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)

A signal challenge of twenty-first century psychiatry is the effective treatment of existential/spiritual suffering in palliative care. This chapter will concentrate on research to assess the therapeutic potential of psilocybin to assuage that suffering. If a “psychedelic experience” can facilitate an acceptance of impending death, and reduce the existential suffering of those who endure it, it could prove to be a valuable intervention where one is sorely needed. The therapeutic use of psilocybin with dying patients (hereinafter patients) raises numerous questions (...) about research trial design, the model of psychiatry that might accommodate it, and the kind of experience it induces. Are these the sorts of experience that psychiatric treatment should effect on troubled patients? Is spiritual care within the ambit of psychiatry? There are epistemological questions as to the veridicality of the psychedelic experience. How much credence should we give it? I will argue in cautious support of ongoing research to evaluate the therapeutic use of psilocybin in palliative care. This argument can be extended to research on its therapeutic use in psychotherapy. The chapter will focus on four questions: (1) what is the ethical justification for this research on patients? (2) What types of research trial design are best used to assess the purported benefits of a psychedelic drug experience? (3) What is the epistemic warrant of the “mystical” and “noetic” facets of this experience? (4) What models of (a) psychiatry and (b) drug action could accommodate the therapeutic use of psilocybin in palliative care? (shrink)

The familiar irony of ‘real existing socialism’ is that it never was. Socialist ideals were used to legitimize regimes that fell far short of realizing those ideals – indeed, that violently repressed anyone who tried to realize them. This paper suggests that the derogatory concept of ‘the criminal’ may be allowing liberal ideals to operate in contemporary political philosophy and real politics in a worryingly similar manner. By depoliticizing deep dissent from the prevailing order of property, this concept can obscure (...) what I call the legitimation gap. This is the gulf between (a) liberal accounts of state legitimacy, and (b) the actual functioning of liberal states. Feminists have long pointed out that the exclusion of what is deemed ‘personal’ from political consideration is itself a political move. I propose that the construction of the criminal as a category opposed to the political works similarly to perpetuate unjust forms of social power. (shrink)

We argue performance in the serial reaction time task is associated with gradations of awareness that provide examples of fringe consciousness [Mangan, B. . Taking phenomenology seriously: the “fringe” and its implications for cognitive research. Consciousness and Cognition, 2, 89–108, Mangan, B. . The conscious “fringe”: Bringing William James up to date. In B. J. Baars, W. P. Banks & J. B. Newman , Essential sources in the scientific study of consciousness . Cambridge, MA: The MIT Press.], and address limitations (...) of the traditional SRT procedure, including criticism of exclusion generation tasks. Two experiments are conducted with a modified SRT procedure where irrelevant stimulus attributes obscure the sequence rule. Our modified paradigm, which includes a novel exclusion task, makes it easier to demonstrate a previously controversial influence of response stimulus interval on awareness. It also allows identification of participants showing fringe consciousness rather than explicit sequence knowledge, as reflected by dissociations between different awareness measures. The NEO-PI-R variable Openness to Feelings influenced the diversity of subjective feelings reported during two awareness measures, but not the degree of learning and awareness as previously found with traditional SRT tasks [Norman, E., Price, M. C., & Duff, S. C. . Fringe consciousness in sequence learning: the influence of individual differences. Consciousness and Cognition, 15, 723–760.]. This suggests possible distinctions between two components of fringe consciousness. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Reviewed by:Plutarch's Lives: Exploring Virtue and ViceFrances B. TitchenerTim Duff. Plutarch's Lives: Exploring Virtue and Vice. Oxford: Clarendon Press, 1999. xx + 423 pp. Cloth, $95.This excellent book by an able scholar will set a new standard in Plutarch studies, particularly for scholars interested in historiography and moral philosophy. Here is Duff's aim in his own words: "This book is an attempt to explore two related aspects of the (...) ParallelLives: their moralizing purpose and the comparative [End Page 586] structure through which Plutarch's moralism is so often mediated. It will look at the ways in which the ParallelLives explore issues of right and wrong, good and evil; the ways in which they cause us to question or to understand our world" (1). Duff describes his book as "an attempt to read Plutarch's Lives not as mines for history but as an area of study in their own right, and one which throws light on the intellectual climate of Plutarch's own day. It is less concerned with the 'truth-status' of Plutarch's narrative, more with how that narrative is constructed and how it would have been read in its original context" (9). Duff succeeds brilliantly in both areas, Plutarch's moralism and his place in historiography.The book is divided into three parts. Part 1, entitled "The Moralizing Programme," presents a detailed reading of Plutarch's surviving programmatic statements (such as the question of "great natures"), examines how well he succeeds in his aim of improving the reader, and discusses his assumptions about human psychology. Part 2 uses case studies of specific pairs of biographies, a tried-and-true method for students of Plutarch, to examine the moral and literary program in practice. The pairs Duff selects are Pyrrhos-Marius,Phokion-CatoMinor,Lysander-Sulla, and Coriolanus-Alkibiades (Duff adheres to literal transliteration, not on a whim, but rather from a strong belief that "to Latinize the Greek would be a reversal of Plutarch's cultural programme, which functioned to Hellenize the Roman" [xii, Duff's emphasis]). There is a substantial discussion about the parallelism of the biographies and a plea for them to be read in pairs, as their author intended. Part 3 examines "two special circumstances," the comparisons or synkriseis and the cultural and political implications of Plutarch's program of writing in parallel.In his preface, Duff notes, "It is a pleasing coincidence, and one which Plutarch would have enjoyed (see Sertorius 1.1-8), that the last monograph to be written in English on Plutarch's Lives was by one of my predecessors at Reading (Wardman 1974)" (ix). Duff bases his comparison of his work with Wardman's on their common academic institution, but the comparison is actually much more apt. For years, Wardman's book Plutarch'sLives set an important standard in Plutarch studies. Scholars in the earlier part of the twentieth century studied Plutarch almost exclusively in terms of Quellenforschung. Most serious scholarship on the biographies began by rehearsing the argument about whether or not Plutarch had read Thucydides or was using a kind of handbook, and by necessity focused on rehabilitation of the biographer. Wardman's book took a big step forward in studying Plutarch for his own sake; Duff's is another such step forward. Duff is simultaneously thorough and methodical in his analysis of not only the daunting corpus of Plutarch's own work but also of the tremendous bibliography amassed during the past century, and yet his emphasis on synkrisis and its significance to studies of historiography (biography in particular) and of Plutarch's work moves these areas of study forward. With his careful attention and clear prose, Duff has relieved an entire generation of scholars from the tedium of rehearsing basic issues, such as whether or not Plutarch knew Latin (he did). [End Page 587] Duff's calm, organized, and clear-sighted work gracefully retires these nonproblems, and we can now hope that discussion will continue to move forward unencumbered. For scholars of Plutarch this relief is hard to exaggerate. Plutarch is a compelling and provocative author, something justly recognized by Duff in his concluding paragraph: "This book has emphasized throughout... (shrink)

