(Statement of Responsibility) by Timothy S. Huebner.

The neuregulin gene encodes a series of polypeptide growth factors that can influence the growth state of target vertebrate cells in culture. Recently, three studies have explored the in vivo function of the neuregulin signaling system in mice by disrupting the genes encoding the neuregulin ligand(1) and two of its receptors, ErbB2(2) and ErbB4(3). Each of the genes is essential for development, and aberrations in cardiac and neural development are particularly prominent in mutant embryos. The observed defects, together with the (...) localization of expression of the neuregulin signaling components within these tissues, highlight a paracrine mechanism for neuregulin‐mediated intercellular communication. (shrink)

Stimulation of mitogenesis by the epidermal growth factor (EGF) operates through a pathway involving the receptor, the small G‐protein Ras and protein kinases of the MAP kinase cascade. It is proposed that two of the critical steps of that pathway utilize localization of components to the plasma membrane where Ras is located: recruitment of the nucleotide exchange protein Sos to the phosphorylated EGF receptor via a complex with the SH2/SH3‐containing protein Grb2 and recruitment of the protein kinase Raf to activated (...) Ras. Moreover, it is then proposed that Raf associates with the cytoskeleton at the membrane as it is being activated. Other signaling elements, including class I receptor kinases, nonreceptor tyrosine kinases and tyrosine phosphatases, are known to function at specific cellular sites. These observations have led us to propose that localization of signaling components, and particularly sites at membrane‐microfilament interfaces, play critical roles in cellular regulation. (shrink)

MUC1 and MUC4 are the two membrane mucins that have been best characterized. Although they have superficially similar structures and have both been shown to provide steric protection of epithelial surfaces, recent studies have also implicated them in cellular signaling. They act by substantially different mechanisms, MUC4 as a receptor ligand and MUC1 as a docking protein for signaling molecules. MUC4 is a novel intramembrane ligand for the receptor tyrosine kinase ErbB2/HER2/Neu, triggering a specific phosphorylation of the ErbB2 in the (...) absence of other ErbB ligands and potentiating phosphorylation and signaling through the ErbB2/ErbB3 heterodimeric receptor complex formed in the presence of neuregulin. In contrast, MUC1 has a highly conserved cytoplasmic tail, which binds β‐catenin, a key component of adherens junctions and a regulator of transcription, in a process that is tightly regulated by MUC1 phosphorylation. The specific localization of these membrane mucins to the apical surfaces of epithelial cells suggests that their signaling functions may be important as sensor mechanisms in response to invasion or damage of epithelia. BioEssays 25:66–71, 2003. © 2002 Wiley Periodicals, Inc. (shrink)

O‐glycosylation is the post‐translational process whereby carbohydrate is added to hydroxylated amino acids of proteins. The major O‐glycosylation pathway in animal cells is involved in the synthesis of oligosaccharides linked by N‐acetylgalactosamine to serine or threonine residues in ‘mucin‐type’ proteins or their analogs. In this review, we discuss the evidence for the cellular localization of the biosynthetic steps in this pathway and propose a simplified, consensus version. We also propose variations of the simple pathway to account for its heterogeneity and (...) variability in different cell types and differentiation states. (shrink)

Microfilament interactions with the plasma membranes of animal cells appear to vary with cell type and localization. In the erythrocyte, actin oligomers are associated with the membrane via spectrin and ankyrin. The ends of stress fibers in cultured cells, such as fibroblasts, are attached to the plasma membrane at focal adhesion sites and may involve the protein vinculin as a linking protein. In intestinal brush border microvilli a 110,000 dalton protein links the microfilament bundles to sites on the microvillus. A (...) transmembrane complex containing actin stably associated with a cell surface glycoprotein can be isolated from ascites tumor cell microvilli and can be obtained still associated with microfilaments by gentle extraction and gradient centrifugation of the microvilli. These varied interaction mechanisms are believed to be needed to satisfy the different structural and dynamic requirements of the particular systems. (shrink)

This review provides a current perspective on the insertion of genes into plants. Some of the knowledge on the structure and control of plant genes gained recently from genetic engineering approaches is described, together with developments that can be expected to emerge from further exploitation of gene transfer techniques.

