An examination of the ethical issues raised by the possibility of human life extension, including its desirability, unequal access, and the threat of overpopulation. -/- Life extension—slowing or halting human aging—is now being taken seriously by many scientists. Although no techniques to slow human aging yet exist, researchers have successfully slowed aging in yeast, mice, and fruit flies, and have determined that humans share aging-related genes with these species. In New Methuselahs, John Davis offers a philosophical discussion of (...) the ethical issues raised by the possibility of human life extension. Why consider these issues now, before human life extension is a reality? Davis points out that, even today, we are making policy and funding decisions about human life extension research that have ethical implications. With New Methuselahs, he provides a comprehensive guide to these issues, offering policy recommendations and a qualified defense of life extension. -/- After an overview of the ethics and science of life extension, Davis considers such issues as the desirability of extended life; whether refusing extended life is a form of suicide; the Malthusian threat of overpopulation; equal access to life extension; and life extension and the right against harm. In the end, Davis sides neither with those who argue that there are no moral objections to life enhancement nor with those who argue that the moral objections are so strong that we should never develop it. Davis argues that life extension is, on balance, a good thing and that we should fund life extension research aggressively, and he proposes a feasible and just policy for preventing an overpopulation crisis. (shrink)

Signal transduction pathways constructed around a core module of three consecutive protein kinases, the most distal being a member of the extracellular signal‐regulated kinase (ERK) family, are ubiquitous among eukaryotes. Recent work has defined two cascades activated preferentially by the inflammatory cytokines TNF‐α and IL‐1‐β, as well as by a wide variety of cellular stresses such as UV and ionizing radiation, hyperosmolarity, heat stress, oxidative stress, etc. One pathway converges on the ERK subfamily known as the ‘stress activated’ protein kinases (...) (SAPKs, also termed Jun N‐terminal kinases, JNKs), whereas the second pathway recruits the p38 kinases. Upstream inputs are diverse, and include small GTPases (primarily Rac and Cdc42; secondarily Ras) acting through mammalian homologs of the yeast Ste20 kinase, other kinase subfamilies (e.g. GC kinase) and ceramide, a putative second messenger for certain TNF‐α actions. These two cascades signal cell cycle delay, cellular repair or apoptosis in most cells, as well as activation of immune and reticuloendothelial cells. (shrink)

Major events of the cell cycle—DNA synthesis, mitosis and cell division—are regulated by a complex network of protein interactions that control the activities of cyclin‐dependent kinases. The network can be modeled by a set of nonlinear differential equations and its behavior predicted by numerical simulation. Computer simulations are necessary for detailed quantitative comparisons between theory and experiment, but they give little insight into the qualitative dynamics of the control system and how molecular interactions determine the fundamental physiological properties of cell (...) replication. To that end, bifurcation diagrams are a useful analytical tool, providing new views of the dynamical organization of the cell cycle, the role of checkpoints in assuring the integrity of the genome, and the abnormal regulation of cell cycle events in mutants. These claims are demonstrated by an analysis of cell cycle regulation in fission yeast. BioEssays 24:1095–1109, 2002. © 2002 Wiley‐Periodicals, Inc. (shrink)

Methionine aminopeptidases with a universal specificity have been revealed from the sequences of the amino‐terminal region of mutant forms of yeast iso‐1‐cytochrome c and from a systematic examination of the literature for amino‐terminal sequences formed at initiation sites. The aminopeptidase removes amino‐terminal residues of methionine when they precede certain amino acids, with a specificity that appears to be determined mainly by the residue adjacent to the methionine residue at the amino terminus. The result with the mutationally altered iso‐1‐cytochromes c (...) and the results from published sequences of other proteins from a wide range of prokaryotes and eukaryotes suggest that the aminopeptidase usually cleaves amino‐terminal methionine when it precedes residues of alanine, cysteine, glycine, proline, serine, threonine and valine but not when it precedes residues of arginine, asparagine, aspartic acid, glutamine, glutamic acid, isoleucine, leucine, lysine or methionine. We suggest that the specificity is almost always determined simply by the size of the side chain of the penultimate residue; methionine is usually cleaved from residues with a side chain having a radius of gyration of 1·29 Å or less, but is not cleaved from residues with larger side chains. (shrink)

We have synthesized a 582,970-base pair Mycoplasma genitalium genome. This synthetic genome, named M. genitalium JCVI-1.0, contains all the genes of wild-type M. genitalium G37 except MG408, which was disrupted by an antibiotic marker to block pathogenicity and to allow for selection. To identify the genome as synthetic, we inserted "watermarks" at intergenic sites known to tolerate transposon insertions. Overlapping "cassettes" of 5 to 7 kilobases (kb), assembled from chemically synthesized oligonucleotides, were joined by in vitro recombination to produce intermediate (...) assemblies of approximately 24 kb, 72 kb ("1/8 genome"), and 144 kb ("1/4 genome"), which were all cloned as bacterial artificial chromosomes in Escherichia coli. Most of these intermediate clones were sequenced, and clones of all four 1/4 genomes with the correct sequence were identified. The complete synthetic genome was assembled by transformation-associated recombination cloning in the yeast Saccharomyces cerevisiae, then isolated and sequenced. A clone with the correct sequence was identified. The methods described here will be generally useful for constructing large DNA molecules from chemically synthesized pieces and also from combinations of natural and synthetic DNA segments. 10.1126/science.1151721. (shrink)