In recent years important contributions to the interpretation of the eighth book of Lucan have been made by Professor Postgate , and by Mr.J.D.Duff .The following notes make a further attempt to solve some of the many problems presented by the book.

[opening paragraph]: Our sense of free will depends upon a balance between reliability and flexibility in relation to cause-and-effect. Without the former, all outcomes would be arbitrary; without the latter, all outcomes would be predetermined. In neither case would there be any way of putting one's will into effect. So much is clear, yet establishing that precarious balance has proved so difficult that Kant himself declared ‘freedom of the will’ to be one of only three metaphysical problems which lie beyond (...) the powers of the human intellect . Western debate on this topic reflects a complex ethical and religious inheritance. Insights from Greek philosophy and Hebrew scripture were combined and filtered through Christian and Jewish traditions which developed in late antiquity and through the middle ages. These formed the context for the Enlightenment, whose dominant thinkers in turn provide the backdrop against which today's scholars act and react. (shrink)

One of the most troubling aspects of dealing with past injustice in the former East Block is the conflict between positive law and law as the expression of higher principles of justice. In his Die Metaphysik der Sitten, Kant attempts to give content to, and place limitations on, what one may reasonably call "law". The purpose of this paper is to examine Kant's theories of commutative justice in a state of nature and distributive justice in a civil state in an (...) effort to define principles that are binding for every legal system. The paper examines two sets of four cases, namely 1) equity, necessity, pardons and duels; and 2) gifts, loans, bona fide purchasers and oaths, where Kant establishes limitations on state power with respect to the individual and to the society of individuals as a whole. Kant's legal system reveals itself to be a system devoted to liberal individualism and the maximum of protection of individual liberties. Einer der am meisten beunruhigenden Aspekte beim Umgang mit vergangenem Unrecht im früheren Ostblock besteht in dem Konflikt zwischen positivem Recht einerseits und Recht als Ausdruck höherer Prinzipien der Gerechtigkeit andererseits. In seinem Werk Die Metaphysik der Sitten versucht Kant, Inhalt und Grenzen dessen zu bestimmen, was man vernünftigerweise als "Recht" bezeichnen kann. Die Aufgabe dieses Beitrags besteht darin, Kants Theorien kommutativer Gerechtigkeit im Naturzustand sowie distributiver Gerechtigkeit im bürgerlichen Zustand zu untersuchen, um auf diese Weise Prinzipien zu ermitteln, die für jedes Rechtssystem bindend sind. Es werden dabei zwei Gruppen von je vier Fällen näher betrachtet, und zwar 1) Billigkeit, Notstand, Duell und Gnadenerweis sowie 2) Schenkung, Leihe, Gutglaubenserwerb und Eidesleistung, in denen Kant der staatlichen Macht im Hinblick auf das Individuum und die Gesellschaft der Individuen insgesamt Grenzen zieht. Kants Rechtssystem erweist sich hier als ein System, das dem liberalen Individualismus und einem maximalen Schutz individueller Freiheit verpflichtet ist. (shrink)

Isolation in the back-country: George Chamier, G.B. Lancaster, Katherine Mansfield, John Mulgan, and Graham Billing -- Outsiders and misfits in fragmented social milieux: William Satchell, Vincent Pyke, John A. Lee, Robin Hyde, Frank Sargeson, and others -- The lonely and the alone in the fiction of Janet Frame -- Maurice Gee and postmodern isolation -- Women, isolation, and history: Fiona Kidman, Noel Hilliard, and Patricia Grace -- Cultural deracination and isolation : Witi Ihimaera, Keri Hulme, and Alan Duff.