Multidrug resistance resulting from expression of an energy‐dependent drug efflux pump encoded by the human MDR1 gene is a major impediment to effective cancer therapy. Pharmacologic intervention aimed at inhibiting this multidrug transporter should improve existing chemotherapy of human cancer, but drug development has been delayed by the difficulty and expense of developing valid animal models. Using recombinant DNA technology, a transgenic mouse has been engineered whose bone marrow is protected from the toxic effects of chemotherapy by expression of the (...) MDR1 gene. This animal system allows the rapid screening of drugs which inhibit the multidrug transporter and heralds a new era of using transgenic animals for pharmacologic screening. (shrink)

The Psalter exhibits a complex literary structure that not only determines its shape but also provides the reader with interpretive clues for reading both the whole and its parts.

A non-universal Immediate Dominance Condition on identity deletion is proposed to explain the systematic differences between languages like Chinese and languages like English in their respective patterns of coordination, topicalization, dislocation, and relativization. By assuming that this condition holds for languages of the Chinese-type, but not for those of the English-type, it is possible to account for the well-formed coordinations of all languages by means of a single universal principle of coordination reduction, and it is possible to derive the well-formed (...) topicalizations, dislocations, and relative clause constructions of all languages by means of the same set of universal principles of Copying, Deletion, and Pronominalization. (shrink)

This study explores linkages between what Chinese managers generally know about environmental issues, how strongly they value environmental protection, and different types of behaviours/actions they may take within their organizations on behalf of the environment. From a sample of 305 managers in Guangzhou and Beijing, it was found that both environmental knowledge and values are more predictive of more personal managerial behaviours, such as keeping informed of relevant company issues and working within the system to minimize environmental impacts, than more (...) overt behaviours. Moreover, for these more personal actions, environmental knowledge and values were found to have both main and interactive effects. By comparison, it was found that both environmental values and knowledge had additive effects on managerial tendencies to initiate new programs within their domain of responsibility. Only environmental values was found to have a modest influence environmental advocacy. (shrink)

The mechanistic significance of a kinetic isotope effect on a cytochrome P‐450catalyzed reaction depends, fundamentally, on the nature of the interaction of the substrate with the active site of the enzyme as well as on the nature of the chemistry of the reaction catalyzed. Consequently, kinetic isotope effects can be used to extract information on the topology of the enzyme and the mechanism of substrate oxidation. Kinetic isotope effect studies are sometimes accompanied by ‘metabolic switching’ or a change in metabolic (...) pathway, catalyzed either by the same enzyme or by a different enzyme. For the specific case where ‘metabolic switching’ gives rise to a change in regional specificity for the cytochrome P‐450 catalyzed metabolism of a compound, this change can be explained in terms of the topological constraints on substrate binding imposed by the active site of the enzyme. (shrink)

The vertebrate retina is said to be inverted because the photoreceptors are oriented in the posterior direction and are thus unable to maximize photodetection under conditions of low illumination. The tapetum lucidum is a photoreflective structure located posterior to the photoreceptors in the eyes of some fish and terrestrial animals. The tapetum reflects light forward, giving incident photons a “second chance” to collide with a photoreceptor, substantially enhancing retinal photosensitivity in dim light. Across vertebrates (and arthropods), there are a wide (...) variety of tapeta that vary in structure, chemical composition, and even tissue architecture, indicating repeated convergent evolution. To date, the tapetum has not been observed in any cephalopod, however, which also possess a camera‐like eye, but with the retinal photoreceptors oriented in the anterior direction. We therefore hypothesize that the tapetum lucidum is a compensatory adaptation for the suboptimal design of the inverted retina of vertebrates. (shrink)

Mortal and immortal DNA : Craig Venter and the lure of "lamia" -- Homeopathy : Holmes, hogwarts, and the Prince of Wales -- Citizen Pinel and the madman at Bellevue -- The experimental pathology of stress : Hans Selye to Paris Hilton -- Gore's fever and Dante's Inferno : Chikungunya reaches Ravenna -- Giving things their proper names : Carl Linnaeus and W.H. Auden -- Spinal irritation and fibromyalgia : Lincoln's surgeon general and the three graces -- Tithonus and the (...) fruit fly : new science and old myths -- Swiftboating "America the beautiful" : Katharine Lee Bates and a Boston marriage -- Nothing makes sense in medicine except in the light of biology -- Apply directly to the forehead : Holmes, Zola, and Hennapecia -- Elizabeth Blackwell breaks the bonds -- Chronic lyme disease and medically unexplained syndromes -- Eugenics and the immigrant : Rosalyn Yalow and Rita Levi-Montalcini -- Science in the Middle East : Robert Koch and the cholera war -- How to win a Nobel prize : thinking inside and outside the box -- Homer Smith and the lungfish : the last gasp of intelligent design -- DDT is back : let us spray! -- Academic boycotts and the Royal Society -- Teach evolution, learn science : John William Draper and the "bone bill" -- Diderot and the yeti crab : the encyclopedias of life -- Dengue fever in Rio : Macumba versus Voltaire. (shrink)

