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)

‘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)

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)

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)

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)

In La filosofia dell’arte, Giovanni Gentile assigned a prominent new role to the sentiments. This change struck some critics as a major departure from the earlier, classic accounts of actual idealism, in which Gentile argued that thought and language comprise the entirety of reality. Sentiments do not fit cleanly into a theory so narrowly concerned with thought and thinking. Their introduction, runs the objection, only compounds certain existing ambiguities in Gentile’s conception of the relation between mind and world. This article (...) describes and criticizes Gentile’s attempts to integrate feeling into actual idealism. It is argued that the appearance of feeling in his mature theory does not undermine but instead clarifies his views on the relation between thought and the act of thinking. Yet it also shows the strain under which idealist language was being put by the late 1920s. Gentile’s attempts to lay out a comprehensive and phenomenologically accurate account of how thinkers actually experience... (shrink)

In this article I examine the metaphysical foundations of Guido de Ruggiero’s liberalism and ask what these can tell us about his changing view of Giovanni Gentile's actualism, which was such an influence on de Ruggiero before the First World War. I argue that de Ruggiero’s ‘actualism’ was never the same as Gentile’s, but was drawn from the same intellectual sources; that the actualist conception of free and self-conscious agency runs through both versions of the doctrine, though interpreted in different (...) ways; and finally that the contrasts between de Ruggiero’s and Gentile’s political allegiances result from something other than their differing interpretations of actualism, which serves, in the end, not so much as a theory as a set of basic principles, images and ideals that each philosopher tried to modify and match to the political circumstances in which he found himself. (shrink)

Originally published in 1934, this book contains the Cromer Greek Prize-winning essay for that year on the subject of the still little-understood Greek religion Orphism. Watmough examines Orpheus and Orphism through a distinctly Protestant lens, arguing that both were religions 'of reform' sharing similar views on asceticism and the wages of sin in the afterlife. This book will be of value to anyone with an interest in Greek mysticism and ancient religion.

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.

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)

In the present research, two studies test the efficacy of an innovative procedure designed to reduce distortion and enhance communication of accurate childhood memories. One hundred two 7-year-olds participated in a staged activity and were randomly assigned to one of two treatment conditions . Two weeks later, half of the children participated in the innovative procedure designed to increase resistance to misleading questions by addressing sociolinguistic and socioemotional factors thought to promote acquiescence to misinformation. The other half of the children (...) participated in control sessions and were given motivating instructions to do their best. Then, memory for the staged activity was tested in an interview with an unfamiliar authority figure. The results of both studies suggest that the children who participated in the innovative procedure made significantly fewer errors in response to misleading questions than children in the control groups, hence diminishing acquiescence. This was accomplished without generating additional errors on the other question types. These findings are interpreted as a promising first step toward reducing the potential for distortion in the recall of childhood memories. Implications for adult recall of childhood trauma are discussed. (shrink)

A change in sense of self is an outcome commonly associated with Buddhist meditation. However, the sense of self is construed in multiple ways, and which changes in self-related processing are expected, intended, or possible through meditation is not well understood. In a qualitative study of meditation-related challenges, six discrete changes in sense of self were reported by Buddhist meditators: change in narrative self, loss of sense of ownership, loss of sense of agency, change in sense of embodiment, change in (...) self-other or self-world boundaries, and loss of sense of basic self. Changes in sense of self could be transient or enduring, positive or distressing, enhancing or impairing. These changes were also given varied appraisals, ranging from insights associated with Buddhist doctrines to psychopathologies such as depersonalization. In this study of practitioners reporting meditation-related challenges, more global changes in sense of self were associated with higher levels of impairment. These results have implications for both Buddhist meditation as well as mindfulness-based interventions. (shrink)

This article investigates the claim that some truths are fundamentally or really true — and that other truths are not. Such a distinction can help us reconcile radically minimal metaphysical views with the verities of common sense. I develop an understanding of the distinction whereby Fundamentality is not itself a metaphysical distinction, but rather a device that must be presupposed to express metaphysical distinctions. Drawing on recent work by Rayo on anti-Quinean theories of ontological commitments, I formulate a rigourous theory (...) of the notion. In the final sections, I show how this package dovetails with ' interpretationist' theories of meaning to give sober content to thought that some things — perhaps sets, or gerrymandered mereological sums — can be 'postulated into existence'. (shrink)

This paper examines two puzzles of indeterminacy. The first puzzle concerns the hypothesis that there is a unified phenomenon of indeterminacy. How are we to reconcile this with the apparent diversity of reactions that indeterminacy prompts? The second puzzle focuses narrowly on borderline cases of vague predicates. How are we to account for the lack of theoretical consensus about what the proper reaction to borderline cases is? I suggest (building on work by Maudlin) that the characteristic feature of indeterminacy is (...) alethic normative silence, and use this to explain both plurality and lack of consensus. (shrink)