Oxidative damage to DNA has been associated with neurodegenerative diseases. Developmental exposure to lead has been shown to elevate the Alzheimer's disease related beta-amyloid peptide , which is known to generate reactive oxygen species in the aging brain. This study measures the lifetime cerebral 8-hydroxy-2'-deoxyguanosine levels and the activity of the DNA repair enzyme 8-oxoguanine DNA glycosylase in rats developmentally exposed to Pb. Oxo8dG was transiently modulated early in life , but was later elevated 20 months after exposure to Pb (...) had ceased, while Ogg1 activity was not altered. Furthermore, an age-dependent loss in the inverse correlation between Ogg1 activity and oxo8dG accumulation was observed. The effect of Pb on oxo8dG levels did not occur if animals were exposed to Pb in old age. These increases in DNA damage occurred in the absence of any Pb-induced changes in copper/zinc-superoxide dismutase , manganese-SOD , and reduced-form glutathion . These data suggest that oxidative damage and neurodegeneration in the aging brain could be impacted by the developmental disturbances. (shrink)

Alzheimer's disease is characterized by amyloid-beta peptide -loaded plaques in the brain. Abeta is a cleavage fragment of amyloid-beta protein precursor and over production of APP may lead to amyloidogenesis. The regulatory region of the APP gene contains consensus sites recognized by the transcription factor, specificity protein 1 , which has been shown to be required for the regulation of APP and Abeta. To understand the role of SP1 in APP biogenesis, herein we have characterized the relative distribution and localization (...) of SP1, APP, and Abeta in various brain regions of rodent and primate models using immunohistochemistry. We observed that overall distribution and cellular localization of SP1, APP, and Abeta are similar and neuronal in origin. Their distribution is abundant in various layers of neocortex, but restricted to the Purkinje cell layer of the cerebellum, and the pyramidal cell layer of hippocampus. These findings suggest that overproduction of Abeta in vivo may be associated with transcriptional pathways involving SP1 and the APP gene. (shrink)

Alzheimer's disease is characterized by plaques of amyloid-beta peptide, cleaved from amyloid-beta protein precursor . Our hypothesis is that lifespan profiles of AD-associated mRNA and protein levels in monkeys would differ from mice and that differential lifespan expression profiles would be useful to understand human AD pathogenesis. We compared profiles of AbetaPP mRNA, AbetaPP protein, and Abeta levels in rodents and primates. We also tracked a transcriptional regulator of the AbetaPP gene, specificity protein 1 , and the beta amyloid precursor (...) cleaving enzyme . In mice, AbetaPP and SP1 mRNA and their protein products were elevated late in life; Abeta levels declined in old age. In monkeys, SP1, AbetaPP, and BACE1 mRNA declined in old age, while protein products and Abeta levels rose. Proteolytic processing in both species did not match production of Abeta. In primates, AbetaPP and SP1 mRNA levels coordinate, but an inverse relationship exists with corresponding protein products as well as Abeta levels. Comparison of human DNA and mRNA sequences to monkey and mouse counterparts revealed structural features that may explain differences in transcriptional and translational processing. These findings are important for selecting appropriate models for AD and other age-related diseases. (shrink)

The sporadic nature of Alzheimer's disease argues for an environmental link that may drive AD pathogenesis; however, the triggering factors and the period of their action are unknown. Recent studies in rodents have shown that exposure to lead during brain development predetermined the expression and regulation of the amyloid precursor protein and its amyloidogenic beta-amyloid product in old age. Here, we report that the expression of AD-related genes [APP, BACE1 ] as well as their transcriptional regulator were elevated in aged (...) monkeys exposed to Pb as infants. Furthermore, developmental exposure to Pb altered the levels, characteristics, and intracellular distribution of Abeta staining and amyloid plaques in the frontal association cortex. These latent effects were accompanied by a decrease in DNA methyltransferase activity and higher levels of oxidative damage to DNA, indicating that epigenetic imprinting in early life influenced the expression of AD-related genes and promoted DNA damage and pathogenesis. These data suggest that AD pathogenesis is influenced by early life exposures and argue for both an environmental trigger and a developmental origin of AD. (shrink)

Contributed articles on Buddhist doctrines and philosophy; festschrift in honor of Narayan Hemandas Samtani, Buddhist scholar.

