Characterization of a Drosophila Alzheimer's Disease Model: Pharmacological Rescue of Cognitive Defects

Transgenic models of Alzheimer's disease (AD) have made significant contributions to our understanding of AD pathogenesis, and are useful tools in the development of potential therapeutics. The fruit fly, Drosophila melanogaster, provides a genetically tractable, powerful system to study the biochemical, genetic, environmental, and behavioral aspects of complex human diseases, including AD. In an effort to model AD, we over-expressed human APP and BACE genes in the Drosophila central nervous system. Biochemical, neuroanatomical, and behavioral analyses indicate that these flies exhibit aspects of clinical AD neuropathology and symptomology. These include the generation of Aβ40 and Aβ42, the presence of amyloid aggregates, dramatic neuroanatomical changes, defects in motor reflex behavior, and defects in memory. In addition, these flies exhibit external morphological abnormalities. Treatment with a γ-secretase inhibitor suppressed these phenotypes. Further, all of these phenotypes are present within the first few days of adult fly life. Taken together these data demonstrate that this transgenic AD model can serve as a powerful tool for the identification of AD therapeutic interventions

14 MeV calibration of JET neutron detectors-phase 1:calibration and characterization of the neutron source

\u3cp\u3eIn view of the planned DT operations at JET, a calibration of the JET neutron monitors at 14 MeV neutron energy is needed using a 14 MeV neutron generator deployed inside the vacuum vessel by the JET remote handling system. The target accuracy of this calibration is 10% as also required by ITER, where a precise neutron yield measurement is important, e.g. for tritium accountancy. To achieve this accuracy, the 14 MeV neutron generator selected as the calibration source has been fully characterised and calibrated prior to the in-vessel calibration of the JET monitors. This paper describes the measurements performed using different types of neutron detectors, spectrometers, calibrated long counters and activation foils which allowed us to obtain the neutron emission rate and the anisotropy of the neutron generator, i.e.The neutron flux and energy spectrum dependence on emission angle, and to derive the absolute emission rate in 4π sr. The use of high resolution diamond spectrometers made it possible to resolve the complex features of the neutron energy spectra resulting from the mixed D/T beam ions reacting with the D/T nuclei present in the neutron generator target. As the neutron generator is not a stable neutron source, several monitoring detectors were attached to it by means of an ad hoc mechanical structure to continuously monitor the neutron emission rate during the in-vessel calibration. These monitoring detectors, two diamond diodes and activation foils, have been calibrated in terms of neutrons/counts within ± 5% total uncertainty. A neutron source routine has been developed, able to produce the neutron spectra resulting from all possible reactions occurring with the D/T ions in the beam impinging on the Ti D/T target. The neutron energy spectra calculated by combining the source routine with a MCNP model of the neutron generator have been validated by the measurements. These numerical tools will be key in analysing the results from the in-vessel calibration and to derive the response of the JET neutron detectors to DT plasma neutrons starting from the response to the generator neutrons, and taking into account all the calibration circumstances.\u3c/p\u3

Overview of the JET preparation for deuterium-tritium operation with the ITER like-wall

\u3cp\u3eFor the past several years, the JET scientific programme (Pamela et al 2007 Fusion Eng. Des. 82 590) has been engaged in a multi-campaign effort, including experiments in D, H and T, leading up to 2020 and the first experiments with 50%/50% D-T mixtures since 1997 and the first ever D-T plasmas with the ITER mix of plasma-facing component materials. For this purpose, a concerted physics and technology programme was launched with a view to prepare the D-T campaign (DTE2). This paper addresses the key elements developed by the JET programme directly contributing to the D-T preparation. This intense preparation includes the review of the physics basis for the D-T operational scenarios, including the fusion power predictions through first principle and integrated modelling, and the impact of isotopes in the operation and physics of D-T plasmas (thermal and particle transport, high confinement mode (H-mode) access, Be and W erosion, fuel recovery, etc). This effort also requires improving several aspects of plasma operation for DTE2, such as real time control schemes, heat load control, disruption avoidance and a mitigation system (including the installation of a new shattered pellet injector), novel ion cyclotron resonance heating schemes (such as the three-ions scheme), new diagnostics (neutron camera and spectrometer, active Alfven eigenmode antennas, neutral gauges, radiation hard imaging systems...) and the calibration of the JET neutron diagnostics at 14 MeV for accurate fusion power measurement. The active preparation of JET for the 2020 D-T campaign provides an incomparable source of information and a basis for the future D-T operation of ITER, and it is also foreseen that a large number of key physics issues will be addressed in support of burning plasmas.\u3c/p\u3

From paediatrics to geriatrics: a life course perspective on the MRC National Survey of Health and Development

