The conventional approach to developing disease‐modifying treatments for neurodegenerative conditions has been to identify drivers of pathology and inhibit such pathways. Here we discuss the possibility that the efficacy of such approaches may be increasingly attenuated as disease progresses. This is based on experiments using mouse models of spinocerebellar ataxia type 1 and Huntington's disease (HD), where expression of the dominantly acting mutations could be switched off, as well as studies in human HD, which suggest that the primary genetic driver (...) of age‐of‐onset of disease is a much weaker determinant of disease progression in affected individuals. The idea that one may approach a point in the disease course where such rational therapeutic strategies based on targets which determine onset of disease have minimal efficacy, suggests that one needs to consider other approaches to therapies and clinical trial design, including initiation of therapies in presymptomatic individuals. (shrink)

Autophagy and YAP1‐WWTR1/TAZ signalling are tightly linked in a complex control system of forward and feedback pathways which determine different cellular outcomes in differing cell types at different time‐points after perturbations. Here we extend our previous experimental and modelling approaches to consider two possibilities. First, we have performed additional mathematical modelling to explore how the autophagy‐YAP1 crosstalk may be controlled by posttranslational modifications of components of the pathways. Second, since analogous contrasting results have also been reported for autophagy as a (...) regulator of other transduction pathways engaged in tumorigenesis (Wnt/β‐catenin, TGF‐β/Smads, NF‐kB or XIAP/cIAPs), we have considered if such discrepancies may be explicable through situations involving competing pathways and feedback loops in different cell types, analogous to the autophagy‐YAP/TAZ situation. Since distinct posttranslational modifications dominate those pathways in distinct cells, these need to be understood to enable appropriate cell type‐specific therapeutic strategies for cancers and other diseases. (shrink)

This overview of the "sister arts" of the nineteenth century by younger scholars in art history, literature, and American studies presents a startling array of perspectives on the fundamental role played by images in culture and society. Drawing on the latest thinking about vision and visuality as well as on recent developments in literary theory and cultural studies, the contributors situate paintings, sculpture, monument art, and literary images within a variety of cultural contexts. The volume offers fresh and sometimes extended (...) discussions of single works as well as reevaluations of artistic and literary conventions and analyses of the economic, social, and technological forces that gave them shape and were influenced by them in turn. A wide range of figures are significantly reassessed, including the painters Charles Willson Peale, Washington Allston, Thomas Cole, George Caleb Bingham, Fitz Hugh Lane, and Mary Cassatt, and such writers as James Fenimore Cooper, Nathaniel Hawthorne, Henry David Thoreau, and William Dean Howells. One overarching theme to emerge is the development of an American national subjectivity as it interacted with the transformation of a culture dominated by religious values to one increasingly influenced by commercial imperatives. The essays probe the ways in which artists and writers responded to the changing conditions of the cultural milieu as it was mediated by such factors as class and gender, modes of perception and representation, and conflicting ideals and realities. (shrink)

One of Hume's most well-known works and a masterpiece of philosophy, A Treatise of Human Nature is indubitably worth taking the time to read.

In this article 1 I have two theological interests and a less direct philosophical one.

Whether John Locke's Two Treatises is a justification of revolution or a demand for revolution, it is a book about political revolution. Yet it is also a book about property. This is so not only because of the obviously central place that Locke's discussion of property holds in the Second Treatise but also because his account of when revolution is justified hinges, in three crucial respects, on his account of how private, or, exclusive, rights to property arise.

By means of an example, shows the possibility of beliefs that are separately rational whilst together inconsistent.

William James is frequently considered one of America's most important philosophers, as well as a foundational thinker for the study of religion. Despite his reputation as the founder of pragmatism, he is rarely considered a serious philosopher or religious thinker. In this new interpretation David Lamberth argues that James's major contribution was to develop a systematic metaphysics of experience integrally related to his developing pluralistic and social religious ideas. Lamberth systematically interprets James's radically empiricist world-view and argues for an (...) early dating for his commitment to the metaphysics of radical empiricism. He offers a close reading of Varieties of Religious Experience; and concludes by connecting James's ideas about experience, pluralism and truth to current debates in philosophy, the philosophy of religion, and theology, suggesting James's functional, experiential metaphysics as a conceptual aid in bridging the social and interpretive with the immediate and concrete while avoiding naive realism. (shrink)

I argue that in four important respects locke's views on faith and reason are similar to aquinas' position. However, Locke drew some conclusions from these views with which thomas would not have agreed, And it was concerning these matters that locke was accused of unorthodoxy. I suggest that in the 17th century context some of those charges were justified and that locke's views in any event are inadequate.

