Progress from ASDEX Upgrade experiments in preparing the physics basis of ITER operation and DEMO scenario development

An overview of recent results obtained at the tokamak ASDEX Upgrade (AUG) is given. A work flow for predictive profile modelling of AUG discharges was established which is able to reproduce experimental H-mode plasma profiles based on engineering parameters only. In the plasma center, theoretical predictions on plasma current redistribution by a dynamo effect were confirmed experimentally. For core transport, the stabilizing effect of fast ion distributions on turbulent transport is shown to be important to explain the core isotope effect and improves the description of hollow low-Z impurity profiles. The L-H power threshold of hydrogen plasmas is not affected by small helium admixtures and it increases continuously from the deuterium to the hydrogen level when the hydrogen concentration is raised from 0 to 100%. One focus of recent campaigns was the search for a fusion relevant integrated plasma scenario without large edge localised modes (ELMs). Results from six different ELM-free confinement regimes are compared with respect to reactor relevance: ELM suppression by magnetic perturbation coils could be attributed to toroidally asymmetric turbulent fluctuations in the vicinity of the separatrix. Stable improved confinement mode plasma phases with a detached inner divertor were obtained using a feedback control of the plasma β. The enhanced D α H-mode regime was extended to higher heating power by feedback controlled radiative cooling with argon. The quasi-coherent exhaust regime was developed into an integrated scenario at high heating power and energy confinement, with a detached divertor and without large ELMs. Small ELMs close to the separatrix lead to peeling-ballooning stability and quasi continuous power exhaust. Helium beam density fluctuation measurements confirm that transport close to the separatrix is important to achieve the different ELM-free regimes. Based on separatrix plasma parameters and interchange-drift-Alfvén turbulence, an analytic model was derived that reproduces the experimentally found important operational boundaries of the density limit and between L- and H-mode confinement. Feedback control for the X-point radiator (XPR) position was established as an important element for divertor detachment control. Stable and detached ELM-free phases with H-mode confinement quality were obtained when the XPR was moved 10 cm above the X-point. Investigations of the plasma in the future flexible snow-flake divertor of AUG by means of first SOLPS-ITER simulations with drifts activated predict beneficial detachment properties and the activation of an additional strike point by the drifts

Overview of physics studies on ASDEX Upgrade

The ASDEX Upgrade (AUG) programme, jointly run with the EUROfusion MST1 task force, continues to significantly enhance the physics base of ITER and DEMO. Here, the full tungsten wall is a key asset for extrapolating to future devices. The high overall heating power, flexible heating mix and comprehensive diagnostic set allows studies ranging from mimicking the scrape-off-layer and divertor conditions of ITER and DEMO at high density to fully non-inductive operation (q 95 = 5.5, ) at low density. Higher installed electron cyclotron resonance heating power 6 MW, new diagnostics and improved analysis techniques have further enhanced the capabilities of AUG. Stable high-density H-modes with MW m-1 with fully detached strike-points have been demonstrated. The ballooning instability close to the separatrix has been identified as a potential cause leading to the H-mode density limit and is also found to play an important role for the access to small edge-localized modes (ELMs). Density limit disruptions have been successfully avoided using a path-oriented approach to disruption handling and progress has been made in understanding the dissipation and avoidance of runaway electron beams. ELM suppression with resonant magnetic perturbations is now routinely achieved reaching transiently . This gives new insight into the field penetration physics, in particular with respect to plasma flows. Modelling agrees well with plasma response measurements and a helically localised ballooning structure observed prior to the ELM is evidence for the changed edge stability due to the magnetic perturbations. The impact of 3D perturbations on heat load patterns and fast-ion losses have been further elaborated. Progress has also been made in understanding the ELM cycle itself. Here, new fast measurements of and E r allow for inter ELM transport analysis confirming that E r is dominated by the diamagnetic term even for fast timescales. New analysis techniques allow detailed comparison of the ELM crash and are in good agreement with nonlinear MHD modelling. The observation of accelerated ions during the ELM crash can be seen as evidence for the reconnection during the ELM. As type-I ELMs (even mitigated) are likely not a viable operational regime in DEMO studies of 'natural' no ELM regimes have been extended. Stable I-modes up to have been characterised using -feedback. Core physics has been advanced by more detailed characterisation of the turbulence with new measurements such as the eddy tilt angle - measured for the first time - or the cross-phase angle of and fluctuations. These new data put strong constraints on gyro-kinetic turbulence modelling. In addition, carefully executed studies in different main species (H, D and He) and with different heating mixes highlight the importance of the collisional energy exchange for interpreting energy confinement. A new regime with a hollow profile now gives access to regimes mimicking aspects of burning plasma conditions and lead to nonlinear interactions of energetic particle modes despite the sub-Alfvénic beam energy. This will help to validate the fast-ion codes for predicting ITER and DEMO

Definitive Neural Stem Cell Clonally Generated from Pluripotent Stem Cells Promote Recovery following Spinal Cord Injury