From the early days of European settlement in North America, Christianity has had a profound impact on American law and culture. This volume profiles nineteen of America's most influential Christian jurists from the early colonial era to the present day. Anyone interested in American legal history and jurisprudence, the role Christianity has played throughout the nation's history, and the relationship between faith and law will enjoy this worthy and unique study. The jurists covered in this collection were pious men and (...) women, but that does not mean they agreed on how faith should inform law. From Roger Williams and John Cotton to Antonin Scalia and Mary Ann Glendon, America's great Christian jurists have brought their faith to bear on the practice of law in different ways and to different effects. (shrink)

Historians and biologists identify the debate between mechanists and vitalists over the nature of life itself with the arguments of Driesch, Loeb, and other prominent voices. But what if the conversation was broader and the consequences deeper for the field? Following the suspicions of Joseph Needham in the 1930s and Francis Crick in the 1960s, we deployed tools of the digital humanities to an old problem in the history of biology. We analyzed over 31,000 peer-reviewed scientific papers and learned that (...) bioexceptionalism participated in a robust discursive landscape throughout subfields of the life sciences, occupied even by otherwise unknown biologists. (shrink)

From March 1841 until the end of 1845, W. R. Grove held the post of Professor of Experimental Philosophy at the London Institution. No previous study of the Institution has dealt in detail with the period of Grove's tenure of this, the first professorship. Here, by reference to the various manuscripts and publications of the Institution, and to Grove's papers and correspondence, it is possible to describe the background to Grove's appointment and the achievements of his term of office.

From unemployment to Brexit to climate change, capitalism is in trouble and ill-prepared to cope with the challenges of the coming decades. How did we get here? While contemporary economists and policymakers tend to ignore the political and social dimensions of capitalism, some of the great economists of the past - Adam Smith, Friedrich List, John Maynard Keynes, Joseph Schumpeter, Karl Polanyi and Albert Hirschman - did not make the same mistake. Leveraging their insights, sociologists John L. Campbell and John (...) A. Hall trace the historical development of capitalism as a social, political, and economic system throughout the twentieth and early twenty-first centuries. They draw comparisons across eras and around the globe to show that there is no inevitable logic of capitalism. Rather, capitalism's performance depends on the strength of nation-states, the social cohesion of capitalist societies, and the stability of the international system - three things that are in short supply today. (shrink)

There are, by now, many rival, sophisticated philosophical accounts of causation that qualify as ‘metaphysically reductive’. This is a good thing: these collective efforts have vastly improved our understanding of causation over the last 30 years or so. They also put us in an excellent position to reflect on some central methodological questions: What exactly is the point of offering a metaphysical reduction of causation? What philosophical scruples ought to guide the pursuit of such a reduction? Finally, how should answers (...) to these latter questions affect one’s assessment of the main contemporary approaches? That’s what we investigate in this essay. Section 1 lays out our presuppositions. Section 2 reviews a sample of philosophical accounts. Then comes the main event: Section 3 looks in detail at the foregoing methodological questions, closing with a reconsideration of our sample accounts, in light of what we’ve found. (shrink)

Causation is a deeply intuitive and familiar relation, gripped powerfully by common sense. Or so it seems. As is typical in philosophy, however, that deep intuitive familiarity has not led to any philosophical account of causation that is at once clean, precise, and widely agreed upon. Not for lack of trying: the last thirty years or so have seen dozens of attempts to provide such an account, and the pace of development is, if anything, accelerating. (See Collins et al. [2003a] (...) for a comprehensive sampling of the latest work.). (shrink)

Causation is at once familiar and mysterious. Neither common sense nor extensive philosophical debate has led us to anything like agreement on the correct analysis of the concept of causation, or an account of the metaphysical nature of the causal relation. Causation: A User's Guide cuts a clear path through this confusing but vital landscape. L. A. Paul and Ned Hall guide the reader through the most important philosophical treatments of causation, negotiating the terrain by taking a set of (...) examples as landmarks. They clarify the central themes of the debate about causation, and cover questions about causation involving omissions or absences, preemption and other species of redundant causation, and the possibility that causation is not transitive. Along the way, Paul and Hall examine several contemporary proposals for analyzing the nature of causation and assess their merits and overall methodological cogency.The book is designed to be of value both to trained specialists and those coming to the problem of causation for the first time. It provides the reader with a broad and sophisticated view of the metaphysics of the causal relation. (shrink)

The interventionist account of causal explanation, in the version presented by Jim Woodward, has been recently claimed capable of buttressing the widely felt—though poorly understood—hunch that high-level, relatively abstract explanations, of the sort provided by sciences like biology, psychology and economics, are in some cases explanatorily optimal. It is the aim of this paper to show that this is mistaken. Due to a lack of effective constraints on the causal variables at the heart of the interventionist causal-explanatory scheme, as presently (...) formulated it is either unable to prefer high-level explanations to low, or systematically overshoots, recommending explanations at so high of a level as to be virtually vacuous. (shrink)

