Current theories of breast cancer progression have been greatly influenced by the development and refinement of mouse transgenic and gene targeting technologies. Early transgenic mouse models confirmed the involvement of oncogenes, previously implicated in human breast cancer, by establishing a causal relationship between overexpression or activation of these genes and mammary tumorigenesis. More recently, the importance of genes located at sites of loss of heterozygosity in human breast cancer have been examined in mice by their targeted disruption via homologous recombination. (...) The union of these two approaches allows the generation of complex animal models that more accurately reflect the multistep nature of human breast cancer. This review will examine how the study of transgenic mice has increased our understanding of the molecular events responsible for oncogenic transformation of the mammary gland. BioEssays 22:554–563, 2000. © 2000 John Wiley & Sons, Inc. (shrink)

Variations in levels of apolipoprotein E have been tied to the risk and progression of Alzheimer's disease . Our group has previously compared and contrasted the promoters of the mouse and human ApoE gene promoter sequences and found notable similarities and significant differences that suggest the importance of the APOE promoter's role in the human disease. We examine here three specific single-nucleotide polymorphisms within the human APOE promoter region, specifically at -491 , -427 , and at -219 upstream from the (...) +1 transcription start site. The -219 and -491 polymorphic variations have significant association with instance of AD, and -491AA has significant risk even when stratified for the APOEepsilon4 allele. We also show significant effects on reporter gene expression in neuronal cell cultures, and, notably, these effects are modified by species origin of the cells. The -491 and -219 polymorphisms may have an interactive effect in addition to any independent activity. DNA-protein interactions differ between each polymorphic state. We propose SP1 and GATA as candidates for regulatory control of the -491 and -219 polymorphic sites. This work's significance lies in drawing connection among APOE promoter polymorphisms' associations with AD to functional promoter activity differences and specific changes in DNA-protein interactions in cell culture-based assays. Taken together, these results suggest that APOE expression levels are a risk factor for AD irrespective of APOEepsilon4 allele status. (shrink)

Progressive supranuclear palsy is a movement disorder with prominent tau neuropathology. Brain diseases with abnormal tau deposits are called tauopathies, the most common of which is Alzheimer's disease. Environmental causes of tauopathies include repetitive head trauma associated with some sports. To identify common genetic variation contributing to risk for tauopathies, we carried out a genome-wide association study of 1,114 individuals with PSP and 3,247 controls followed by a second stage in which we genotyped 1,051 cases and 3,560 controls for the (...) stage 1 SNPs that yielded P ≤ 10-3. We found significant previously unidentified signals associated with PSP risk at STX6, EIF2AK3 and MOBP. We confirmed two independent variants in MAPT affecting risk for PSP, one of which influences MAPT brain expression. The genes implicated encode proteins for vesicle-membrane fusion at the Golgi-endosomal interface, for the endoplasmic reticulum unfolded protein response and for a myelin structural component. © 2011 Nature America, Inc. All rights reserved. (shrink)

‘After it, the philosophy of perception cannot be discussed in ways it usually was discussed before.’ This is said about Sense and Sensibilia by Mr Bernard Williams in an article, ‘J. L. Austin's philosophy’, published in the Oxford Magazine of 6 December 1962. It is not quite clear what Mr Williams means by the remark. It might be understood as an endorsement of Austin's insistence that philosophers have lapsed into crudity and error through their neglect of distinctions marked by the (...) rich variety of linguistic expressions in ordinary use. But Mr Williams himself in his article makes some effective criticisms of Austin's opinion that ordinary language is a reservoir of philosophically significant distinctions, and points out also that Austin's own practice in these lectures did not exhibit any close connection between his survey of the variety of the uses of such words as ‘look’, ‘seem’, ‘appear’, and his criticism of theories of perception. (shrink)

The idea that saying it are doings is a platitude among speech act theorists.In the following I argue that the assimilations of the speakers intentions, belieft and desires to the linguistic meaning of expression types in J.R. Searles influential speech act theory precludes or explaining saying truely as doings, iE. speciftcly as linguistic actions.An adequate explanation of speech acts must treat linguistic meaning of expression type and the speakers intentions, beliefs and desires as seperate, but coordinate factors in the performance (...) and understanding of linguistic acts. (shrink)

