Small-molecule drug screening identifies drug Ro 31-8220 that reduces toxic phosphorylated tau in Drosophila melanogaster.

The intraneuronal aggregates of hyperphosphorylated and misfolded tau (neurofibrillary tangles, NFTs) cause a stereotypical spatiotemporal Alzheimer's disease (AD) progression that correlates with the severity of the associated cognitive decline. Kinase activity contributes to the balance between neuron survival and cell death. Hyperactivation of kinases including the conventional protein kinase C (PKC) is a defective molecular event accompanying associative memory loss, tau phosphorylation, and progression of AD or related neurodegenerative diseases. Here, we investigated the ability of small therapeutic compounds (a custom library) to improve tau-induced rough-eye phenotype in a Drosophila melanogaster model of frontotemporal dementia. We also assessed the tau phosphorylation in vivo and selected hit compounds. Among the potential hits, we investigated Ro 31-8220, described earlier as a potent PKCα inhibitor. Ro 31-8220 robustly improved the rough-eye phenotype, reduced phosphorylated tau species in vitro and in vivo, reversed tau-induced memory impairment, and improved the fly motor functions. In a human neuroblastoma cell line, Ro 31-8220 reduced the PKC activity and the tau phosphorylation pattern, but we also have to acknowledge the compound's wide range of biological activity. Nevertheless, Ro 31-8220 is a novel therapeutic mitigator of tau-induced neurotoxocity.

Novel phased isolation ditch system for enhanced nutrient removal and its optimal operating strategy.

Phased isolation ditch system with intrachannel clarifier is a simplified novel oxidation ditch system enhancing simultaneous removal of biological nitrogen and phosphorus in municipal wastewater. The system employs two ditches with intra-clarifier, and eliminates external final clarifier, additional preanaerobic reactor, and recycle of sludge and nitrified effluent. Separation of anoxic, anaerobic, and aerobic phases can be accomplished by alternating flow and intermittent aeration. Its pilot-scale system operated at HRTs of 10-21 h, SRTs of 15-41 days, and a cycle times of 2-8 h showed removals of BOD, TN, and TP in the range of mixed liquor temperature above 10 degrees C as high as 88-97, 70-84, and 65-90%, respectively. As the SRTs became longer, the effluent TN decreased dramatically, whereas the effluent TP increased. Higher nitrogen removal was accomplished at shorter cycle times, while better phosphorus removal was achieved in longer cycle times. Optimal system operating strategies maximizing the performance and satisfying both the best nitrogen and phosphorus removals included HRTs ranged 10-14 h, SRTs ranged 25-30 days, and a cycle time of 4 h at the mixed liquor temperature above 10 degrees C. Thus, complete phase separation in a cycle maximizing phosphorus release and uptake as well as nitrification and denitrification was accomplished by scheduling of alternating flow and intermittent aeration in the simplified process scheme. Especially, temporal phase separation for phosphorus release without additional anaerobic reactor was successfully accomplished during anaerobic period without any nitrate interference and carbon-limiting.