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Abstract Changes in brain mitochondrial metabolism are coincident with functional decline; however, direct links between the two have not been established. Here, we show that mitochondrial targeting via the adiponectin receptor activator AdipoRon (AR) clears neurofibrillary tangles (NFTs) and rescues neuronal tauopathy-associated defects. AR reduced levels of phospho-tau and lowered NFT burden by a mechanism involving the energy-sensing kinase AMPK and the growth-sensing kinase GSK3b. The transcriptional response to AR included broad metabolic and functional pathways. Induction of lysosomal pathways involved activation of LC3 and p62, and restoration of neuronal outgrowth required the stress-responsive kinase JNK. Negative consequences of NFTs on mitochondrial activity, ATP production, and lipid stores were corrected. Defects in electrophysiological measures (e.g., resting potential, resistance, spiking profiles) were also corrected. These findings reveal a network linking mitochondrial function, cellular maintenance processes, and electrical aspects of neuronal function that can be targeted via adiponectin receptor activation. 

Ookami [3] is a computer technology testbed supported by the United States National Science Foundation. It provides researchers with access to the A64FX processor developed by Fujitsu [17] in collaboration with RIKΞN [35, 37] for the Japanese path to exascale computing, as deployed in Fugaku [36], the fastest computer in the world [34]. By focusing on crucial architectural details, the ARM-based, multi-core, 512-bit SIMD-vector processor with ultrahigh-bandwidth memory promises to retain familiar and successful programming models while achieving very high performance for a wide range of applications. We review relevant technology and system details, and the main body of the paper focuses on initial experiences with the hardware and software ecosystem for micro-benchmarks, mini-apps, and full applications, and starts to answer questions about where such technologies fit into the NSF ecosystem.