During the past decade, it has become apparent that it is within our grasp to understand fully the development and functioning of complex organisms. It is widely accepted that this undertaking must include the elucidation of the genetic blueprint – the genome sequence – of a number of model organisms. As a prelude to the determination of these sequences, clonebased physical maps of the genomes of a number of multicellular animals and plants are being constructed. Yeast artificial chromosome (YAC) (...) vectors, by virtue of their relatively unbiased cloning capabilities and capacity to carry large inserts, have come to play a central role in the construction of these maps. The application of YACs to the physical map of the Caenorhabditis elegans genome has enabled cosmid clone ‘islands’ to be linked together in an efficient manner. The long‐range continuity has improved the linkage between the genetic and physical maps, greatly increasing its utility. Since the genome can be represented by a relatively small number of YACs, it has been possible to make replica filters of genomically ordered YACs available to the community at large. (shrink)

The yeast two‐hybrid system is a genetic method that detects protein‐protein interactions. One application is the detection by library screening of new interactors of a protein of known function. In the August issue of Nature Genetics, Fromont‐Racine et al.1 showed for the first time that the construction of the protein interaction map of a complex pathway, such as that of the mRNA splicing machinery, is now possible, because of the combination of recent technical improvements elaborated in several laboratories. With (...) a yeast cell mating procedure that increases screen efficiency, they used their complex yeast genomic library of 5 × 106 clones to test 700 × 106 interactions against 15 proteins. They identified and classified 170 potential interactors, including approximately 70 proteins of previously unknown function. More than 25% of the interactors are probably biologically relevant. The achievements of Fromont‐Racine et al. have opened the way to the systematic analysis of the protein interaction networks of the 6,000 open reading frames‐yeast proteome. This task requires, however, automation of the library screens and creation of a two‐hybrid library database. BioEssays 20:1–5, 1998. © 1998 John Wiley & Sons, Inc. (shrink)

Homologous chromosome pairing is required for proper chromosome segregation and recombination during meiosis. The mechanism by which a pair of homologous chromosomes contact each other to establish pairing is not fully understood. When pairing occurs during meiotic prophase in the fission yeast, Schizosaccharomyces pombe, the nucleus oscillates between the cell poles and telomeres remain clustered at the leading edge of the moving nucleus. These meiosis‐specific activities produce movements of telomere‐bundled chromosomes. Several lines of evidence suggest that these movements facilitate (...) homologous chromosome pairing by aligning homologous chromosomes and promoting contact between homologous regions. Since telomere clustering and nuclear or chromosome movements in meiotic prophase have been observed in a wide range of eukaryotic organisms, it is suggested that telomere‐mediated chromosome movements are general activities that facilitate homologous chromosome pairing. BioEssays 23:526–533, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Several psychological experiments have suggested that concepts can influence perceived color (e.g., Delk and Fillenbaum in Am J Psychol 78(2):290–293, 1965, Hansen et al. in Nat Neurosci 9(11):1367–1368, 2006, Olkkonen et al. in J Vis 8(5):1–16, 2008). Observers tend to assign typical colors to objects even when the objects do not have those colors. Recently, these findings were used to argue that perceptual experience is cognitively penetrable (Macpherson 2012). This interpretation of the experiments has far-reaching consequences: it implies that the (...) way we think of objects determines how we see them, thus threatening the role of perception in justifying beliefs. In this paper, I show that the psychological findings can be accounted for without admitting cognitive penetrability. An underestimated but key feature of the experiments is that observers had to judge colors in borderline cases, in conditions of reduced acuity, or on the basis of color-concepts instead of matching. Such judgments are sensitive to the form of bias that Tversky and Kahneman (Science 185:1124–1131, 1974) have termed ‘anchoring’. Adopting a suggestion from Raffman (Philos Rev 103(1):41–74, 1994), I argue that the way subjects in the experiments think of the objects could affect their color judgments without altering their color experiences. (shrink)

