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)

David Hume is the greatest figure in the empiricist tradition in philosophy and was a particular source of inspiration for the logical positivists (see logical positivism). Hume was born in 1711 and entered Edinburgh University at the age of 12. After graduating, he had a varied career in commerce, diplomacy, as a librarian, and as a writer of history. Twice he was secretary to General St Clair and on one occasion set off with him on an expedition to drive the (...) French out of Canada. Forced back by the wind, it was decided instead to make a brief incursion on the coast of Brittany. This failed, for the expedition had maps of Canada, but none of Brittany. During a three‐year stay in France he wrote his major philosophical work Treatise of Human Nature. It appeared in 1739 and, in his own words, “fell dead‐born from the Press.” His Inquiry Concerning Human Understanding, which was intended to be a more popular version of book I of his Treatise, was published in 1748 but was only a little more favorably received. His six‐volume History of England, on the other hand, was a great success. He died in 1776, never having succeeded in his ambition to be appointed to a professorship of philosophy in Scotland, due to his religious skepticism. (shrink)

The prolific English poet John Lydgate has been known as the “monk of Bury” since the early fifteenth century. Both his popularity and perceptions of his literary merit have fluctuated wildly since his zenith as the famous laureate of Henry V, Henry VI and Duke Humphrey, but readers have been constant in their association of Lydgate with the Benedictine abbey from which the epithet derives. However, there has been remarkably little examination of the details of Lydgate's existence at Bury: the (...) critical emphasis has been on Lydgate's contact with Lancastrian society rather than on his quotidian life as a monk. “To trace in detail the connection between the Bury library and the characteristic configuration of Lydgate's thought and work, to see how his mind was formed and influenced by the books with which he was in such familiar contact” remains an unfulfilled desire. In particular, given the range of Lydgate's literary and intellectual allusions, it is surprising that there has been no full attempt to compare what we know of Bury's sizeable late medieval library, catalogued in the late fourteenth century by Henry Kirkstede, with Lydgate's poetic output. Likewise, few critics have attempted to trace connections between Lydgate's poetry and the intellectual and cultural atmosphere of a grand Benedictine abbey in the late medieval period. This article, a study of one manuscript from Bury that Lydgate certainly handled and that is typical of the type of book he would have encountered in great numbers in the monastic library, endeavours to reassert the importance to his poetry of the environment in which Lydgate spent most of his life. (shrink)

Paul Ricoeur and the Lived Body’s explorations into the ethical, social, cultural, and affective dimensions of our corporeal existence draw on Paul Ricoeur’s reflection on the lived body. Starting with the fact that one’s own body is irreducible to an object, these essays critically contribute to discourses on the body.

In this paper I attempt to trace certain aspects of the evolution of theories of space-time and mechanics as revealed by a brief comparative study of Newtonian theory, Robb's theory, general relativity, and Milne's kinematical relativity. The first object is to emphasise how each theory leaves us in a position in which the succeeding one appears as a perfectly natural next step in the development of ideas. The second object is to show how, in spite of superficial differences in character, (...) the theories all necessarily possess the same general structure constituted by the presence of hypotheses, from which certain general mathematical relations are deduced, which in their turn are used to predict relations between observable quantities. (shrink)

The literary criticism of the Greeks and Romans furnishes some of the most baffling documents which have come down to us from antiquity. Nor could it be otherwise. Few elements of language can be at once so ephemeral and so elusive as the overtones of words used in aesthetic contexts; even in our own language it is only with a conscious effort that the appropriate overtones of words used by quite recent critics can be recalled. Such recall must be much (...) more difficult where the reader is concerned with a dead language; in the case of some terms it may well be virtually impossible; but where the ancient critic is discussing ethical criteria for literature, as Aristotle does in Poetics 13, the modern interpreter is in a somewhat better position, for ethical terms are used in wider contexts, contexts which involve action, and there is more opportunity for studying their usage and endeavouring to recapture their elusive overtones. (shrink)

I believe the time is come for a re-estimation of the status of minds in the universe. I use the word mind quite naïvely at first, in the belief that it has a nucleus of meaning that is sufficiently clear. I do not wish its meaning to be restricted to the phenomena of clear consciousness, still less of self-consciousness.

A number of scholars have discussed the difficulty of preserving accurately—or at all—information about the past1 in the Greek Dark Ages when the literacy of Minoan/Mycenean Greece had been lost. Such preservation necessarily depended on the memories of the members of the society, especially those of the professional ‘rememberers’, the bards of the oral tradition: in such a society, if knowledge of an event is to be available to future generations, it must not be forgotten.