Advancements in medical management for spinal cord injury (SCI) have resulted in greatly improved survival rates following this devastating event; although medical interventions to regenerate the injured spinal cord and restore function remain limited. Neural stem cells (NSCs) from embryonic or fetal/adult tissues sources show considerable promise in regenerative strategies for traumatic SCI. However, there are limitations with their use related to availability, immunogenicity, immunological rejection and uncertainty of mechanism. To address these issues, our laboratory has investigated the use of NSCs derived from induced pluripotent stem (iPS) cells generated using a non-viral and mutation-free approach. NSCs were generated from pluripotent cells using a free-floating neurospheres methodology previously used by our lab. To delineate the mechanism of action, specifically the role of exogenous myelination, NSCs derived from wildtype (wt) and non-myelinating Shiverer (shi) iPS cell lines were used in a mouse thoracic SCI model with sub-acute intraspinal transplantation. Behavioral, histological and electrophysiological outcomes were analyzed to assess the safety and efficacy of this treatment. Variable neural propensity in the iPS cell lines were identified and overcome by agonizing the NOTCH pathway, yielding a clinically relevant population of NSCs for transplantation. The wt- and shi-iPS-NSCs were validated and shown to be equivalent except in myelination capacity. Both iPS-NSC lines were transplanted following thoracic SCI, but only the wt-iPS-NSC treatment resulted in a functional benefit. Wt-iPS-NSC transplantation resulted in significantly improved hindlimb locomotor function, histological outcomes and action potential amplitudes compared to the non-myelinating and cell-free controls. This supports remyelination as the key process by which NSC treatment provides a benefit following thoracic SCI. This work addresses a significant knowledge gap in the field of regenerative medicine for SCI. It demonstrated that pluripotent cells, specifically iPS cells, can be used to generate clinical relevant NSCs for application in SCI. Even though NSCs have been shown to provide a diverse range of functions in the spinal cord, remyelination is the predominate mechanism of recovery following thoracic SCI. This work will have significant impact in shaping how iPS-NSCs will be potentially translated to a clinical setting.Ph.D

Inhibition of Beta2 Integrin-mediated Leukocyte Adhesion Attenuates the Inflammatory Response and is Neuroprotective Following Global Cerebral Ischemia

Leukocyte adhesion to cerebral endothelial cells plays a critical role in the inflammatory response following transient global cerebral ischemia but its contribution to delayed neuronal cell death is not completely understood. We compared ischemic mice treated with a monoclonal antibody to β2-integrin adhesion receptors (anti-CD18) or a non-binding control antibody following ischemia. Inflammation was characterized by increased CD18 expression on leukocytes and inflammatory mediators in the peripheral blood and brain tissue. Notably, interleukin-1β, which has been shown to mediate cell death in neurons, was elevated in the blood and brain. Anti-CD18 blocked leukocyte adhesion as well as the inflammatory responses, including interleukin-1β expression in neurons. Blocking leukocyte adhesion protected the structural integrity of the hippocampus, cerebral cortex and thalamus, and preserved spatial. Leukocytes adhesion to endothelial cells plays an important role in the evolution of neurological deficit in global cerebral ischemia despite the lack of transmigration of leukocytes across blood-brain-barrier.MAS

Neural stem cell mediated recovery is enhanced by Chondroitinase ABC pretreatment in chronic cervical spinal cord injury

<div><p>Traumatic spinal cord injuries (SCIs) affect millions of people worldwide; the majority of whom are in the chronic phase of their injury. Unfortunately, most current treatments target the acute/subacute injury phase as the microenvironment of chronically injured cord consists of a well-established glial scar with inhibitory chondroitin sulfate proteoglycans (CSPGs) which acts as a potent barrier to regeneration. It has been shown that CSPGs can be degraded <i>in vivo</i> by intrathecal Chondroitinase ABC (ChABC) to produce a more permissive environment for regeneration by endogenous cells or transplanted neural stem cells (NSCs) in the subacute phase of injury. Using a translationally-relevant clip-contusion model of cervical spinal cord injury in mice we sought to determine if ChABC pretreatment could modify the harsh chronic microenvironment to enhance subsequent regeneration by induced pluripotent stem cell-derived NSCs (iPS-NSC). Seven weeks after injury—during the chronic phase—we delivered ChABC by intrathecal osmotic pump for one week followed by intraparenchymal iPS-NSC transplant rostral and caudal to the injury epicenter. ChABC administration reduced chronic-injury scar and resulted in significantly improved iPSC-NSC survival with clear differentiation into all three neuroglial lineages. Neurons derived from transplanted cells also formed functional synapses with host circuits on patch clamp analysis. Furthermore, the combined treatment led to recovery in key functional muscle groups including forelimb grip strength and measures of forelimb/hindlimb locomotion assessed by Catwalk. This represents important proof-of-concept data that the chronically injured spinal cord can be ‘unlocked’ by ChABC pretreatment to produce a microenvironment conducive to regenerative iPS-NSC therapy.</p></div

Patch-clamped transplanted GFP⁺ cells in <i>ex vivo</i> cords demonstrate functional action potentials.

<p>(A) Electrical tracing demonstrating currents evoked by voltage pulses which contain transient inward sodium currents and outward potassium currents. Membrane potential was held at -80 mV and depolarized to +30 mV with an increment of 10 mV step (48 ms long). (B) Representative spontaneous postsynaptic currents with burst and sporadic firing patterns. (C) Time expanded tracings of key (i) burst and (ii) sporadic postsynaptic currents in B. (ii) Two types of spontaneous postsynaptic currents are seen with slow decay time and (*) fast decay time. Membrane potential was held at -80 mV in B and C. n = 4 animals and 12 GFP⁺ cells per group. iPS-NSC transplant enhances recovery of in vivo motor evoked potentials (MEPs). MEPs were stimulated at the C2 cervical spinal cord and recorded from the hypothenar muscles. (D) At 16 weeks post-SCI, only mice treated with iPS-NSCs had significantly shorter MEP latencies while (E) higher peak MEP amplitudes were found in both the iPS-NSC and ChABC + iPS-NSC treated groups. Data are mean ± SEM values, n = 6 per group. (*) indicates statistical significance at p<0.05</p