Nicotinamide as a Neuroprotective Agent in Mouse Models with Delayed Hypoxemia Following TBI

From the Washington University Office of Undergraduate Research Digest (WUURD), Vol. 13, 05-01-2018. Published by the Office of Undergraduate Research. Joy Zalis Kiefer, Director of Undergraduate Research and Associate Dean in the College of Arts & Sciences; Lindsey Paunovich, Editor; Helen Human, Programs Manager and Assistant Dean in the College of Arts and Sciences Mentor(s): Stuart Fries

Cognitive Optimization in Assistive Living System Development

This paper presents an exploration of the characteristics and structure of a cognitive architecture for control of assisted living systems. The aspects of cognition considered are self-organization, communication, and inherited knowledge. A cognitive solution for a related problem, function optimization, is developed because of the complexity and size of the assistive living problem. Support for this approach stems from the artificial intelligence field where optimization is considered to be a critical aspect of cognition, and from the similarity between the performance metrics for the two problem domains. A search algorithm is developed using the bracketing and gradient methods as inherited knowledge. A key finding is that using a cognitive structure caused the search to display aspects of the characteristics, behavior, and performance of human cognition. In terms of performance, the cognitive search converges faster than either the bracketing or gradient searches alone, and its feasible problem set is larger than the intersection of their individual sets. Similarly, human cognition acts quickly and can address a large set of dissimilar problems. This gives confidence that the guidelines distilled from the development of the cognitive search can produce a similar level of performance when applied to an assistive living system. However, this paper does not address the details involved in actually implementing these guidelines on an assistive living system

Post-translational regulation of FNIP1 creates a rheostat for the molecular chaperone Hsp90

The molecular chaperone Hsp90 stabilizes and activates client proteins. Co-chaperones and post-translational modifications tightly regulate Hsp90 function and consequently lead to activation of clients. However, it is unclear whether this process occurs abruptly or gradually in the cellular context. We show that casein kinase-2 phosphorylation of the co-chaperone folliculin-interacting protein 1 (FNIP1) on priming serine-938 and subsequent relay phosphorylation on serine-939, 941, 946, and 948 promotes its gradual interaction with Hsp90. This leads to incremental inhibition of Hsp90 ATPase activity and gradual activation of both kinase and non-kinase clients. We further demonstrate that serine/threonine protein phosphatase 5 (PP5) dephosphorylates FNIP1, allowing the addition of O-GlcNAc (O-linked N-acetylglucosamine) to the priming serine-938. This process antagonizes phosphorylation of FNIP1, preventing its interaction with Hsp90, and consequently promotes FNIP1 lysine-1119 ubiquitination and proteasomal degradation. These findings provide a mechanism for gradual activation of the client proteins through intricate crosstalk of post-translational modifications of the co-chaperone FNIP1