A set of amino acid side chains that confer specificity for the coenzyme NADPH and the substrate glutathione in the flavoprotein disulphide oxidoreductase, glutathione reductase, has been identified. Systematic replacement of these amino acid residues in the coenzyme‐binding site switches the specificity of the enzyme from its natural strong preference for NADPH to a marked preference For NADH. The amino acids replaced all lie in a structural motif within the dinucleotide‐binding domain of the protein. Since this domain is a feature (...) common to most dehydrogenases (reductases) that use nicotinamide coenzymes, it may be that the coenzyme specificities of all such enzymes can be manipulated in this way. Similarly, amino acid residues involved in the selective recognition of trypanothione by trypanothione reductase, an enzyme related to glutathione reductase and exclusive to trypanosomatids, were identified. Suitable mutation of the corresponding residues in E. coli glutathione reductase switched its substrate specificity towards trypanothione. A better understanding of the substrate specificity of these enzymes could open up a route to the chemotherapy of trypanosomal infections. (shrink)

It is widely assumed that selection history accounts of function can support a fully reductive naturalization of functional properties. I argue that this assumption is false. A problem with the alternative causal role account of function in this context is that it invokes the teleological notion of a goal in analysing real function. The selection history account, if it is to have reductive status, must not do the same. But attention to certain cases of selection history in biology, specifically those (...) involving meiotic drive, shows that selection historical explanations are available in the case of items without any plausible function. Making contributions to goals, here fitness, must be introduced as an additional constraint in the analysis, either explicitly, or implicitly by appeal to individual functions or the selection-of/selection-for distinction. (shrink)

Angiogenesis, the generation of new blood vessels from pre‐existing vessels, is an integral component of wound healing, responses to inflammation and other physiologic processes. It is also an essential part of tumor growth; in the absence of new vessel formation, tumors cannot expand beyond a small volume. Although much is known about angiogenesis and its regulation, there is no overall theory that describes or explains this process. It is here suggested that the intracrine hypothesis, which ascribes to certain extracellular signaling (...) peptides (whether hormones, growth factors, DNA‐binding proteins or enzymes) a role in both intracellular biology and extracellular signaling, can contribute to a more general understanding of angiogenesis. Intracrine factors participate in angiogenesis in the following ways: (1) they can act within the cells that synthesized them (type I intracrine action), (2) they can be secreted and then taken up by their cell of synthesis to act intracellularly (type II intracrine action ), or (3) they can be secreted and internalized by a distant target cell (type III intracrine action). The parallels between the intracrine growth factor mechanisms cancer cells employ in stimulating their own growth and the mechanisms operative in endothelial cell proliferation during angiogenesis (“intracrine reciprocity”) are discussed. Collectively, these explorations lead to testable hypotheses regarding the regulation of normal and pathological angiogenesis, and point to similarities between tumor‐induced angiogenesis and tissue differentiation. BioEssays 28: 943–953, 2006. © 2006 Wiley periodicals, Inc. (shrink)

Alfred D. Chandler, Jr. is a worthy successor to Joseph Schumpeter as analyst of the large corporation and its role in economic growth. His new book, Scale and Scope, a comparative history of corporate capitalism in the U. S., Britain, and Germany, is animated by a vision of the large corporation as the leading force in economic growth, outdistancing older owner?managed forms of organization with a superior ability to invest entrepreneurially in large?scale production, mass distribution, and professional management. Chandler's account (...) implicitly relies on a dynamic?capabilities? theory of competition that reveals the fundamental irrelevance of neoclassical theory and policy, including antitrust policy. In some ways, however, Chandler's vision is too narrow, underplaying the role of markets in economic growth. One needs to know how economic systems build capabilities, not merely how the corporate institution does so. Moreover, there is reason to think that the last few decades have seen an organizational revolution with a dynamic rather different from the one that animates Chandler's account. As a result, Chandler's work is important for understanding the present?day issues of industrial competitiveness, but is only one piece of the puzzle. (shrink)

