Amyloid binding and beyond: a new approach for Alzheimer's disease drug discovery targeting Aβo–PrPC binding and downstream pathways

Amyloid β oligomers (Aβo) are the main toxic species in Alzheimer's disease, which have been targeted for single drug treatment with very little success. In this work we report a new approach for identifying functional Aβo binding compounds. A tailored library of 971 fluorine containing compounds was selected by a computational method, developed to generate molecular diversity. These compounds were screened for Aβo binding by a combined 19F and STD NMR technique. Six hits were evaluated in three parallel biochemical and functional assays. Two compounds disrupted Aβo binding to its receptor PrPC in HEK293 cells. They reduced the pFyn levels triggered by Aβo treatment in neuroprogenitor cells derived from human induced pluripotent stem cells (hiPSC). Inhibitory effects on pTau production in cortical neurons derived from hiPSC were also observed. These drug-like compounds connect three of the pillars in Alzheimer's disease pathology, i.e. prion, Aβ and Tau, affecting three different pathways through specific binding to Aβo and are, indeed, promising candidates for further development

Bioluminescence in the deep sea: free-fall lander observations in the Atlantic Ocean off Cape Verde

A novel autonomous free-fall lander vehicle, with a capability down to 6000 m, was deployed off Cape Verde for studies on bioluminescence in the deep sea. The system was equipped with a high-sensitivity Intensified Silicon Intensified Target (ISIT) video camera, a programmable control-recording unit and an acoustic current meter with depth and temperature sensors. The ISIT lander was used in three modes: (1) free falling at 34 m min-1, with the camera looking downwards at a mesh screen, recording impacts of luminescent organisms to obtain a vertical profile down to the abyssal sea floor, sampling at >100 l s-1; (2) rotating, with the lander on the sea floor and the camera orienting to the bottom current using a servo-controlled turntable, impacts of luminescent organisms carried by the bottom current onto a mesh screen mounted 0.5 m in front of the camera were recorded to estimate abundance in the benthic boundary layer; (3) baited, with the camera focused on a bait placed on the sea floor.Profiles recorded abundance of luminescent organisms as 26.7 m-3 at 500–999 m depth, decreasing to 1.6 m-3 at 2000–2499 m and 0.5 m-3 between 2500 m and the sea floor at 4046 m, with no further detectable significant change with depth. Rotator measurements at a 0.5 m height above the sea floor gave a mean abundance of 0.47 m-3 in the benthic boundary layer at 4046 m and of 2.04 m-3 at 3200 m. Thirty five minutes after the bait was placed on the sea floor at 3200 m, bioluminescent fauna apparently arrived at the bait and produced luminescent displays at a rate of 2 min-1. Moving, flashing light sources were observed and luminescent material was released into the bottom current

The use of portable XRF as a forensic geoscience non-destructive trace evidence tool for environmental and criminal investigations

Hand-held, portable X-Ray fluorescence instruments (pXRF) provide a means of rapid, in-situ chemical characterisation that has considerable application as a rapid trace evidence characterisation tool in forensic geoscience. This study presents both a control test study which demonstrates optimisation of the data collection process, alongside a range of individual forensic case studies, including heavy metal contamination, conflict archaeology, forensic soil characterisation, and verification of human remains, which together validate the technique and provide some comparison between field-based and laboratory-based pXRF applications. Results highlight the time-efficiency and cost-effectiveness of in-situ, field-based pXRF analyses for material characterisation when compared with other trace evidence methods. Analytical precision of various analytes during in-situ analysis was sufficient to demonstrate considerable application of field-based pXRF as a tool for rapid identification of specific areas of interest to be further investigated. Laboratory-based pXRF analyses yielded greater accuracy which could provide an efficient compromise between field-based pXRF and traditional laboratory-based analytical techniques (e.g. WD-XRF, ICP-MS). Further studies should collect more advanced datasets in more diverse locations to further validate the techniques capability to rapidly conduct geochemical surveys in a range of environments