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)

This work has been selected by scholars as being culturally important and is part of the knowledge base of civilization as we know it. This work is in the public domain in the United States of America, and possibly other nations. Within the United States, you may freely copy and distribute this work, as no entity (individual or corporate) has a copyright on the body of the work. Scholars believe, and we concur, that this work is important enough to be (...) preserved, reproduced, and made generally available to the public. To ensure a quality reading experience, this work has been proofread and republished using a format that seamlessly blends the original graphical elements with text in an easy-to-read typeface. We appreciate your support of the preservation process, and thank you for being an important part of keeping this knowledge alive and relevant. (shrink)

The present study examines the physiological alterations in prolactin (PRL) messenger ribonucleic acid (mRNA) and serum PRL levels during the rat estrous cycle and the effed of naloxone, an endogenous opioid peptide receptor antagonist, on PRL gene expression during the rat estrous cycle. Adult female rats exhibiting at least two consecutive 4-day estrous cycles were used in this study. A single injection of naloxone (2mg/kg b.w.) or saline was given sc 30 mm prior to decapitation. Animals were sacrificed at 10:00 (...) h of each stage of the estrous cycle, and at 2-h intervals from 10:00 h to 20:00 h during the proestrus. PRL mRNA and serum PRL levels were determined by an RNA-blot hybridization with the rat PRL cDNA probe and by a PRL radioimmunoassay, respectively. PRL mRNA and serum PRL levels were not dramatically altered in the morning of each stage of diestrus I, II, and proestrus, and naloxone failed to modify the two parameters. During estrus naloxone clearly suppressed serum PRL levels, but it was unable to modify PRL mRNA levels. A more detailed examination of the proestrus stage revealed that PRL mRNA and serum PRL levels fluctuated as a function of time: PRL mRNA levels reached a maximum level at 12:00 h and gradually decreased until 18:00 h. PRL mRNA levels then rose at 20:00 h. No difference in PRL mRNA levels between the control and naloxone-treated groups was observed. Changes in serum PRL level during proestrus were conversely related to changes in PRL mRNA: serum PRL levels were low from 10:00 h to 14:00 h, then increased and reached a maximum level at 16:00-18:00 h. Following then, serum PRL levels were decreased. Naloxone was effective in suppressing the characteristic afternoon surge of PRL from 16:00 h to 20:00 h. These data clearly showed that alterations in PRL mRNA levels were conversely correlated with changes in serum PRL levels on proestrus, indicating differential regulation of PRL gene expression and secretion. (shrink)

Nad barjem je veter in moker je zrak, uši imam v tuniki, v nosu prehlad. Z neba štropotajo nalivi dežja, vojak sem na zidu, ne vem sploh, zakaj. Po sivem kaménju se plazi megla, dekle imam v Tungriji, jaz pa spim sam.

This pedagogical reader of the Greek text of Plato?s Gorgias, originally published for students in Victorian England, is an immensely helpful textbook for the student of the Greek language and literature. Edited by the prominent W. H. Thompson.

Aesthetics, hermeneutics, criticism -- Social Werktreue and the subjectivization of aesthetics -- From musike to metaphysics -- Formalist aesthetics and musical hermeneutics -- Deconstructing the disciplinary divide -- The question of metaphor -- Mimesis and the hermeneutics of music -- Political critique and the politics of music criticism -- Toward a hermeneutics of music criticism.

First published in 1999. Routledge is an imprint of Taylor & Francis, an informa company.

Some years ago, in the course of a general critique of what has sometimes been referred to as the covering law theory of explanation, I made the claim that perfectly satisfactory explanations can often be provided by indicating only one or a few necessary conditions, where we remain ignorant of the sufficient conditions, of what we nevertheless claim to understand. What seemed to me one identifiable type of such explanations I called “explaining how-possibly,” because it was a type more naturally (...) given in response to the question how it could be that a certain thing happened than to the more familiar question why it did so. In the present paper I propose to review certain objections to this thesis which have come to my attention in the interval, and to make such concessions as these seem to require. In fact, the concessions will be minor, since the general thesis still seems to me quite defensible. (shrink)