The amyloid precursor protein controls PIKfyve function

While the Amyloid Precursor Protein (APP) plays a central role in Alzheimer's disease, its cellular function still remains largely unclear. It was our goal to establish APP function which will provide insights into APP's implication in Alzheimer's disease. Using our recently developed proteo-liposome assay we established the interactome of APP's intracellular domain (known as AICD), thereby identifying novel APP interactors that provide mechanistic insights into APP function. By combining biochemical, cell biological and genetic approaches we validated the functional significance of one of these novel interactors. Here we show that APP binds the PIKfyve complex, an essential kinase for the synthesis of the endosomal phosphoinositide phosphatidylinositol-3,5-bisphosphate. This signalling lipid plays a crucial role in endosomal homeostasis and receptor sorting. Loss of PIKfyve function by mutation causes profound neurodegeneration in mammals. Using C. elegans genetics we demonstrate that APP functionally cooperates with PIKfyve in vivo. This regulation is required for maintaining endosomal and neuronal function. Our findings establish an unexpected role for APP in the regulation of endosomal phosphoinositide metabolism with dramatic consequences for endosomal biology and important implications for our understanding of Alzheimer's disease

A hybrid computational and analytical model of irrigation drip emitters

Thesis: S.M., Massachusetts Institute of Technology, Department of Mechanical Engineering, 2017.Cataloged from PDF version of thesis.Includes bibliographical references (pages 63-65).This thesis details a hybrid computational and analytical model to predict the performance of inline pressure-compensating (PC) drip emitters. A verified CFD model is used to predict flow behavior through tortuous paths. A method of extracting a pressure scaling parameter from the CFD results for use in an analytical model is presented. Analytical expressions that describe the bending of asymmetric rectangular membranes in inline drip emitters are detailed. These expressions are combined with finite element analysis (FEA) describing the shearing behavior of the membrane to model the total flow resistance through the emitter. Analytical expressions that describe the fluid mechanics of duct and turbulent flows are used to predict the net flow rate out of the emitter. The final model is verified for three distinct emitter geometries. The hybrid model presented in this paper has wide applicability - it can be applied to asymmetrical emitter geometries that have tortuous paths and other complex flow geometries. The hybrid model benefits from the accuracy of computational modeling for complex flows and contact interactions, and the processing speed of analytical models. Because of its accuracy and speed, the model can be used reliably as a design tool for inline PC emitters.by Jaya Narain.S.M