In recent years the writings of Ludwig Wittgenstein have received much attention from philosophers in general and especially from philosophers interested in religion; and there is no doubt that Wittgenstein's legacy of thought is both highly suggestive and highly problematical. It seems likely, however, that the vogue which Wittgenstein now enjoys owes not a little to his peculiar place in the development of modern philosophy and, in particular, of that empiricist tradition in philosophy which stems from what has been called (...) the revolution in philosophy in the early decades of the present century. (shrink)

In his book on Karl Barth Professor T. F. Torrance spoke at one point of ‘the great watershed of modern theology’. ‘There are,’ he wrote, 1 ‘two basic issues here. On the one hand, it is the very substance of the Christian faith that is at stake, and on the other hand, it is the fundamental nature of scientific method, in its critical and methodological renunciation of prior understanding, that is at stake. This is the great watershed of modern theology: (...) either we take the one way or the other – there is no third alter native… one must go either in the direction taken by Barth or in the direction taken by Bultmann.’. (shrink)

Educational theory; knowledge; sufism, an analytical treatise.

Dewey's 1896 paper, "The Reflex Arc Concept in Psychology," was acclaimed 50 years later as the most important paper published in The Psychological Review in its first half-century of history. Today, Dewey's paper appears to be headed toward oblivion. Considering it worthy of resurrection, we use it as a starting point for tracing out the gradual evolution of Dewey and Bentley's formulation of their transactional viewpoint to its culmination in their book, Knowing and the Known. An exposition of the transactional (...) paradigm is developed via competing, contemporary self-actional and interactional theoretical systems. Then, the space-time postulates of self-actional, interactional, and transactional approaches are spelled out as they enter into philosophical, biological and psychological inquiry. Among prevailing theories, most of which fall into the self-actional/interactional categories, Kantor's interbehavioral viewpoint stands apart from the rest. And while it shares a certain similarity with the transactional approach, the historical record should document it as an independent and parallel development, dating back to Kantor's first publications almost seven decades ago. Furthermore, Kantor's system goes far beyond Dewey and Bentley's "unfractured observation," by providing highly refined analytic procedures in his theoretical constructs. (shrink)

Do people morally deserve what they earn in the market? More specifically, can people legitimately claim to deserve what they earn in the market in a way that counts against redistributing those earnings? As most liberal political philosophers do, I argue that the answer is no. Unlike many of these philosophers, however, I do not focus on whether or not people can be deserving. Instead, I focus on the relationship between social institutions and moral desert, and advance two claims. First, (...) in the market, desert claims are undermined by the very nature of the market even if people can be deserving in general. Second, part of the intuition that motivates accounts of moral desert may be explained instead with reference to a principle of fairness that demands the fulfillment of people's legitimate expectations as to what they will receive, and this principle places much weaker restrictions on redistributive policies than do claims of moral desert. (shrink)

First published in 1999. Routledge is an imprint of Taylor & Francis, an informa company.