This paper critiques the new mechanistic explanatory program on grounds that, even when applied to the kinds of examples that it was originally designed to treat, it does not distinguish correct explanations from those that blunder. First, I offer a systematization of the explanatory account, one according to which explanations are mechanistic models that satisfy three desiderata: they must 1) represent causal relations, 2) describe the proper parts, and 3) depict the system at the right ‘level.’ Second, I argue that (...) even the most developed attempts to fulfill these desiderata fall short by failing to appropriately constrain explanatorily apt mechanistic models. -/- *This paper used to be called "The Emperor's New Mechanisms". (shrink)

Among the factors necessary for the occurrence of some event, which of these are selectively highlighted in its explanation and labeled as causes — and which are explanatorily omitted, or relegated to the status of background conditions? Following J. S. Mill, most have thought that only a pragmatic answer to this question was possible. In this paper I suggest we understand this ‘causal selection problem’ in causal-explanatory terms, and propose that explanatory trade-offs between abstraction and stability can provide a principled (...) solution to it. After sketching that solution, it is applied to a few biological examples, including to a debate concerning the ‘causal democracy’ of organismal development, with an anti-democratic (though not a gene-centric) moral. (shrink)

The Tree of Life has traditionally been understood to represent the history of species lineages. However, recently researchers have suggested that it might be better interpreted as representing the history of cellular lineages, sometimes called the Tree of Cells. This paper examines and evaluates reasons offered against this cellular interpretation of the Tree of Life. It argues that some such reasons are bad reasons, based either on a false attribution of essentialism, on a misunderstanding of the problem of lineage identity, (...) or on a limited view of scientific representation. I suggest that debate about the Tree of Cells and other successors to the traditional Tree of Life should be formulated in terms of the purposes these representations may serve. In pursuing this strategy, we see that the Tree of Cells cannot serve one purpose suggested for it: as an explanation for the hierarchical nature of taxonomy. We then explore whether, instead, the tree may play an important role in the dynamic modeling of evolution. As highly-integrated complex systems, cells may influence which lineage components can successfully transfer into them and how they change once integrated. Only if they do in fact have a substantial role to play in this process might the Tree of Cells have some claim to be the Tree of Life. (shrink)

Philosophical theories of explanation characterize the difference between correct and incorrect explanations. While remaining neutral as to which of these ‘first-order’ theories is right, this paper asks the ‘meta-explanatory’ question: is the difference between correct and incorrect explanation real, i.e., objective or mind-independent? After offering a framework for distinguishing realist from anti-realist views, I sketch three distinct paths to explanatory anti-realism.

The companion volume to Arnold Come's Kierkegaard as Humanist, Kierkegaard as Theologian is an exploration of Søren Kierkegaard's deliberately Christian writings, from Upbuilding Discourses in Various Spirits (1846) to For Self-Examination (1851). In his later writings Kierkegaard sought to "get further forward in the direction of discovering the Christianity of the New Testament" to resolve his own spiritual crisis. His struggle to understand how authentic theologizing relates to the spiritual struggles of personal faith led him to a discussion of the (...) three basic foci of his theologizing: the self as gift, that is, a creation "out of nothing" from God; the self as failure, which brings on a state of despair; and the self redeemed by God's love and healing compassion. Come probes some of the problematic aspects of Kierkegaard's theology. He addresses the question of whether God's high intentions and demands for human achievement of selfhood and spirituality justify the unspeakable sufferings entailed in human failures to fulfil those demands. He also explores the puzzling relation between Kierkegaard's seeming assignment of exclusivity to the Christian understanding and experiences of both sin and salvation as well as his assumption of the capacity of humans to recognize the need to turn to the eternal that is immanent in every human consciousness - so-called Religiousness A. (shrink)

The Danish scholar Jan Pinborg made outstanding contributions to our understanding of medieval language study. The papers in this volume clearly demonstrate the wealth of Pinborg's scholarly interests and the extent of his influence.Though centered on medieval theories of grammar and language, the collection ranges in time from the fourth century B.C. to the seventeenth century A.D.; theories of the pronoun, of mental language, of supposition, of figurative expressions and of mereology are among the topics discussed; and the papers deal (...) with both humble anonymous teachers of grammar and with such well-known men as Aristotle, Plotinus, Augustine, Peter of Spain, Roger Bacon, Robert Kilwardby, Thomas Aquinas, Dante, William of Ockham, Domingo de Soto, and Suárez. The papers are in English, German, or French. (shrink)