The danger of human operators devolving responsibility to machines and failing to detect cases where they fail has been recognised for many years by industrial psychologists and engineers studying the human operators of complex machines. We call it “the control problem”, understood as the tendency of the human within a human–machine control loop to become complacent, over-reliant or unduly diffident when faced with the outputs of a reliable autonomous system. While the control problem has been investigated for some time, up (...) to this point its manifestation in machine learning contexts has not received serious attention. This paper aims to fill that gap. We argue that, except in certain special circumstances, algorithmic decision tools should not be used in high-stakes or safety-critical decisions unless the systems concerned are significantly “better than human” in the relevant domain or subdomain of decision-making. More concretely, we recommend three strategies to address the control problem, the most promising of which involves a complementary coupling between highly proficient algorithmic tools and human agents working alongside one another. We also identify six key principles which all such human–machine systems should reflect in their design. These can serve as a framework both for assessing the viability of any such human–machine system as well as guiding the design and implementation of such systems generally. (shrink)

Adaptive mutation is defined as a process that, during nonlethal selections, produces mutations that relieve the selective pressure whether or not other, nonselected mutations are also produced. Examples of adaptive mutation or related phenomena have been reported in bacteria and yeast but not yet outside of microorganisms. A decade of research on adaptive mutation has revealed mechanisms that may increase mutation rates under adverse conditions. This article focuses on mechanisms that produce adaptive mutations in one strain of Escherichia coli, (...) FC40. These mechanisms include recombination-induced DNA replication, the placement of genes on a conjugal plasmid, and a transient mutator state. The implications of these various phenomena for adaptive evolution in microorganisms are discussed. BioEssays 22:1067–1074, 2000. © 2000 John Wiley & Sons, Inc. (shrink)

Adaptive mutation is defined as a process that, during nonlethal selections, produces mutations that relieve the selective pressure whether or not other, nonselected mutations are also produced. Examples of adaptive mutation or related phenomena have been reported in bacteria and yeast but not yet outside of microorganisms. A decade of research on adaptive mutation has revealed mechanisms that may increase mutation rates under adverse conditions. This article focuses on mechanisms that produce adaptive mutations in one strain of Escherichia coli, (...) FC40. These mechanisms include recombination-induced DNA replication, the placement of genes on a conjugal plasmid, and a transient mutator state. The implications of these various phenomena for adaptive evolution in microorganisms are discussed. BioEssays 22:1067–1074, 2000. © 2000 John Wiley & Sons, Inc. (shrink)

N- and O-linked glycan structures of cell surface and secreted glycoproteins serve a variety of functions related to cell–cell communication in systems affecting development and disease. The more sophisticated N-glycan biosynthesis pathway of metazoans diverges from that of yeast with the appearance of the medial-Golgi β-N-acetylglucosaminyltransferases (GlcNAc-Ts). Tissue-specific regulation of medial- and trans-Golgi glycosyltransferases contribute structural diversity to glycoproteins in metazoans, and this can affect their molecular properties including localization, half-life, and biological activity. Null mutations in glycosyltransferase genes positioned (...) later in the biosynthetic pathway disrupt expression of smaller subsets of glycan structures and are progressively milder in phenotype. In this review, we examine data on targeted mutations affecting glycosylation in mice and congenital mutations in man, with a view to understanding the molecular functions of glycan structures as modulators of glycoprotein activity. Finally, pathology associated with the expression of GlcNAc-Ts in cancer and diabetes-induced cardiac hypertrophy suggest that inhibitors of these enzymes may have therapeutic value. BioEssays 21:412–421, 1999. © 1999 John Wiley & Sons, Inc. (shrink)

Heterotrimeric G proteins, consisting of α, β, and γ subunits, couple ligand-bound seven transmembrane domain receptors to the regulation of effector proteins and production of intracellular second messengers. G protein signaling mediates the perception of environmental cues in all higher eukaryotic organisms, including yeast, Dictyostelium, plants, and animals. The nematode Caenorhabditis elegans is the first animal to have complete descriptions of its cellular anatomy, cell lineage, neuronal wiring diagram, and genomic sequence. In a recent paper, Jansen et al.(1) used (...) sequence searches of the C. elegans genome database to identify all heterotrimeric G protein genes (20 Gα, 2 Gβ, 2 Gγ). C. elegans encodes one ortholog of each of the four Gα classes found in metazoans and 16 new Gα genes. The orthologous genes are widely expressed, whereas 14 of the divergent Gα genes are almost exclusively expressed in sensory neurons where they may regulate perception and chemotaxis.BioEssays 21:713–717, 1999. © 1999 John Wiley & Sons, Inc. (shrink)

Cell morphogenesis encompasses all processes required to establish a three-dimensional cell shape. Cells acquire the architecture specific to their developmental context by using the spatial information provided by internal or external cues. As a response to these signals, cells become reorganized and establish functionally distinct subcellular domains that ultimately lead to morphological changes. In its simplest form, cell morphogenesis results in the establishment of asymmetry along one axis, a cell polarity. Although cell polarity has been studied intensively in budding (...) class='Hi'>yeast and epithelial cells, little is known about more complex modes of cell morphogenesis involving multiple axes. In this review we compare the regulation of cell morphogenesis of different genetically well-characterized cell types in Arabidopsis thaliana. BioEssays 20:20–29, 1998. © 1998 John Wiley & Sons, Inc. (shrink)

