Cyclin-dependent kinase 5 has been implicated in Alzheimer's disease pathogenesis. Here, we demonstrate that overexpression of p25, an activator of cdk5, led to increased levels of BACE1 mRNA and protein in vitro and in vivo. A p25/cdk5 responsive region containing multiple sites for signal transducer and activator of transcription was identified in the BACE1 promoter. STAT3 interacts with the BACE1 promoter, and p25-overexpressing mice had elevated levels of pSTAT3 and BACE1, whereas cdk5-deficient mice had reduced levels. Furthermore, mice with a (...) targeted mutation in the STAT3 cdk5 responsive site had lower levels of BACE1. Increased BACE levels in p25 overexpressing mice correlated with enhanced amyloidogenic processing that could be reversed by a cdk5 inhibitor. These data demonstrate a pathway by which p25/cdk5 increases the amyloidogenic processing of APP through STAT3-mediated transcriptional control of BACE1 that could have implications for AD pathogenesis. (shrink)

Across a wide range of legal contexts, E. Thomas Sullivan and Richard S. Frase identify three basic ways that government measures and private remedies have been ...

The stochastic phase-space solution of the particle localizability problem in relativistic quantum mechanics is reviewed. It leads to relativistically covariant probability measures that give rise to covariant and conserved probability currents. The resulting particle propagators are used in the formulation of stochastic geometries underlying a concept of quantum spacetime that is operationally based on stochastically extended quantum test particles. The epistemological implications of the intrinsic stochasticity of such quantum spacetime frameworks for microcausality, the EPR paradox, etc., are discussed.

In this volume, I have given attention to what I consider to be some of the central problems and topics in the philosophical thought of SJ2jren Kierkegaard. Some of the chapters have been previously publish ed but were revised for their appearance here. Others were written expressly for this book. I have tried to focus on issues which have not been customarily dealt with or emphasized in the scholarship on Kierkegaard with the exception of the writings of David Swenson and (...) Paul L. Holmer to which (and to whom) I am greatly indebted. Some of the positions for which I have argued in this volume (especially in Chapters IV and V) may be controversial. I am grateful to all those who enabled me to carry out or influenced me in my studies of Kierkegaard or who assisted with regard to the research for or preparation of this volume. Among these are: Professors Paul L. Holmer, F. Arthur Jacobson, and Dennis A. Rohatyn; Dean Wallace A. Russell and Vice President Daniel J. Zaffarano of Iowa State University. (shrink)