scaling theory of the fluctuation spectrum of $C_2$ and of the electric field in wavenumber space. The electric-field spectrum is sufficiently steep for the nonlinear mixing to be controlled by the largest-scale electric fields, and so the $C_2$ cascade resembles the Batchelor cascade of a passive scalar. Our theory is supported by simulations of a forced 1D-1V plasma. We predict that the cascade is terminated at the wavenumber where the turbulent electric-field spectrum gives way to the thermal noise spectrum. The time scale for this small-scale cutoff to be reached is the dynamical time of phase-space mixing times a logarithmic factor in the plasma parameter - this is the first concrete demonstration of this property of Vlasov-Poisson turbulence, akin to how fluid turbulence dissipates energy at a rate independent (or nearly independent) of molecular diffusion. In the presence of the sub-Debye phase-space cascade - a scenario that may be ubiquitous - standard collisional plasma theory ceases to be valid. This calls for the development of new collision operators suited to such turbulent environments.

We report the first experimental detection of a zero-frequency fluctuation that is pumped by an Alfvén mode in a magnetically confined plasma. Core-localized Alfvén modes of frequency inside the toroidicity-induced gap (and its harmonics) exhibit three-wave coupling interactions with a zero-frequency fluctuation. The observation of the zero-frequency fluctuation is consistent with theoretical and numerical predictions of zonal modes pumped by Alfvén modes, and is correlated with an increase in the deep core ion temperature, temperature gradient, confinement factor H_{89,P}, and a reduction in the main ion heat diffusivity. Despite the energetic particle transport induced by the Alfvén eigenmodes, the generation of a zero-frequency fluctuation that can suppress the turbulence leads to an overall improvement of confinement.

We consider a nearly collisionless plasma consisting of a species of `test particles' in 1D-1V, stirred by an externally imposed stochastic electric field. The mean effect on the particle distribution function is stochastic heating. Accompanying this heating is the generation of fine-scale structure in the distribution function, which we characterize with the collisionless (Casimir) invariant $C_2 \propto \iint dx dv \, \langle f^2 \rangle$. We find that $C_2$ is transferred from large scales to small scales in both position and velocity space via a phase-space cascade enabled by both particle streaming and nonlinear interactions between particles and the stochastic electric field. We compute the steady-state fluxes and spectrum of $C_2$ in Fourier space, with $k$ and $s$ denoting spatial and velocity wavenumbers, respectively. Whereas even the linear phase mixing alone would lead to a constant flux of $C_2$ to high $s$ (towards the collisional dissipation range) at every $k$, the nonlinearity accelerates this cascade by intertwining velocity and position space so that the flux of $C_2$ is to both high $k$ and high $s$ simultaneously. Integrating over velocity (spatial) wavenumbers, the $k$-space ($s$-space) flux of $C_2$ is constant down to a dissipation length (velocity) scale that tends to zero as the collision frequency does, even though the rate of collisional dissipation remains finite. The resulting spectrum in the inertial range is a self-similar function in the $(k,s)$ plane, with power-law asymptotics at large $k$ and $s$. We argue that stochastic heating is made irreversible by this entropy cascade and that, while collisional dissipation accessed via phase mixing occurs only at small spatial scales rather than at every scale as it would in a linear system, the cascade makes phase mixing even more effective overall in the nonlinear regime than in the linear one.