In early embryonic development, the cell cycle is paced by a biochemical oscillator involving cyclins and cyclin-dependent kinases (cdks). Essentially the same machinery operates in all eukaryotic cells, although after the first few divisions various braking mechanisms (the so-called checkpoints) become significant. Haase and Reed have recently shown that yeast cells have a second, independent oscillator which coordinates some of the events of the G1 phase of the cell cycle.(1) Although the biochemical nature of this oscillator is not known,it (...) seems unlikely to be a redundant cyclin/cdk system. BioEssays 22:3–5, 2000. ©2000 John Wiley & Sons, Inc. (shrink)

The model organism Saccharomyces cerevisiae is providing new insights into the molecular and cellular changes that are related to aging. The yeast protein Sir2p (Silent Information Regulator 2) is a histone deacetylase involved in transcriptional silencing and the control of genomic stability. Recent results have led to the identification of Sir2p as a crucial determinant of yeast life span. Dosage, intracellular localization, and activity of Sir2p all have important effects on yeast longevity. For instance, calorie restriction apparently (...) increases yeast life span by increasing Sir2p activity. Since Sir2p‐related proteins have been identified in many prokaryotic and eukaryotic organisms, the fundamental principles derived from the studies in yeast may prove valuable in directing our future research toward an understanding of the mechanisms of aging in higher eukaryotes. BioEssays 23:327–332, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Two reports have shown that mammalian artificial chromosomes (MAC) can be constructed from cloned human centromere DNA and telomere repeats, proving the principle that chromosomes can form from naked DNA molecules transfected into human cells. The MACs were mitotically stable, low copy number and bound antibodies associated with active centromeres. As a step toward second-generation MACs, yeast and bacterial cloning systems will have to be adapted to achieve large MAC constructs having a centromere, two telomeres, and genomic copies of (...) mammalian genes. Available construction techniques are discussed along with a new P1 artificial chromosome (PAC)-derived telomere vector (pTAT) that can be joined to other PACs in vitro, avoiding a cloning step during which large repetitive arrays often rearrange. The PAC system can be used as a route to further define the optimal DNA elements required for efficient MAC formation, to investigate the expression of genes on MACs, and possibly to develop efficient MAC-delivery protocols. BioEssays 1999;21:76–83. © 1999 John Wiley & Sons, Inc. (shrink)

No mathematical background is necessary to appreciate this classic of probability theory, which remains unsurpassed in its clarity, readability, and sheer charm. Its author, British logician John Venn (1834-1923), popularized the famous Venn Diagrams that are commonly used in teaching elementary mathematics.

Period homeostasis is the defining characteristic of a biological clock. Strict period homeostasis is found for the ultradian clocks of eukaryotic microbes. In addition to being temperature-compensated, the period of these rhythms is unaffected by differences in nutrient composition or changes in other environmental variables. The best-studied examples of ultradian clocks are those of the ciliates Paramecium tetraurelia and Tetrahymena sp. and of the fission yeast, Schizosaccharomyces pombe. In these single cell eukaryotes, up to seven different parameters display ultradian (...) rhythmicity with the same, species- and strain-specific period. In fission yeast, the molecular genetic analysis of ultradian clock mechanisms has begun with the systematic analysis of mutants in identified candidate genes. More than 40 “clock mutants” have already been identified, most of them affected in components of major regulatory and signalling pathways. These results indicate a high degree of complexity for a eukaryotic clock mechanism. BioEssays 22:16–22, 2000. ©2000 John Wiley & Sons, Inc. (shrink)

Fresnel's theory of light was (a) impressively predictively successful yet (b) was based on an "entity" (the elastic-solid ether) that we now "know" does not exist. Does this case "confute" scientific realism as Laudan suggested? Previous attempts (by Hardin and Rosenberg and by Kitcher) to defuse the episode's anti-realist impact. The strongest form of realism compatible with this case of theory-rejection is in fact structural realism. This view was developed by Poincare who also provided reasons to think that it is (...) the only realist view of theories that really makes sense. (shrink)