The period between 1945 and 1952 marked the development of Professor Ryle's conception of the principles of inference as performance rules. This development has paralleled that of his now well-known distinction between knowing-how and knowing-that. Indeed, the former is a corollary to the latter. Beginning with the inaugural address to the Aristotelian Society in 1945 and reaching full fruition in The Concept of Mind in 1949, it finds its most detailed and illuminating expression in “‘If’, ‘So’, and ‘Because’,” which appeared (...) in 1950. The present essay will attempt to explore this conception of rules in some detail, in the hope of clarifying the nature of Professor Ryle's views on classical logic and on certain problems within the philosophy of logic. Professor Ryle belongs, if his views may be so labeled, to the school of informal language analysts. On the other hand, we incline more toward formalism. We tend to agree with those philosophers who consider certain schemata indispensable tools for the solution of philosophical problems. Logic and the philosophy of logic are, as everyone knows, the areas in which the formalists’ technique originated. In these areas it is accepted by virtually everybody. The only recent exception is a group of English writers, many of whom take their inspiration from Ryle. One may hope, then, that the present criticism of Ryle's view from the other standpoint will throw some light on both positions. What follows falls naturally into two parts. The first deals mainly with Ryle's objections to current logical theory, the second with his own philosophy of logic. (shrink)

It is a curious fact that the much maligned ontological argument to prove the existence of God has in recent times enjoyed a revival of interest to which even Karl Barth, the arch-enemy of natural theology has contributed; but since the revival of interest has appared in a wide diversity of intellectual contexts, both philosophical and theological, the revival is itself almost as problematic as the argument itself.

In his article ‘Professor Bartley's Theory of Rationality and Religious Belief’ Mr W. D. Hudson has brought considerable clarification to the rather confused situation occasioned by Professor W. W. Bartley's book The Retreat to Commitment and its subsequent discussion; but the process can, I think, be carried still further.

The 1940s and 1950s were marked by intense debates over the origin of drug resistance in microbes. Bacteriologists had traditionally invoked the notions of ‘training’ and ‘adaptation’ to account for the ability of microbes to acquire new traits. As the field of bacterial genetics emerged, however, its participants rejected ‘Lamarckian’ views of microbial heredity, and offered statistical evidence that drug resistance resulted from the selection of random resistant mutants. Antibiotic resistance became a key issue among those disputing physiological vs. genetic (...) explanations of variation in bacteria. Postwar developments connected with the Lysenko affair gave this debate a new political valence.Proponents of the neo-Darwinian synthesis weighed in with support for the genetic theory. However, certain features of drug resistance seemed inexplicable by mutation and selection, particularly the phenomenon of ‘multiple resistance’—the emergence of resistance in a single strain against several unrelated antibiotics. In the late 1950s, Tsutomu Watanabe and his collaborators solved this puzzle by determining that resistance could be conferred by cytoplasmic resistance factors rather than chromosomal mutation. These R factors could carry resistance to many antibiotics and seemed able to promote their own dissemination in bacterial populations. In the end, the vindication of the genetic view of drug resistance was accompanied by a recasting of the ‘gene’ to include extrachromosomal hereditary units carried on viruses and plasmids. (shrink)

ABSTRACT Rosalind Franklin is best known for her informative X-ray diffraction patterns of DNA that provided vital clues for James Watson and Francis Crick's double-stranded helical model. Her scientific career did not end when she left the DNA work at King's College, however. In 1953 Franklin moved to J. D. Bernal's crystallography laboratory at Birkbeck College, where she shifted her focus to the three-dimensional structure of viruses, obtaining diffraction patterns of Tobacco mosaic virus (TMV) of unprecedented detail and clarity. During (...) the next five years, while making significant headway on the structural determination of TMV, Franklin maintained an active correspondence with both Watson and Crick, who were also studying aspects of virus structure. Developments in TMV research during the 1950s illustrate the connections in the emerging field of molecular biology between structural studies of nucleic acids and of proteins and viruses. They also reveal how the protagonists of the “race for the double helix” continued to interact personally and professionally during the years when Watson and Crick's model for the double-helical structure of DNA was debated and confirmed. (shrink)

