The Highs and Lows of Memantine-An Autophagy and Mitophagy Inducing Agent That Protects Mitochondria.

Memantine is an FDA-approved, non-competitive NMDA-receptor antagonist that has been shown to have mitochondrial protective effects, improve cell viability and enhance clearance of Aß42 peptide. Currently, there are uncertainties regarding the precise molecular targets as well as the most favourable treatment concentrations of memantine. Here, we made use of an imaging-based approach to investigate the concentration-dependent effects of memantine on mitochondrial fission and fusion dynamics, autophagy and mitochondrial quality control using a neuronal model of CCCP-induced mitochondrial injury so as to better unpack how memantine aids in promoting neuronal health. GT1-7 murine hypothalamic cells were cultured under standard conditions, treated with a relatively high and low concentration (100 µM and 50 µM) of memantine for 48 h. Images were acquired using a Zeiss 780 PS1 platform. Utilising the mitochondrial event localiser (MEL), we demonstrated clear concentration-dependent effects of memantine causing a protective response to mitochondrial injury. Both concentrations maintained the mitochondrial network volume whilst the low concentration caused an increase in mitochondrial number as well as increased fission and fusion events following CCCP-induced injury. Additionally, we made use of a customised Python-based image processing and analysis pipeline to quantitatively assess memantine-dependent changes in the autophagosomal and lysosomal compartments. Our results revealed that memantine elicits a differential, concentration-dependent effect on autophagy pathway intermediates. Intriguingly, low but not high concentrations of memantine lead to the induction of mitophagy. Taken together, our findings have shown that memantine is able to protect the mitochondrial network by preserving its volume upon mitochondrial injury with high concentrations of memantine inducing macroautophagy, whereas low concentrations lead to the induction of mitophagy.

Pilot behaviors in the face of adverse weather: A new look at an old problem.

INTRODUCTION: Weather-related general aviation accidents remain one of the most significant causes for concern in aviation safety. Previous studies have typically compared accident and non-accident cases. In contrast, the current study does not concentrate on occurrence outcome. Instead, the emphasis is on the different behaviors that pilots exhibit in the face of adverse weather and, by inference, on the decision-making processes that underlie those behaviors. METHODS: This study compares three weather-related behaviors that reflect different levels of risk: visual flight rules flight into instrument meteorological conditions ('VFR into IMC'); precautionary landing; and other significant weather avoidance actions. Occurrence data (n=491) were drawn from the Australian Transport Safety Bureau database of aviation occurrences, and included weather-related accidents, incidents, and 'normal operationsd.' RESULTS: There were few significant differences between the three weather-related behavior groups in terms of pilot demographics, aircraft characteristics, geographic or environmental factors, or absolute flight distances. The pattern of relative flight distances (a psychological construct) was markedly different for the three groups, with pilots in the weather avoidance group being distinguished by taking timely action. DISCUSSION: The relative distance results suggest that the mid-point of the flight can be a 'psychological turning point' for pilots, irrespective of the absolute flight distance involved. Hence, pilots' behavior was sometimes influenced by psychological factors not related to any particular operational aspect of the flight. The results of the weather avoidance group indicate that a safe pilot is a proactive pilot. Dealing with adverse weather is not a one-off decision but a continually evolving process. This aspect is discussed in terms of the concept of 'mindfulness'.