Meiosis is the process by which diploid germ cells divide to produce haploid gametes for sexual reproduction. The process is highly conserved in eukaryotes, however the recent availability of mouse models for meiotic recombination has revealed surprising regulatory differences between simple unicellular organisms and those with increasingly complex genomes. Moreover, in these higher eukaryotes, the intervention of physiological and sex-specific factors may also influence how meiotic recombination and progression are monitored and regulated. This review will focus on the recent studies (...) involving mouse mutants for meiosis, and will highlight important differences between traditional model systems for meiosis (such as yeast) and those involving more complex cellular, physiological and genetic criteria. BioEssays 23:996–1009, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Two reports have shown that mammalian artificial chromosomes (MAC) can be constructed from cloned human centromere DNA and telomere repeats, proving the principle that chromosomes can form from naked DNA molecules transfected into human cells. The MACs were mitotically stable, low copy number and bound antibodies associated with active centromeres. As a step toward second-generation MACs, yeast and bacterial cloning systems will have to be adapted to achieve large MAC constructs having a centromere, two telomeres, and genomic copies of (...) mammalian genes. Available construction techniques are discussed along with a new P1 artificial chromosome (PAC)-derived telomere vector (pTAT) that can be joined to other PACs in vitro, avoiding a cloning step during which large repetitive arrays often rearrange. The PAC system can be used as a route to further define the optimal DNA elements required for efficient MAC formation, to investigate the expression of genes on MACs, and possibly to develop efficient MAC-delivery protocols. BioEssays 1999;21:76–83. © 1999 John Wiley & Sons, Inc. (shrink)

En este artículo se analizan las relaciones del conocimiento científico con las sociedades en las que se produce. Tras repasar sus diversas funciones en tipos distintos de sociedades, la discusión se centra en los fines de la ciencia en las sociedades democráticas pluralistas. Frente al cada vez mayor rol instrumental de la ciencia, por el que ha recibido los nombres de «ciencia postacadémica» o «tecnociencia», se defienden los roles no instrumentales tradicionales de la investigación académica clásica. Se argumenta que sólo (...) si la ciencia académica mantiene su autonomía y su integridad frente a intereses políticos o empresariales podrá ser de utilidad al público al ofrecerle conocimiento imparcial y fidedigno frente a los sesgos producidos por la naturaleza propia de la ciencia postacadémica. (shrink)

John Woods' The Logic of Fiction, now thirty-five years old, is a ground-breaking event in the establishment of the semantics of fiction as a stand-alone research programme in the philosophies of language and logic. There is now a large literature about these matters, but Woods' book retains a striking freshness, and still serves as a convincing template of the treatment options for the field's key problems. The book now appears in a second edition with a new Foreword by Nicholas (...) Griffin and an extended bibliography covering the period 1969-2009. As Griffin notes in his Foreword, it is "surprising on looking back to discover how little was written on the semantics of fiction before John Woods' The Logic of Fiction was published in 1974. The surprise is the greater because Woods' book appeared after almost a quarter century of fierce philosophical debate about reference Fictional discourse, one would have thought, would be an important testing ground for philosophical theories of referential expressions and one, moreover, in which the standard theories would likely be tested to destruction. " " One of the great merits of Woods' book is that it takes seriously the wide-ranging demands that fiction imposes on logic and semantics, and does not try to force fiction into some pre-conceived logical mould. but thanks to Woods' pioneering efforts, we are much closer to one now than we were when he set out to write his book. His book was not the last word on the logic of fiction; it was much more important: it was nearly the first." NICHOLAS GRIFFIN is Canada Research Chair in Philosophy at McMaster University. Recent publications include Russell vs Meinong: The Legacy of "On Denoting," edited with Dale Jacquette. JOHN WOODS is Director of the Abductive Systems Group at the University of British Columbia and Charles S. Peirce Visiting Professor of Logic in the Group on Logic and Computational Science, King's College London. He has two forthcoming books on fiction - an edited volume, Fictions and Models: New Essays, and a research monograph, Sherlock's Member: New Perspectives on the Semantics of Fiction, both to appear in 2010. (shrink)

