Monoamine oxidase-A promotes protective autophagy in human SH-SY5Y neuroblastoma cells through Bcl-2 phosphorylation.

Monoamine oxidases (MAOs) are located on the outer mitochondrial membrane and are drug targets for the treatment of neurological disorders. MAOs control the levels of neurotransmitters in the brain via oxidative deamination and contribute to reactive oxygen species (ROS) generation through their catalytic by-product H2O2. Increased ROS levels may modulate mitochondrial function and mitochondrial dysfunction is implicated in a vast array of disorders. However, the downstream effects of MAO-A mediated ROS production in a neuronal model has not been previously investigated. In this study, using MAO-A overexpressing neuroblastoma cells, we demonstrate that higher levels of MAO-A protein/activity results in increased basal ROS levels with associated increase in protein oxidation. Increased MAO-A levels result in increased Lysine-63 linked ubiquitination of mitochondrial proteins and promotes autophagy through Bcl-2 phosphorylation. Furthermore, ROS generated locally on the mitochondrial outer membrane by MAO-A promotes phosphorylation of dynamin-1-like protein, leading to mitochondrial fragmentation and clearance without complete loss of mitochondrial membrane potential. Cellular ATP levels are maintained following MAO-A overexpression and complex IV activity/protein levels increased, revealing a close relationship between MAO-A levels and mitochondrial function. Finally, the downstream effects of increased MAO-A levels are dependent on the availability of amine substrates and in the presence of exogenous substrate, cell viability is dramatically reduced. This study shows for the first time that MAO-A generated ROS is involved in quality control signalling, and increase in MAO-A protein levels leads to a protective cellular response in order to mediate removal of damaged macromolecules/organelles, but substrate availability may ultimately determine cell fate. The latter is particularly important in conditions such as Parkinson's disease, where a dopamine precursor is used to treat disease symptoms and highlights that the fate of MAO-A containing dopaminergic neurons may depend on both MAO-A levels and catecholamine substrate availability

Progress in hybrid plasma wakefield acceleration

Plasma wakefield accelerators can be driven either by intense laser pulses (LWFA) or by intense particle beams (PWFA). A third approach that combines the complementary advantages of both types of plasma wakefield accelerator has been established with increasing success over the last decade and is called hybrid LWFA→PWFA. Essentially, a compact LWFA is exploited to produce an energetic, high-current electron beam as a driver for a subsequent PWFA stage, which, in turn, is exploited for phase-constant, inherently laser-synchronized, quasi-static acceleration over extended acceleration lengths. The sum is greater than its parts: the approach not only provides a compact, cost-effective alternative to linac-driven PWFA for exploitation of PWFA and its advantages for acceleration and high-brightness beam generation, but extends the parameter range accessible for PWFA and, through the added benefit of co-location of inherently synchronized laser pulses, enables high-precision pump/probing, injection, seeding and unique experimental constellations, e.g., for beam coordination and collision experiments. We report on the accelerating progress of the approach achieved in a series of collaborative experiments and discuss future prospects and potential impact

PIConGPU setup: LPWFA downramp injection

PIConGPU source code and setup files used for the LPWFA downramp injection simulation stud

Effect of driver charge on wakefield characteristics in a plasma accelerator probed by femtosecond shadowgraphy

We report on experimental investigations of plasma wave structures in a plasma wakefield acceleration (PWFA) stage which is driven by electron beams from a preceding laser plasma accelerator. Femtosecond optical probing is utilized to allow for direct visualization of the plasma dynamics inside the target. We compare two regimes in which the driver propagates either through an initially neutral gas, or a preformed plasma. In the first case, plasma waves are observed that quickly damp after a few oscillations and are located within a narrow plasma channel ionized by the driver, having about the same transverse size as the plasma wakefield cavities. In contrast, for the latter robust cavities are recorded sustained over many periods. Furthermore, here an elongation of the first cavity is measured, which becomes stronger with increasing driver beam charge. Since the cavity length is linked to the maximum accelerating field strength, this elongation implies an increased field strength. This observation is supported by 3D particle-in-cell simulations performed with PIConGPU. This work can be extended for the investigation of driver depletion by probing at different propagation distances inside the plasma, which is essential for the development of high energy efficiency PWFAs

Seeded free-electron laser driven by a compact laser plasma accelerator

Free-electron lasers generate high-brilliance coherent radiation at wavelengths spanning from the infrared to the X-ray domains. The recent development of short-wavelength seeded free-electron lasers now allows for unprecedented levels of control on longitudinal coherence[1], opening new scientific avenues as ultra-fast dynamics on complex systems and X-ray nonlinear optics. While those devices rely on state-of-the-art large-scale accelerators, advancements on laser-plasma accelerators, which harness giga-volt-per-centimeter accelerating fields, showcase a promising technology as compact drivers for free-electron lasers. Using such miniaturized accelerators, exponential amplification of a shot-noise type of radiation in a self-amplified spontaneous emission configuration was recently achieved [2]. However, employing this compact approach for the delivery of temporally coherent pulses in a controlled manner remained a major challenge. Here, we present the experimental demonstration of a laser-plasma accelerator driven free-electron laser in a seeded configuration, where control over the radiation wavelength is accomplished. Furthermore, the appearance of interference fringes, resulting from the interaction between the phase-locked emitted radiation and the seed, confirms longitudinal coherence. Building on our scientific achievements, we anticipate a straightforward scaling to extreme-ultraviolet wavelengths, paving the way towards university-scale free-electron lasers, unique tools for a multitude of applications. [1] Meyer, M. FELs of europe: Whitebook on science with free electron lasers 8–19 (2016). [2] Wang, W. et al. Free-electron lasing at 27 nanometres based on a laser wakefield accelerator

Seeded free-electron laser driven by a compact laser plasma accelerator

International audienceAbstract Free-electron lasers generate high-brilliance coherent radiation at wavelengths spanning from the infrared to the X-ray domains. The recent development of short-wavelength seeded free-electron lasers now allows for unprecedented levels of control on longitudinal coherence, opening new scientific avenues such as ultra-fast dynamics on complex systems and X-ray nonlinear optics. Although those devices rely on state-of-the-art large-scale accelerators, advancements on laser-plasma accelerators, which harness gigavolt-per-centimetre accelerating fields, showcase a promising technology as compact drivers for free-electron lasers. Using such footprint-reduced accelerators, exponential amplification of a shot-noise type of radiation in a self-amplified spontaneous emission configuration was recently achieved. However, employing this compact approach for the delivery of temporally coherent pulses in a controlled manner has remained a major challenge. Here we present the experimental demonstration of a laser-plasma accelerator-driven free-electron laser in a seeded configuration, where control over the radiation wavelength is accomplished. Furthermore, the appearance of interference fringes, resulting from the interaction between the phase-locked emitted radiation and the seed, confirms longitudinal coherence. Building on our scientific achievements, we anticipate a navigable pathway to extreme-ultraviolet wavelengths, paving the way towards smaller-scale free-electron lasers, unique tools for a multitude of applications in industry, laboratories and universities