This paper examines the US Atomic Energy Commission’s radioisotope distribution program, established in 1946, which employed the uranium piles built for the wartime bomb project to produce specific radioisotopes for use in scientific investigation and medical therapy. As soon as the program was announced, requests from researchers began pouring into the Commission’s office. During the first year of the program alone over 1000 radioisotope shipments were sent out. The numerous requests that came from scientists outside the United States, however, sparked (...) a political debate about whether the Commission should or even could export radioisotopes. This controversy manifested the tension between the aims of the Marshall Plan and growing US national security concerns after World War II. Proponents of international circulation of radioisotopes emphasized the political and scientific value of collaborating with European scientists, especially biomedical researchers. In the end, radioisotopes were shipped from the Commission’s Oak Ridge facility to many laboratories in England and continental Europe, where they were used in biochemical research on animals, plants, and microbes. However, the issue of radioisotope export continued to draw political fire in the United States, even after the establishment of national atomic energy facilities elsewhere. (shrink)

ABSTRACT Rosalind Franklin is best known for her informative X-ray diffraction patterns of DNA that provided vital clues for James Watson and Francis Crick's double-stranded helical model. Her scientific career did not end when she left the DNA work at King's College, however. In 1953 Franklin moved to J. D. Bernal's crystallography laboratory at Birkbeck College, where she shifted her focus to the three-dimensional structure of viruses, obtaining diffraction patterns of Tobacco mosaic virus (TMV) of unprecedented detail and clarity. During (...) the next five years, while making significant headway on the structural determination of TMV, Franklin maintained an active correspondence with both Watson and Crick, who were also studying aspects of virus structure. Developments in TMV research during the 1950s illustrate the connections in the emerging field of molecular biology between structural studies of nucleic acids and of proteins and viruses. They also reveal how the protagonists of the “race for the double helix” continued to interact personally and professionally during the years when Watson and Crick's model for the double-helical structure of DNA was debated and confirmed. (shrink)

The widespread adoption of radioisotopes as tools in biomedical research and therapy became one of the major consequences of the "physicists' war" for postwar life science. Scientists in the Manhattan Project, as part of their efforts to advocate for civilian uses of atomic energy after the war, proposed using infrastructure from the wartime bomb project to develop a government-run radioisotope distribution program. After the Atomic Energy Bill was passed and before the Atomic Energy Commission was formally established, the Manhattan Project (...) began shipping isotopes from Oak Ridge. Scientists and physicians put these reactor-produced isotopes to many of the same uses that had been pioneered with cyclotron-generated radioisotopes in the 1930s and early 1940s. The majority of early AEC shipments were radioiodine and radiophosphorus, employed to evaluate thyroid function, diagnose medical disorders, and irradiate tumors. Both researchers and politicians lauded radioisotopes publicly for their potential in curing diseases, particularly cancer. However, isotopes proved less successful than anticipated in treating cancer and more successful in medical diagnostics. On the research side, reactor-generated radioisotopes equipped biologists with new tools to trace molecular transformations from metabolic pathways to ecosystems. The U.S. government's production and promotion of isotopes stimulated their consumption by scientists and physicians, such that in the postwar period isotopes became routine elements of laboratory and clinical use. In the early postwar years, radioisotopes signified the government's commitment to harness the atom for peace, particularly through contributions to biology, medicine, and agriculture. (shrink)