Information can be public among a group. Whether or not information is public matters, for example, for accounts of interdependent rational choice, of communication, and of joint intention. A standard analysis of public information identifies it with (some variant of) common belief. The latter notion is stipulatively defined as an infinite conjunction: for p to be commonly believed is for it to believed by all members of a group, for all members to believe that all members believe it, and so (...) forth. This analysis is often presupposed without much argument in philosophy. Theoretical entrenchment or intuitions about cases might give some traction on the question, but give little insight about why the identification holds, if it does. The strategy of this paper is to characterize a practical-normative role for information being public, and show that the only things that play that role are (variants of) common belief as stipulatively characterized. In more detail: a functional role for “taking a proposition for granted” in non-isolated decision making is characterized. I then present some minimal conditions under which such an attitude is correctly held. The key assumption links this attitude to beliefs about what is public. From minimal a priori principles, we can argue that a proposition being public among a group entails common commitment to believe among that group. Later sections explore partial converses to this result, the factivity of publicity and publicity from the perspective of outsiders to the group, and objections to the aprioricity of the result deriving from a posteriori existential presuppositions. (shrink)

That space and time should be integrated into a single entity, spacetime, is the great insight of Einstein's special theory of relativity, and leads us to regard spacetime as a fundamental context in which to make sense of the world around us. But it is not the only one. Causality is equally important and at least as far as the special theory goes, it cannot be subsumed under a fundamentally geometrical form of explanation. In fact, the agent of propagation of (...) causal influence is electromagnetic radiation. In this examination, the authors find support for a rationalist approach to physics, never neglecting experimentation, but rejecting a simple empiricist or positivist view of science. (shrink)

Aristotle and the sea battle, by G. E. M. Anscombe.--Aristotle's different possibilities, by K. J. J. Hintikka.--On Aristotle's square of opposition, by M. Thompson.--Categories in Aristotle and in Kant, by J. C. Wilson.--Aristotle's Categories, chapters I-V: translation and notes, by J. L. Ackrill--Aristotle's theory of categories, by J. M. E. Moravcsik.--Essence and accident, by I. M. Copi.--Tithenai ta phainomena, by G. E. L. Owen.--Matter and predication in Aristotle, by J. Owens.--Problems in Metaphysics Z, chapter 13, by M. J. Woods.--The meaning (...) of agathon in the Ethics of Aristotle, by H. A. Prichard.--Agathon and eudaimonia in the Ethics of Aristotle, by J. L. Austin.--The final good in Aristotle's Ethics, by W. F. R. Hardie.--Aristotle on pleasure, by J. O. Urmson.--Bibliography (p. 335-41). (shrink)

The best philosophy of science during the last generation has been highly historical; and the best history of science, highly philosophical. No one has better exemplified this intimate relationship between history and philosophy than has Robert E. Butts in his work. Through out his numerous writings, science, its philosophy, and its history have been treated as a seamless web. The result has been a body of work that is sensitive in its conception, ambitious in its scope, and illuminat ing in (...) its execution. Not only has his work opened new paths of inquiry, but his enthusiasm for the discipline, his encouragement of others (particularly students and younger colleagues), and his tireless efforts to build an international community of scholars, have stimulated the growth of HPS throughout Europe and North America. Many of the essays in this volume reflect that influence. Our title, of course, is deliberately ambiguous. The essays herein are by colleagues and former students, all of us wishing to honour an intimate friend. Happy Birthday, Bob! IX INTRODUCTION The essays herein cover a variety of concerns: from Descartes to reduction, from Galileo to gambling, from Freud's psychoanalysis to Kant's thing-in-itself. But under this diversity there is an approach common to them all. Things are largely done with a concern for and a sensitivity to historical matters (including contemporary history, of course). (shrink)