Heterotrimeric G proteins, consisting of α, β, and γ subunits, couple ligand-bound seven transmembrane domain receptors to the regulation of effector proteins and production of intracellular second messengers. G protein signaling mediates the perception of environmental cues in all higher eukaryotic organisms, including yeast, Dictyostelium, plants, and animals. The nematode Caenorhabditis elegans is the first animal to have complete descriptions of its cellular anatomy, cell lineage, neuronal wiring diagram, and genomic sequence. In a recent paper, Jansen et al.(1) used (...) sequence searches of the C. elegans genome database to identify all heterotrimeric G protein genes (20 Gα, 2 Gβ, 2 Gγ). C. elegans encodes one ortholog of each of the four Gα classes found in metazoans and 16 new Gα genes. The orthologous genes are widely expressed, whereas 14 of the divergent Gα genes are almost exclusively expressed in sensory neurons where they may regulate perception and chemotaxis.BioEssays 21:713–717, 1999. © 1999 John Wiley & Sons, Inc. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Hume Studies Volume 29, Number 1, April 2003, pp. 125-141 Dr. George Cheyne, Chevalier Ramsay, and Hume's Letter to a Physician JOHN P. WRIGHT The publication of a new intellectual biography of George Cheyne1 provides a "propitious" occasion for "a thoroughly skeptical review"2 of the question which has long exercised Hume scholars, whether Cheyne was the intended recipient of David Hume's fascinating pie-Treatise Letter to a Physician,3 the (...) letter which describes his own hypochondriacal physical and mental symptoms and gives an account of his early philosophical development.4 Hume's nineteenth-century biographer, John Hill Burton, argued that Hume was probably writing to Cheyne,5 while Ernest Mossner claimed to definitively refute that hypothesis in an article entitled "Hume's Epistle to Dr. Arbuthnot," published in 1944.6 Anita Guerrini's intellectual biography does not discuss Cheyne as a possible recipient of Hume's letter, but she does present a well-rounded picture of this interesting eighteenth-century physician from which we can judge his appropriateness as its addressee. In the following discussion I will make use of the biographical material found in this new biography of Cheyne, as well as other sources, to show that Mossner's arguments are less than definitive, and that it would be wrong to dismiss the possibility that the letter was sent to George Cheyne.7 This is a possibility that, for reasons that I will make clear, makes good biographical and philosophical sense. At the same time, it is important to keep a proper suspense of judgment as Burton did, for the evidence that the letter was either intended for or actually sent to Cheyne is not definitive. John P. Wright is Professor of Philosophy, Central Michigan University, Mt. Pleasant, MI 48859, USA. e-mail: [email protected] 126 John P. Wright Burton, who first published the autobiographical letter of the 22-yearold Hume in 1846, narrowed down the possible addressees of Hume's letter to either Cheyne or John Arbuthnot. He also pointed out that it is possible that the letter was never sent, and that the ten and a half page manuscript is only a neatly written draft, rather than a fair copy of an actual letter. Nevertheless, Burton thought he could identify the unnamed addressee on the basis of the internal evidence of the manuscript and the records of Scottish physicians practicing in England at the time. In the letter, Hume refers to the intended recipient as his "Countryman, a Scotchman [,]... a skilful Physician, a man of Letters, of Wit, of Good Sense, & of great Humanity."8 Further he writes that he is consulting him because he is a person "of great Learning beyond [his]... own Profession" who is acquainted with the "Motions of the Mind" he has described in his letter, and that "Fame pointed [him]... out as the properest person to resolve my Doubts..." about the cure of his disorder.9 Burton tells us that "the first name that suggested itself... was Arbuthnot, whose fine genius was just then flickering in the socket."10 (John Arbuthnot had been ill for some time, and died a year later.) But he then added that "a more full consideration showed to my satisfaction that it must have been destined for Dr. George Cheyne." His main reason for settling on Cheyne was that Cheyne's immensely popular The English Malady (1733) had recently been published, and that "there is a certain unison of tone between Hume's letter and this book." Burton quotes a portion of Cheyne's own long autobiographical account of his own disease in The English Malady. Cheyne's autobiography begins with the claim that "I passed my Youth in close study, and almost constant Application to the abstracted Sciences, (wherein my chief pleasure consisted) and consequently in great Temperance and a Sedentary Life"; it is followed by the reflection that any overindulgence in food or drink led to physical and psychological problems.11 He goes on to describe these in great detail for 39 pages, along with a history of his life. Burton also quotes a section of the book in which Cheyne describes how a studious and sedentary life causes the symptoms... (shrink)

The lysosome serves as a site for delivery of materials targeted for removal from the eukaryotic cell. The mechanisms underlying the biogenesis of this organelle are currently the subject of renewed interest due to advances in our understanding of the protein sorting machinery. Genetic model systems such as yeast and Drosophila have been instrumental in identifying both protein and lipid components of this machinery. Importantly, many of these components, as well as the processes in which they are involved, are (...) proving conserved in mammals. Other recently identified components, however, appear to be unique to higher eukaryotes. BioEssays 23:333–343, 2001. Published 2001 John Wiley & Sons, Inc. (shrink)

John Dewey's Experience and Nature has been considered the fullest expression of his mature philosophy since its eagerly awaited publication in 1925. Irwin Edman wrote at that time that "with monumental care, detail and completeness, Professor Dewey has in this volume revealed the metaphysical heart that beats its unvarying alert tempo through all his writings, whatever their explicit themes." In his introduction to this volume, Sidney Hook points out that "Dewey's Experience and Nature is both the most suggestive and (...) most difficult of his writings." The meticulously edited text published here as the first volume in the series The Later Works of John Dewey, 1925-1953 spans that entire period in Dewey's thought by including two important and previously unpublished documents from the book's history: Dewey's unfinished new introduction written between 1947 and 1949, edited by the late Joseph Ratner, and Dewey's unedited final draft of that introduction written the year before his death. In the intervening years Dewey realized the impossibility of making his use of the word 'experience' understood. He wrote in his 1951 draft for a new introduction: "Were I to write (or rewrite) Experience and Nature today I would entitle the book Culture and Nature and the treatment of specific subject-matters would be correspondingly modified. I would abandon the term 'experience' because of my growing realization that the historical obstacles which prevented understanding of my use of 'experience' are, for all practical purposes, insurmountable. I would substitute the term 'culture' because with its meanings as now firmly established it can fully and freely carry my philosophy of experience.". (shrink)