Composed more than 2,000 years ago during a turbulent period of Chinese history, the Dao de jing set forth an alternative vision of reality in a world torn apart by violence and betrayal. Daoism, as this subtle but enduring philosophy came to be known, offers a comprehensive view of experience grounded in a full understanding of the wonders hidden in the ordinary. Now in this luminous new translation, based on the recently discovered ancient bamboo scrolls, China scholars Roger T. Ames (...) and David L. Hall bring the timeless wisdom of the Dao de jing into our contemporary world. Though attributed to Laozi, “the Old Master,” the Dao de jing is, in fact, of unknown authorship and may well have originated in an oral tradition four hundred years before the time of Christ. Eschewing philosophical dogma, the Dao de jing set forth a series of maxims that outlined a new perspective on reality and invited readers to embark on a regimen of self-cultivation. In the Daoist world view, each particular element in our experience sends out an endless series of ripples throughout the cosmos. The unstated goal of the Dao de jing is self-transformation–the attainment of personal excellence that flows from the world and back into it. Responding to the teachings of Confucius, the Dao de jing revitalizes moral behavior by recommending a spontaneity made possible by the cultivated “habits” of the individual. In this elegant volume, Ames and Hall feature the original Chinese texts of the Dao de jing and translate them into crisp, chiseled English that reads like poetry. Each of the eighty-one brief chapters is followed by clear, thought-provoking commentary exploring the layers of meaning in the text. The book’s extensive introduction is a model of accessible scholarship in which Ames and Hall consider the origin of the text, place the emergence of Daoist philosophy in its historical and political context, and outline its central tenets. The Dao de jing is a work of timeless wisdom and beauty, as vital today as it was in ancient China. This new version will stand as both a compelling introduction to the complexities of Daoist thought and as the classic modern English translation. (shrink)

Examines the issues of self (including gender), truth, and transcendence in classical Chinese and Western philosophy.

Will democracy figure prominently in China's future? If so, what kind of democracy? In this insightful and thought-provoking book, David Hall and Roger Ames explore such questions and, in the course of answering them, look to the ideas of John Dewey and Confucius.

Among the many philosophers who hold that causal facts1 are to be explained in terms of—or more ambitiously, shown to reduce to—facts about what happens, together with facts about the fundamental laws that govern what happens, the clear favorite is an approach that sees counterfactual dependence as the key to such explanation or reduction. The paradigm examples of causation, so advocates of this approach tell us, are examples in which events c and e— the cause and its effect— both occur, (...) but: had c not occurred, e would not have occurred either. From this starting point ideas proliferate in a vast profusion. But the remarkable disparity among these ideas should not obscure their common foundation. Neither should the diversity of opinion about the prospects for a philosophical analysis of causation obscure their importance. For even those philosophers who see these prospects as dim—perhaps because they suffer post-Quinean queasiness at the thought of any analysis of any concept of interest—can often be heard to say such things as that causal relations among events are somehow “a matter of” the patterns of counterfactual dependence to be found in them. (shrink)

One of the most basic functions of human language is to convey who did what to whom. In the world's languages, the order of these three constituents (subject [S], verb [V], and object [O]) is uneven, with SOV and SVO being most common. Recent experiments using experimentally elicited pantomime provide a possible explanation of the prevalence of SOV, but extant explanations for the prevalence of SVO could benefit from further empirical support. Here, we test whether SVO might emerge because (a) (...) SOV is not well suited for describing reversible events (a woman pushing a boy) and (b) pressures to be efficient and mention subjects before objects conspire to rule out many other alternatives. We tested this by asking participants to describe reversible and non‐reversible events in pantomime, and we instructed some participants to be consistent in the form of their gestures and to teach them to the experimenter. These manipulations led to the emergence of SVO in speakers of both English (SVO) and Turkish (SOV). (shrink)

In _"Masterpiece" Studies_ Kermit Champa offers new ways to interpret modernism that have previously been closed off by the application of the reigning art-historical methodologies to the study of the modernist achievement. He focuses on four separate phenomena—Manet's last Salon painting, _Bar at the Folies-Bergèr_e;_ L'Oeuvre_, Zola's novel about the realist/impressionist movement; Van Gogh's problematic versions of a single painting, _La Berceuse_; and the immanent "series" phenomenon of Monet's work of the period. Champa reveals the importance of music, in (...) particular Wagner's music, as a paradigm for later nineteenth-century French painting. He also shows the crucial significance of the concept of the masterpiece as thematized by Zola in his novel for our understanding of certain aspects of the art of Manet, Monet, and Van Gogh. Employing postformalist methodology, the book explores the conversation between works of art produced in close succession and elaborates an aesthetic context for that conversation. Champa also shows how paintings and fictional representations of paintings can announce their points in common, and it is out of this exploration that he radically redefines what constitutes "context.". (shrink)