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)

XLRI, in association with a few Tata Group companies, established the XLRI-JRD Tata Foundation in Business Ethics in 1991 to mark their long-standing commitment and contribution to business ethics in India. The foundation seeks to address this by publicly affirming the urgent need for ethics in business and the need to bring about a conducive culture in which it can thrive.

The juxtaposition of models of God and Christian faith may seem repugnant to many, as models are tentative and faith aims at an abiding certainty. In fact, for many Christians, using models of God in worship amounts to idolatry. By examining Biblical and extra-Biblical views of idolatry, I argue that models are not idols. To the contrary, the practice of God-modeling inoculates Christians against one of the most seductive idols of our age: the love of certainty. Furthermore, by examining meditations (...) upon certainty in Melville’s Moby Dick and the early discourses of the Buddha, I suggest that overweening conviction is a vice that hinders rather than guarantees Christian discipleship, and that Christian faith is better defined as any or all of the following: relative confidence in propositions, faithful relationship, and a virtue of disciplined credulity. (shrink)

A friend, correspondent and intellectual successor to David Ricardo, John Ramsay McCulloch forged his reputation in the emerging field of political economy by publishing deeply researched articles in Scottish periodicals and the Encyclopaedia Britannica. From 1828 he spent nearly a decade as professor of political economy at the newly founded University of London, thereafter becoming comptroller of the Stationery Office. Perhaps the first professional economist, McCulloch had become internationally renowned by the middle of the century, recognised for sharing his ideas (...) through lucid lecturing and writing. The present work, first published in 1845, has been hailed as 'the first systematic account of the theory and policy of public finance'. After a general introductory chapter, the book discusses direct and indirect taxation, before considering national debt and how to deal with it. Several other works written or edited by McCulloch are also reissued in the Cambridge Library Collection. (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 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)

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.

Many of the original Saturday Night Live (SNL) cast and writers believed that cocaine was non‐addictive and that it was a logical drug to use to sustain the long hours of intense preparation necessary for a weekly live show. It's no secret that drugs and alcohol have been fuel for some SNL cast members. In the early days, the culture and writing of SNL were fueled by drugs, particularly cocaine and marijuana. So John Belushi's drug use was not at all (...) unique, and it justified his belief that people in the entertainment business needed to do drugs to cope with pressure and stress. Sadly, though, John and Chris Farley both lost their lives to overdoses at the young age of 33. Although Stuart Smalley pokes fun at the Pollyanna tone of recovery gurus, Al Franken himself has been a great advocate for the kind of twelve‐step programs that Chris Farley succeeded with for a time. (shrink)