Eukaryotes organize certain chromosomal intervals into domains capable of si lencing most genes. Examples of silencing domains include the HML/HMR loci and subtelomeric chromatin in yeast, the Barr body X chromosome in mammals, and the pericentric heterochromatin of Drosophila. Silencing chromatin is often correlated with more regularized nucleosomal array than that found in active chromatin, and transcriptional activators appear to be missing from their target sites in silent chromatin. In Drosophila, gene silencing by heterochromatin is often variegated, indicating that (...) a gene may escape silencing in some cells. In a recent study, Ahmad and Henikoff(1) show that a yeast activator can compete successfully with Drosophila heterochromatic silencing factors for target sites in DNA. This competition, together with developmental change in the stability of heterochromatin itself, decides the transcriptional state for a gene subject to heterochromatin repression. BioEssays 23:767–771, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

I want to discuss a doctrine and a concept in theory of knowledge which has various manifestations from at least the seventeenth to the early twentieth century. The concept is that of direct or immediate cognition, the doctrine says that only what is like mind can be directly or immediately present to mind. This doctrine raises the question of how we can know things other than ourselves and our experiences: the concept of direct presence most usually had the consequence of (...) making our knowledge of the world indirect, uncertain, or impossible. The directly present must in some way inform us about the indirectly present. (shrink)

Late in his life, Hans-Georg Gadamer was asked to explain what the universal aspect of hermeneutics consisted in, and he replied, enigmatically, “in the _verbum interius_.” Gadamer devoted a pivotal section of his magnum opus, _Truth and Method_, to this Augustinian concept, and subsequently pointed to it as a kind of passkey to his thought. It remains, however, both in its origins and its interpretations, a mysterious concept. From out of its layered history, it remains a provocation to thought, expressing (...) something about the relation of language and understanding that has yet to be fully worked out. The scholastic idea of a word that is fully formed in the mind but not articulated served Augustine as an analogy for the procession of the Trinity, and served Thomas Aquinas as an analogy for the procession between divine ideas and human thought. Gadamer turned the analogy on its head by using the verbum interius to explain the obscure relation between language and human understanding. His learned interpretation of the idea of the inner word through Neoplatonism, Lutheranism, idealism, and historicism may seem nearly as complex as the medieval source texts he consulted and construed in his exegesis, but the profoundity of his insights are unquestioned. In unpacking Gadamer's interpretive feat, John Arthos provides an overview of the philosophy of the logos out of which the _verbum interius_ emerged. He summarizes the development of the _verbum _in ancient and medieval doctrine, traces its path through German thought, and explains its relevance to modern hermeneutic theory. His work unfolds in two parts, as an expansive intellectual history and as a close analysis and commentary on source texts on the inner word, from Augustine to Gadamer. As such, this book serves as an indispensable guide and reference for hermeneutics and the intellectual traditions out of which it arose, as well as an original theoretical statement in its own right. “Consummately researched, lucidly written, and persuasively argued throughout, __The Inner Word_ _succeeds brilliantly in bringing to light this neglected but pivotal matter in Gadamer’s work. Arthos is learned in the best ‘humanist’ way, for he succeeds in creating something new of his own that will speak eloquently to all of us.” —_Walter Jost, University of Virginia_ “Gadamer suggests that the Christian idea of incarnation is a key to his hermeneutics, but does not explain his position in a detailed or systematic manner. Arthos brings his considerable knowledge of hermeneutics and rhetoric to bear on Gadamer's insight, recounting the rich intellectual history to which Gadamer gestures, and providing an extended and detailed exegesis of this pivotal point in the third part of _Truth and Method_. Gadamer's account of 'linguisticality,' Arthos explains, can best be understood through his use of a complex metaphor—the ‘inner word.’ Arthos matches his erudition with clear and clean prose, and his account exemplifies, rather than just describes, Gadamer's hermeneutical philosophy. Any scholar interested in Gadamer's philosophy should have this book on his or her shelf.” —_Francis J. Mootz III, William S. Boyd Professor of Law, William S. Boyd School of Law_ “Arthos's strength lies for me in his careful reading of the sources. He effectively commands the literature on the subject. This work shows in a sophisticated way the legacy of trinitarian theology for philosophical hermeneutics. The very complex task of illuminating the phenomenon of the _verbum interius _and indicating its centrality for philosophical hermeneutics is accomplished by John Arthos with great sensitivity to the subject matter.” —_Andrzej Wiercinski, The International Institute for Hermeneutics_. (shrink)