We explore ways in which purely qualitative belief change in the AGM tradition throws light on options in the treatment of conditional probability. First, by helping see why it can be useful to go beyond the ratio rule defining conditional from one-place probability. Second, by clarifying what is at stake in different ways of doing that. Third, by suggesting novel forms of conditional probability corresponding to familiar variants of qualitative belief change, and conversely. Likewise, we explain how recent work on (...) the qualitative part of probabilistic inference leads to a very broad class of 'proto-probability' functions. (shrink)

Increasingly, the world seems to shrink due to our ever-expanding technological and communication capacities. Correspondingly, our awareness of other cultures increases. This is especially true in the field of bioethics because the technological progress of medicine throughout the world is causing dramatic and challenging intersections with traditionally held values. Think of the use of pregnancy monitoring technologies like ultrasound to abort fetuses of the “wrong” sex in India, the sale of human organs in and between countries, or the disjunction between (...) the haves and the have-nots in South America when it comes to bone marrow transplants, while thousands of other children die for want of fundamental goods and services like clean water, basic inoculations, and food itself. (shrink)

Disagreement in the sixteenth century on the meaning of the First Commandment prompted dissension over such related issues as the nature of the Lord's Supper, the authority of the Old Testament for the church and the pace of ecclesiastical reform—issues that are still in dispute.

In philosophy of aesthetics, scholars commonly express a commitment to the premise that there is a distinctive type of judgment that can be meaningfully labeled “aesthetic”, and that these judgments are distinctively different from other types of judgments. We argue that, within an Aristotelian framework, there is no clear avenue for meaningfully differentiating “aesthetic” judgment from other types of judgment, and, as such, we aim to question the assumption that aesthetic judgment does in fact constitute a distinctive kind of judgment (...) that is in need of, or can be subject to, distinctive theorizing. We advance our argument primarily through demonstrating that leading contemporary accounts of aesthetic judgment do not successfully distinguish a type of judgment in that they do not tell us how making an aesthetic judgment differs substantially from judging that 2 + 3 = 5, that football is entertaining, or that today is Tuesday. (shrink)

Thomasma and Graber, medical ethics theorists and clinical practitioners, present a definitive examination of the actions that fall under the aegis of euthanasia--the art of painlessly putting to death persons suffering from incurable conditions or diseases. They distinguish active euthanasia as an intentional act that causes death, while passive euthanasia is seen as an intentional act to avoid prolonging the dying process. They maintain that the distinction between these two modes of euthanasia depends not on motive, but on means. The (...) authors present a theoretical discussion of which forms are justified and unjustified, and explore, with the help of case studies, four main perspectives on the issue: those of the individual, the family, the medical profession, and society as a whole. ISBN 0-8264-0470-7: $24.95. (shrink)

Increasingly, the world seems to shrink due to our ever-expanding technological and communication capacities. Correspondingly, our awareness of other cultures increases. This is especially true in the field of bioethics because the technological progress of medicine throughout the world is causing dramatic and challenging intersections with traditionally held values. Think of the use of pregnancy monitoring technologies like ultrasound to abort fetuses of the “wrong” sex in India, the sale of human organs in and between countries, or the disjunction between (...) the haves and the have-nots in South America when it comes to bone marrow transplants, while thousands of other children die for want of fundamental goods and services like clean water, basic inoculations, and food itself. (shrink)

Biology has been advancing with explosive pace over the last few years and in so doing has raised a host of ethical issues. This book, aimed at the general reader, reviews the major advances of recent years in biology and medicine and explores their ethical implications. From birth to death the reader is taken on a tour of human biology - covering genetics, reproduction, development, transplantation, aging, dying and also the use of animals in research and the impact of human (...) populations on this planet. In each chapter there is a sketch of a field's most recent scientific advances, combined with discussions of the ethical and moral principles and implications for social frameworks and public policy raised by those advances. Anybody interested or concerned about the ethical dilemmas caused by advances in science and medicine should read this book. (shrink)

This book offers a rich variety of thoughtful explorations on the nature of the human person especially as related to health care, medicine, and mental health. Rarely are so many different viewpoints collected in one place about the intriguing puzzle that is the concept of person, human dignity, and the special place human beings hold in the goals of healing and the social structures of medical delivery. Ramifications of the theory of personhood are presented for bioethics, genetics, individuality, uniqueness, international (...) law, feminism, and human rights in health care. Intended for professionals in the fields of philosophy of medicine, law, and bioethics, this book will also appeal to psychologists and medical anthropologists. (shrink)