The author of the acclaimed Gay Fiction Speaks brings us new interviews with twelve prominent gay writers who have emerged in the last decade. Hear Us Out demonstrates how in recent decades the canon of gay fiction has developed, diversified, and expanded its audience into the mainstream. Readers will recognize names like Michael Cunningham, whose Pulitzer Prize-winning novel The Hours inspired the hit movie; and others like Christopher Bram, Bernard Cooper, Stephen McCauley, and Matthew Stadler. These accounts explore the vicissitudes (...) of writing on gay male themes in fiction over the last thirty years--prejudices of the literary marketplace; social and political questions; the impact of AIDS; commonalities between gay male and lesbian fiction... and even some delectable bits of gossip. (shrink)

A decade on after it first published to international acclaim, the seminal Handbook of Organization Studies has been updated to capture exciting new developments in the field. Providing a retrospective and prospective overview of organization studies, this Handbook continues to challenge and inspire readers with its synthesis of knowledge and literature. As ever, contributions have been selected to reflect the diversity of the field. New chapters cover areas such as organizational change, knowledge management and organizational networks.

According to the thought experiment most commonly used to argue against reliabilism, Mr. Truetemp is given an unusual but reliable cognitive faculty. Since he is unaware of the existence of this faculty, its deliverances strike him as rather odd. Many think that Truetemp would not have justified beliefs. Since he satisfies the reliabilist conditions for justified belief, reliabilism appears to be mistaken. I argue that the Truetemp case is underdescribed and that this leads readers to make erroneous assumptions about Truetemp's (...) epistemic situation. After examining empirical studies of actual subjects who, like Truetemp, have received new perceptual faculties, I show that Truetemp must have been endowed with all of the reorganized neural circuitry and cognitive skills that subjects with new perceptual faculties normally acquire during a long and difficult process of adaptation and development. When readers realize how much more the designers of Truetemp's new faculty had to do than simply slip an artificial device under Truetemp's scalp, I find that they no longer think his beliefs would be unjustified. Because the thought experiment fails to support anti-reliabilist intuitions when further details of the case are made explicit, the Truetemp thought experiment does not constitute a clear and decisive counterexample to reliabilism. (shrink)

In this article, Lucas maintains the falseness of Mechanism - the attempt to explain minds as machines - by means of Incompleteness Theorem of Gödel. Gödel’s theorem shows that in any system consistent and adequate for simple arithmetic there are formulae which cannot be proved in the system but that human minds can recognize as true; Lucas points out in his turn that Gödel’s theorem applies to machines because a machine is the concrete instantiation of a formal system: therefore, for (...) every machine consistent and able of doing simple arithmetic, there is a formula that it can’t produce as true but that we can see to be true, and so human minds and machines have to be different. Lucas considers as well in this article some possible objections to his argument: for any Gödelian formula we could, for instance, construct a machine able to produce it or we could put the Gödelian formulae that we had proved as axioms of a further machine. However - as Lucas underlines - for every of such machines we could again formulate another Gödelian formula, the Gödelian formula of these machines, that they are not able to proof but that we can recognize as true. More general arguments, such as the possibility to escape Gödelian argument by suggesting that Gödel’s theorem applies to consistent systems while we could be inconsistent ones, are moreover refuted by Lucas by maintaining that our inconsistency corresponds to occasional malfunctioning of a machine and not to his normal inconsistency; indeed, a inconsistent machine is characterized by producing any statement, on the contrary human being are selective and not disposed to assert anything. (shrink)

Although there is a high degree of consensus in the existing literature regarding the importance of respect in mental health care, a realistic appraisal suggests that there is something of a disconnect between what is espoused in policy documents and what actually occurs in practice. As a result, this article seeks to explore and advance our understanding of the phenomenon of respect in mental health care and draws on real practice situations to illustrate this schism. To this end, the authors (...) present three case studies that focus on the following: “use of seclusion,” “respecting professional boundaries,” and “horizontal workplace violence.” The authors advance the, perhaps for some, provocative argument that it is relatively easy to write/speak about respect, while the reality of communicating respect to others is more difficult, challenging, and makes significant demands on the individual psychiatric/mental health nurse. (shrink)