John Barrow is increasingly recognized as one of our most elegant and accomplished science writers, a brilliant commentator on cosmology, mathematics, and modern physics. Barrow now tackles the heady topic of impossibility, in perhaps his strongest book yet. Writing with grace and insight, Barrow argues convincingly that there are limits to human discovery, that there are things that are ultimately unknowable, undoable, or unreachable. He first examines the limits on scientific inquiry imposed by the deficiencies of the human mind: (...) our brain evolved to meet the demands of our immediate environment, Barrow notes, and much that lies outside this small circle may also lie outside our understanding. Barrow investigates practical impossibilities, such as those imposed by complexity, uncomputability, or the finiteness of time, space, and resources. Is the universe finite or infinite? Can information be transmitted faster than the speed of light? The book also examines the deeper theoretical restrictions on our ability to know, including Godel's theorem--which proved that there were things that could not be proved--and Arrow's Impossibility theorem about democratic voting systems. Finally, having explored the limits imposed on us from without, Barrow considers whether there are limits we should impose upon ourselves. For instance, if the secrets of the atom are to be found only by recreating extreme environments at great financial cost, just how much should we devote to that quest? Weaving together this intriguing tapestry, he illuminates some of the most profound questions of science, from the possibility of time travel to the very structure of the universe. (shrink)

Philosophy as a separate discipline is a rather new phenomenon. This presents problems for our understanding of what constitutes the history of philosophy. Past writers often approached their concerns from a multi-disciplinary perspective; thus to understand them we have to do more than answer a contemporary set of issues. To that end, I suggest we attend to Locke's advice on how to read a text. Following this advice may permit us to avoid several puzzles which result from misreading a text.

This paper represents the first installment of alarger project devoted to the relevance of pragmatism forbioethics. One self-consciously pragmatist move would be toreturn to the classical pragmatist canon of Peirce, James andDewey in search of substantive doctrines or methodologicalapproaches that might be applied to current bioethicalcontroversies. Another pragmatist (or neopragmatist) move wouldbe to subject the regnant principlist paradigm to Richard Rorty'ssubversive assaults on foundationalism in epistemology andethics. A third pragmatist method, dubbed ``freestandingpragmatism'' by its proponents, embraces a ``pragmatist'' approachto practical (...) reasoning without discernable moorings either to theclassical canon or to Rorty's neopragmatism. This thirdpragmatist approach to method in practical ethics is the subjectof this article. I begin with an examination of freestandingpragmatism in the theory of judicial decision making. I arguethat this version of legal pragmatism – so described on account ofits commitments to contextualism, instrumentalism, eclecticism,and freedom from grand theory – bears a striking resemblance tomuch self-described pragmatist work in bioethics today. Ifurther argue that if this is what we mean by ``pragmatism,'' thenin a certain sense ``we are all pragmatists now.''. (shrink)

David Hume's A Treatise of Human Nature presents the most important account of skepticism in the history of modern philosophy. In this lucid and thorough introduction to the work, John P. Wright examines the development of Hume's ideas in the Treatise, their relation to eighteenth-century theories of the imagination and passions, and the reception they received when Hume published the Treatise. He explains Hume's arguments concerning the inability of reason to establish the basic beliefs which underlie science and morals, (...) as well as his arguments showing why we are nevertheless psychologically compelled to accept such beliefs. The book will be a valuable guide for those seeking to understand the nature of modern skepticism and its connection with the founding of the human sciences during the Enlightenment. (shrink)

Studies in Empirical Philosophy was published in 1962 shortly after Anderson's death and had been prepared by him to include most of his published articles from the Australasian Journal of Philosophy and Psychology. It also includes a couple of articles written especially for the book. It remains the main published source of material on Anderson's systematic philosophy. John Passmore has kindly granted permission for his introduction to be included in this new release. John Anderson (1893-1962) was Challis Professor (...) of Philosophy at the University of Sydney from 1927 until 1958. He is generally regarded as the most important philosopher to have worked in Australia. His students included not only academic philosophers but also important figures in politics, law and journalism. His impact upon Sydney's social and cultural life was enormous. (shrink)

What’s so bad about the placebo effect? John Worrall discusses the recent Nurofen labelling “scandal”.

Gerald Sykes -- Aldous Huxley -- Gerald Heard -- Christopher Isherwood -- John van Druten -- Marianna Masin -- J. Crawford Lewis -- Dorothy F. Mercer -- Kurt Friedrichs -- Swami Atulananda -- Jane Molard -- The Countess of Sandwich -- John Yale -- Joan Rayne -- Durgacharan -- Pravrajika Saradaprana.

Since its modern inception in the early 1970s, informal logic has placed a special emphasis on the analysis of fallacies and argumentative dialogue schemes. Concurrent developments in speech communication circles exhibit a like concentration on the dialectical character of argument.