Scientists and historians have often presumed that the divide between biochemistry and molecular biology is fundamentally epistemological.100 The historiography of molecular biology as promulgated by Max Delbrück's phage disciples similarly emphasizes inherent differences between the archaic tradition of biochemistry and the approach of phage geneticists, the ur molecular biologists. A historical analysis of the development of both disciplines at Berkeley mitigates against accepting predestined differences, and underscores the similarities between the postwar development of biochemistry and the emergence of molecular biology (...) as a university discipline. Stanley's image of postwar biochemistry, with its focus on viruses as key experimental systems, and its preference for following macromolecular structure over metabolism pathways, traced the outline of molecular biology in 1950.Changes in the postwar political economy of research universities enabled the proliferation of disciplines such as microbiology, biochemistry, biophysics, immunology, and molecular biology in universities rather than in medical schools and agricultural colleges. These disciplines were predominantly concerned with investigating life at the subcellular level-research that during the 1930s had often entailed collaboration with physicists and chemists. The interdisciplinary efforts of the 1930s (many fostered by the Rockefeller Foundation) yielded a host of new tools and reagents that were standardized and mass-produced for laboratories after World War II. This commercial infrastructure enabled “basic” researchers in biochemistry and molecular biology in the 1950s and 1960s to become more independent from physics and chemistry (although they were practicing a physicochemical biology), as well as from the agricultural and medical schools that had previously housed or sponsored such research. In turn, the disciplines increasingly required their practitioners to have specialized graduate training, rather than admitting interlopers from the physical sciences.These general transitions toward greater autonomy for biochemistry and allied disciplines should not mask the important particularities of these developments on each campus. At the University of Caliornia at Berkeley, agriculture had provided, with medicine, significant sponsorship for biochemistry. The proximity of Lawrence and his cyclotrons supported the early development of Berkeley as a center for the biological uses of radioisotopes, particularly in studies of metabolism and photosynthesis. Stanley arrived to establish his department and virus institute before large-scale federal funding of biomedical research was in place, and he courted the state of California for substantial backing by promising both national prominence in the life sciences and virus research pertinent to agriculture and public health. Stanley's venture benefited significantly from the expansion of California's economy after World War II, and his mobilization against viral diseases resonated with the concerns of the Cold War, which fueled the state's rapid growth. The scientific prominence of contemporary developments at Caltech and Stanford invites the historical examination of the significance of postwar biochemistry and molecular biology within the political and cultural economy of the Golden State.In 1950, Stanley presented a persuasive picture of the power of biochemistry to refurbish life science at Berkeley while answering fundamental questions about life and infection. In the words of one Rockefeller Foundation officer,There seems little doubt in [my] mind that as a personality Stanley will be well able to dominate the other personalities on the Berkeley campus and will be able to drive his dream through to completion, which, incidentally, leaves Dr. Hubert [sic] Evans and the whole ineffective Life Sciences building in the somewhat peculiar position of being by-passed by much of the truly modern biochemistry and biophysics research that will be carried out at Berkeley. Furthermore, it seems likely that Dr. S's show will throw Dr. John Lawrence's Biophysics Department strongly in the shade both figuratively and literally, but should make the University of California pre-eminent not only in physics but in biochemistry as well.101Stanley, Sproul, Weaver, and this officer (William Loomis) all testified to a perceptible postwar opportunity to capitalize on public support for biological research that relied on the technologies from physics and chemistry without being captive to them, and that addressed issues of medicine and agriculture without being institutionally subservient. What is striking, given the expectation by many that Stanley would ‘be able to drive his dream through to completion,” was that in fact he did not. Biochemists who had succeeded in making their expertise valued in specialized niches were resistant to giving up their affiliations to joint Stanley's “liberated” organization. Stanley's failure was not simply due to institutional factors: researchers as well as Rockefeller Foundation officers faulted him for his lack of scientific imagination, which made it difficult for him to gain credibility in leading the field. Moreover, many biochemists did not share Stanley's commitment to viruses as the key material for the “new biochemistry.”In the end, Stanley's free-standing department did become a first-rate department of biochemistry, but only after freeing itself from Stanley's leadership and his single-minded devotion to viruses. Nonetheless, the falling-out with the Berkeley biochemists was rapidly followed by the establishment of a Department of Molecular Biology, attesting to the unabating economic and institutional possibilities for an authoritative “general biology” (or two, for that matter) to take hold. In each case, following Stanley's dream sheds light on how the possible and the real shaped the (re)formation of biochemistry and molecular biology as postwar life sciences. (shrink)

This article aims to discuss the history of medical history in the British medical undergraduate curriculum and it reviews the main characters and organisations that have attempted to earn it a place in the curriculum. It also reviews the arguments for and against the study of the subject that have been used over the last 160 years.