For over 40 years I have enjoyed working collaboratively on research projects to increase understanding of population health with the aim of ultimately improving quality of life. For almost 30 years I have been part of the study team responsible for the MRC National Survey of Health and Development (NSHD), the oldest of the British birth cohort studies; and for the last 10 years have had the privilege of being the NSHD director. Such a long-term study depends on a committed and scientifically productive study team which maintains study member engagement and attracts expert scientific collaborators. For the last 20 years, I have collaborated with Professor Yoav Ben-Shlomo and others to develop the field of life course epidemiology, the study of the long term effects of social and biological exposures and experiences across life on later life health. So at the outset, I acknowledge that this personal opinion piece which I was invited to submit has implicitly and explicitly been influenced by many colleagues. It also should be read in conjunction with an accompanying article in this issue on the recent 24th follow-up of the NSHD at the age of 70 years (Kuh et al., this issue) and a recent updated review of life course epidemiology

Role of fast ion pressure in the isotope effect in JET L-mode plasmas

This paper presents results of JET ITER-like wall L-mode experiments in hydrogen and deuterium (D) plasmas, dedicated to the study of the isotope dependence of ion heat transport by determination of the ion critical gradient and stiffness by varying the ion cyclotron resonance heating power deposition. When no strong role of fast ions in the plasma core is expected, the main difference between the two isotope plasmas is determined by the plasma edge and the core behavior is consistent with a gyro-Bohm scaling. When the heating power (and the fast ion pressure) is increased, in addition to the difference in the edge region, also the plasma core shows substantial changes. The stabilization of ion heat transport by fast ions, clearly visible in D plasmas, appears to be weaker in H plasmas, resulting in a higher ion heat flux in H with apparent anti-gyro-Bohm mass scaling. The difference is found to be caused by the different fast ion pressure between H and D plasmas, related to the heating power settings and to the different fast ion slowing down time, and is completely accounted for in non-linear gyrokinetic simulations. The application of the TGLF quasi-linear model to this set of data is also discussed

Long-lived coupled peeling ballooning modes preceding ELMs on JET

In some JET discharges, type-I edge localised modes (ELMs) are preceded by a class of low-frequency oscillations (Perez et al 2004 Nucl. Fusion 44 609). While in many cases the ELM is triggered during the growth phase of this oscillation, it is also observed that this type of oscillation can saturate and last for several tens of ms until an ELM occurs. In order to identify the nature of these modes, a wide pre-ELM oscillation database, including detailed pedestal profile information, has been assembled and analysed in terms of MHD stability parameters. The existence domain of these pre-ELM oscillations and the statistical distribution of toroidal mode numbers (n) up to n = 16 have been mapped in ballooning alpha (alpha(ball)) and either edge current density (J(edge)) or pedestal collisionality (nu(ee,ped)*) coordinates and compared to linear MHD stability predictions. The pre-ELM oscillations are reliably observed when the J/alpha ratio is high enough for the pedestal to access the coupled peeling-ballooning (PB) domain (aka stability nose). Conversely, when the pedestal is found to be in or near the high-n ballooning domain (which is at low J/alpha ratio), ELMs are usually triggered promptly, i.e. with no detectable pre-ELM oscillations, or with pre-ELM oscillations only observable on ECE whose n appears to be too high to be resolved by the magnetics. Individual discharges can sometimes exhibit a fairly wide range of pre-ELM mode numbers, but for a wider database, the statistical n-number domains are found to be well ordered along the J - alpha stability boundary and behave as expected from PB theory: the higher the J/alpha ratio, the lower the mode's measured n tends to be. Within the measurement uncertainties, the measured n is usually found to be compatible with the most unstable n predicted by the linear stability code MISHKA1. These results confirm the earlier hypothesis that these modes are coupled peeling-ballooning modes, and extend and generalise to higher-mode numbers the work by Huysmans et al (1998 Nucl. Fusion 38 179), who identified the lowest n modes as pure external kink modes. Since the destabilisation of PB modes is widely accepted to give rise to ELMs, the mode saturation and delayed ELM triggering that is sometimes observed is rather unexpected. Possibilities to reconcile the extended lifetime of these modes with current ELM models are briefly discussed, but will require further investigation

Diagnostic of fast-ion energy spectra and densities in magnetized plasmas

The measurement of the energy spectra and densities of alpha-particles and other fast ions are part of the ITER measurement requirements, highlighting the importance of energy-resolved energetic-particle measurements for the mission of ITER. However, it has been found in recent years that the velocity-space interrogation regions of the foreseen energetic-particle diagnostics do not allow these measurements directly. We will demonstrate this for gamma-ray spectroscopy (GRS), collective Thomson scattering (CTS), neutron emission spectroscopy and fast-ion D-alpha spectroscopy by invoking energy and momentum conservation in each case, highlighting analogies and differences between the different diagnostic velocity-space sensitivities. Nevertheless, energy spectra and densities can be inferred by velocity-space tomography which we demonstrate using measurements at JET and ASDEX Upgrade. The measured energy spectra agree well with corresponding simulations. At ITER, alpha-particle energy spectra and densities can be inferred for energies larger than 1.7 MeV by velocity-space tomography based on GRS and CTS. Further, assuming isotropy of the alpha-particles in velocity space, their energy spectra and densities can be inferred by 1D inversion of spectral single-detector measurements down to about 300 keV by CTS. The alpha-particle density can also be found by fitting a model to the CTS measurements assuming the alpha-particle distribution to be an isotropic slowing-down distribution