Background: Xanthine oxidoreductase (XOR) is a multi-functional enzyme that drives metabolism of purines generating uric acid and is a generator of reactive oxygen species. Both functions have been implicated in the pathogenesis of cardiovascular disease. More recently, a third function of XOR as a nitrite reductase has been identified and been shown to play a key role in the benefits of targeting the non-canonical pathway for nitric oxide (NO) generation in the cardiovascular disease setting. This effect has been specifically attributed to XOR dependent recovery of NO levels. However, whether XOR derived NO plays any role in maintaining cardiovascular homeostasis in health is unknown. To explore this, we used global and hepatocyte-specific Xdh-deleted mice to assess cardiovascular homeostasis. Methods: Xdh+/+ and Xdh+/-, Xdhfl/fl and AlbCre-Xdh-/- (HXOR) mice were used to assess blood pressure, cardiac function, endothelial reactivity and leukocyte trafficking. Results: Xdh+/- and HXOR KO mice expressed significantly attenuated liver and plasma nitrite reductase activity and platelet cGMP levels versus littermate controls. These effects were associated with increased systolic blood pressure, left ventricular remodelling, and increased leukocyte activation. These effects were associated with and likely driven by endothelial dysfunction evident in both mouse models. This dysfunction was reflected by increased endothelial adhesion molecule expression (P-selectin), increased ischaemia-induced vasoconstriction, during vessel occlusion, and an impaired flow-mediated dilation response of the iliac artery in vivo. Conclusions: In summary, XOR derived NO is critical for maintaining vascular homeostasis under physiological conditions and is key in mediating the benefits of dietary nitrate regimes in cardiovascular pathology. ### Competing Interest Statement Amrita Ahluwalia is a Co-Director of astart-up, Heartbeet Ltd., which is seeking to identify therapeutic opportunities for dietary nitrate. All other authors declare no competing interests.

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.

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).

The first experimental campaigns of Wendelstein 7-X (W7-X) have shown that turbulence plays a decisive role in the performance of neoclassically optimized stellarators. This stresses the importance of understanding microturbulence from the theoretical and experimental points of view. To this end, this paper addresses a comprehensive characterization of the turbulent fluctuations by means of nonlinear gyrokinetic simulations performed with the code stella in two W7-X scenarios. In the first part of the paper, the amplitude of the density fluctuations is calculated and compared with measurements obtained by Doppler reflectometry (DR) in the OP1 experimental campaigns. It is found that the trend of the fluctuations along the radius is explained by the access of the DR system to different regions of the turbulence wavenumber spectrum. In the second part of the article, frequency spectra of the density fluctuations and the zonal component of the turbulent flow are numerically characterized for comparisons against future experimental analyses. Both quantities feature broad frequency spectra with dominant frequencies of O(1)-O(10) kHz.

ITER's NBI systems are a first of its kind system with very challenging targets for the RF-driven ion source and the acceleration stage. In a step ladder approach, the ion source test facilities BATMAN Upgrade (BUG) and ELISE support the activities carried out at the Neutral Beam Test Facility, Padua, which is equipped with the ion source facility SPIDER and with MITICA being equivalent to the ITER Heating Neutral Beam injector (HNB), capable of operating at the full power and pulse length of the ITER HNBs. The contributions of the prototype ion source at BUG (1/8 scale) and the size scaling experiment ELISE (1/2 size ITER source) to the roadmap are manifold: for hydrogen operation the ion source performance is demonstrated in several sequential 1000 s pulses, whereas long pulse deuterium operation is limited by the heat load of the co-extracted electrons on the extraction grid. Measures like special magnetic filter field configurations or biasing of surfaces and improved Cs management are identified. Both facilities have recently been extended to full steady state compatibility and very first insights of the ion source performance with steady state extraction compared to the previously used beam blips (10 s extraction every 150 s) are already gained. A pulse length of 400 s, as required for the first deuterium campaigns at ITER, seems to be feasible soon, whereas the one hour pulse imposes the highest challenge to overcome. Investigations on beam divergence revealed a divergence at the upper limit of the acceptable value for the HNB. Measurements on the beam uniformity on the scale of beamlet groups and grid segments at ELISE demonstrated a uniformity of better than the required 90%. BUG and ELISE gave input to recent implementations at SPIDER; MITICA and ITER's NBI. Still open points and challenges are addressed, for which a continuation of the step ladder approach is essential.