Drug Safety Communications are used by the Food and Drug Administration to inform health care providers, patients, caregivers, and the general public about safety issues related to FDA-approved drugs. To assess patient knowledge of the messaging contained in DSCs related to the sleep aids zolpidem and eszopiclone, we conducted a large, cross-sectional patient survey of 1,982 commercially insured patients selected by stratified random sampling from the Optum Research Database who had filled at least two prescriptions for either zolpidem or eszopiclone (...) between July 1, 2012 and June 30, 2013. Among the 594 respondents, two-thirds reported hearing generally about drug safety information prior to starting a new drug, with the remaining one-third “rarely” or “never” hearing such information. Providers and pharmacists were primary sources of drug safety information. Two-thirds of zolpidem users and half of eszopiclone users reported having heard about the related DSC messages, ability to accurately identify the major factual messages was limited. Respondents reacted to new drug safety information about their sleep aids by reporting that they would want to learn about alternative ways to help them sleep and seek out more information about the safety of their specific sleeping pill. Opportunities may exist for the FDA to work with providers and pharmacies to help ensure the DSC information is more widely received and is more fully understood by those taking the affected medications. (shrink)

This volume is a “state-of-the-art‘ assessment of comparative philosophy written by some of the leading practitioners of the field. While its primary focus is on gaining methodological clarity regarding the comparative enterprise of “interpreting across boundaries,‘ the book also contains new substantive essays on Indian, Chinese, Japanese, and European thought. The contributors are Roger T. Ames, William Theodore de Bary, Wing-tsit Chan, A. S. Cua, Eliot Deutsch, Charles Hartshorne, Daya Krishna, Gerald James Larson, Sengaku Mayeda, Hajime Nakamura, Raimundo Panikkar, (...) Karl H. Potter, Henry Rosemont, Jr., Ben-Ami Scharfstein, Ninian Smart, Fritz Staal, and Frederick J. Streng. Comparative or cross-cultural philosophy can be seen as a relative newcomer to the field of philosophy. It has its antecedents in the emergence of comparative studies in nineteenth-century European intellectual history, as well as in the sequence of East-West Philosophers’ Conferences at the University of Hawaii, which began in 1939. This book will prove to be of great significance in helping to define a field that is only now becoming fully self-conscious, methodologically and substantively, about its role and function in the larger enterprises of philosophy and comparative studies. (shrink)

Nowhere has H.L.A. Hart's influence on philosophical jurisprudence in the English-speaking world been greater than in the way its fundamental project and method are conceived by its practitioners. Disagreements abound, of course. Philosophers debate the extent to which jurisprudence can or should proceed without appeal to moral or other values. They disagree about which participant perspective—that of the judge, lawyer, citizen, or “bad man”—is primary and about what taking up the participant perspective commits the theorist to. However, virtually unchallenged is (...) the view that jurisprudence is fundamentally interpretive or “hermeneutic”; that it takes for its subject a certain kind of social practice, constituted by the behavior and understandings of its participants; that its task is to explain this practice and its relations to other important social practices; and that it can properly be explained only by taking full account of participant understandings. It is, perhaps, some measure of the hegemony of Hart's influence that Ronald Dworkin mounts his fundamental challenge to Hart's positivism squarely from within this jurisprudential orthodoxy. Dworkin may have exceeded the limits of the method as Hart conceived it, but, as Stephen Perry has argued, “the seeds of Dworkin's strong version of inter-pretivism were sown by Hart himself.”. (shrink)

First published in 1983. The primary argument of this book is that there is a coherent tradition of liberal thinking that extends from L. S. Mill, through liberals like T. H. Green, Bernard Bosanquet, L. T. Hobhouse and John Dewey to John Rawls. The author places Rawls within a longstanding tradition of liberal thinking, while also arguing that Green and Hobhouse are not simply of historical interest but represent genuine and interesting attempts to develop a modern liberal theory. It is (...) argued that modern liberal theory centres on a conception of human nature; that modern liberals have sought to harmonise the pursuit of individuality with participation in social and communal life. Although the book focuses on six modern liberals, the discussion proceeds topically rather than according to author, thus highlighting similarities and disagreements and providing a comprehensive study of modern liberalism. (shrink)