Negative hydrogen or deuterium ion sources for neutral beam injection (NBI) systems used at fusion devices are based on the surface production process at a caesiated low work function converter surface. While producing a stable and globally homogeneous negative ion beam is not an issue, during long pulses typically a pronounced increase in the co-extracted electrons is observed, limiting the pulse length or the achievable performance. This effect is particularly pronounced in deuterium and it is attributed to an increasing work function of the converter surface. In the last years the negative ion source test facilities at IPP Garching, BATMAN Upgrade (using the small prototype source) and ELISE (using a source of the same width but only half the height of the ITER NBI source) have been converted into CW machines, making possible investigating at ITER conditions counter-measures for the increase in the co-extracted electrons. Investigations are performed, mainly at ELISE, on homogenizing and stabilizing the co-extracted electrons by affecting the ion source plasma close to the converter surface by means of biasing (additional) surfaces in the plasma.

MOTIVATION:The scale of omics research presents many obstacles to full sharing and access to analysis results. Current publication models impose limits on the number of pages and figures, requiring careful preparation and selection of content. At the same time, depositing data in open repositories significantly shifts the burden of access and reproduction to readers, who may include people who are not programmers or analysts. RESULTS:We introduce shinyExprPortal, an R package that implements omics web portals with minimal coding effort. The portals allow exploration of transcriptomic or proteomic expression data and phenotypes, showcasing results of various types of analysis including differential expression, co-expression and pathways analysis. The integration with bioinformatics workflows enables researchers to focus on their results and share findings using interactive and publication-quality plots. AVAILABILITY AND IMPLEMENTATION:The shinyExprPortal package is available to download and install from CRAN and https://github.com/C4TB/shinyExprPortal.

A low beamlet divergence is crucial for the efficiency of the ITER-NBI systems, since it affects the transmission of the beam through the duct. There is a requirement of 7 mrad e -folding divergence for the ITER Heating Neutral Beam. Significantly higher divergences (10–15 mrad) have been observed in RF-source based experiments albeit at low beam energy. This could be the consequence of a broad perpendicular velocity distribution of the H − /D − particles before extraction. This paper explores this hypothesis and its implications for ITER. To estimate H − /D − perpendicular temperatures in the RF-driven BATMAN Upgrade test facility, spatially resolved measurements of the beam power density are compared with IBSimu calculations. The estimated perpendicular temperatures show a strong dependence on the source filling pressure, decreasing from approximately 4 eV at 0.3 Pa to 2 eV at 0.4 Pa. Ion-optics calculations of the ITER-HNB grid system are performed to evaluate whether the temperatures estimated in the BATMAN Upgrade test facility are tolerable in view of beam-grid interaction and beamline transmission. The beamline transmission is fairly insensitive to the perpendicular temperature, but the heat loads at the downstream grids increase with the perpendicular temperature.

Microinstabilities drive turbulent fluctuations in inhomogeneous, magnetised plasmas. In the context of magnetic confinement fusion devices, this leads to an enhanced transport of particles, momentum and energy, thereby degrading confinement. In this work, we describe an application of the adjoint method to efficiently determine variations of gyrokinetic linear growth rates on a general set of external parameters in the local $\delta f$-gyrokinetic model. We then offer numerical verification of this approach. When coupled with gradient-based techniques, this methodology can facilitate the optimisation process for the microstability of the confined plasmas across a high-dimensional parameter space. We present a numerical demonstration wherein the ion-temperature-gradient instability growth rate in a tokamak plasma is minimised with respect to flux surface shaping parameters. The adjoint method approach demonstrates a significant computational speed-up compared with a finite-difference gradient calculation.

Artificial intelligence (AI) holds immense promise for accelerating and improving all aspects of drug discovery, not least target discovery and validation. By integrating a diverse range of biological data modalities, AI enables the accurate prediction of drug target properties, ultimately illuminating biological mechanisms of disease and guiding drug discovery strategies. Despite the indisputable potential of AI in drug target discovery, there are many challenges and obstacles yet to be overcome, including dealing with data biases, model interpretability and generalisability, and the validation of predicted drug targets, to name a few. By exploring recent advancements in AI, this review showcases current applications of AI for drug target discovery and offers perspectives on the future of AI for the discovery and validation of drug targets, paving the way for the generation of novel and safer pharmaceuticals.