Kant distinguishes “natural ends” as exhibiting a part-whole reciprocal causal structure in virtue of which we can only conceive them as having been caused through a conception, as if by intelligent design. Here, I put pressure on Kant’s position by arguing that his view of what individuates and makes cognizable material bodies of any kind is inadequate and needs supplementation. Drawing on Spinoza, I further urge that the needed supplement is precisely the whole-part reciprocal causal structure that Kant takes to (...) be distinctive of natural ends alone. (shrink)

The paper argues that Israel Kirzner’s theory of entrepreneurship has been influential on a number of related “dynamic” theories of organization. Kirzner’s theory is animated by a dual concern – the process of rentseeking behavior and the fundamental incompletness of knowledge. Placed in a technological and institutional context, this theory points to the importance of dynamic transaction costs: the coordination costs of acting upon an innovative rent-seeking opportunity. In some contexts, this kind of cost can explain vertical integration; in other (...) contexts, it can explain the reverse phenomenon: vertical disintegration.Cet article soutient que la théorie de l’entrepreneur d’Israel Kirzner a influencé un grand nombre de théories dynamiques de l’organisation. La théorie kirznerienne est animée par un objectif double : – le processus de comportement de recherche de rente et l’incomplétude fondamentale de la connaissance. Replacée dans un contexte technologique et institutionnel, cette théorie souligne l’importance des coûts de transaction dynamiques : les coûts de transaction liés à une opportunité dans la recherche de rente innovante. Dans certaines situations, cette catégorie de coûts peut expliquer l’intégration verticale ; dans d’autres, elle peut expliquer le phénomène inverse : la désintégration verticale. (shrink)

Donald Davidson infamously claims that belief is in its nature veridical, and that skepticism is for this reason fundamentally incoherent. To those who take the issue of external world skepticism seriously, Davidson's arguments may seem to involve a conjuring trick. In particular, his invocation of an ‘omniscient interpreter’, whose intelligibility supposedly ensures that our beliefs must be largely true, has the air of incense and lantern-rubbing about it. Davidson's claim has received considerable critical response in the literature, almost all of (...) it negative. In my view, some commentators have indeed lit on a critical and controversial lemma in Davidson's argument, but this basic result has been obscured by being presented amidst an array of other criticisms that simply make no sense from a Davidsonian point of view. The aim of this paper is to clear away some of the confusion that stands in the way of a more productive evaluation of Davidson's important claim. (shrink)

I examine the arguments Donald Davidson has offered through the years concerning the ontological bona fides of facts. In “Truth and Meaning”, Davidson uses the so-called “slingshot” argument to the effect that if true sentences refer, then they are all coreferential. Through a detailed examination of the assumptions underlying this argument, I show that, while it is effective as part of a reductio of bottom-up, reference based semantics, it has no tendency to establish the truth of its negative conclusion concerning (...) the existence of facts. Davidson also argues against facts by claiming they are of no help in the explication of truth. I claim that his repeated invocation of the slingshot in this context, as well as of arguments from other authors employing assumptions similar to the slingshot's, is inappropriate, especially in light of his own commitment to a top-down semantics — a committment inspired, ironically, by the reductio offered in “Truth and Meaning”. Davidson's other argument against truth as correspondence, namely that our grasp of facts is no better than our grasp of truths, is sound. But this argument does not show that there are no facts; it shows only that no theory of truth in terms of corre- pondence to facts can genuinely illuminate its explanandum. (shrink)

From the neurophysiological perspective, thinking in dreaming and the quality of dream thought have been considered hallucinatory, bizarre, illogical, improbable, or even impossible. This empirical phenomenological research concentrates on testing whether dream thought can be defined as rational in the sense of an intervening mental process between sensory perception and the creation of meaning, leading to a conclusion or to taking action. From 10 individual dream journals of male participants aged 22–59 years and female participants aged 25–49 years, we delimited (...) four dreams per journal and randomly selected five thought units from each dream for scoring. The units provided a base for testing a hypothesis that the thought processes of dream construction are rational. The results support the hypothesis and demonstrate that eight fundamental rational thought processes can be applied to the dreaming process. (shrink)

PLATO'S UNIVERSE by Gregory Vlastos. Clarendon Press: O.U.P., 1975. xiii+130 pp. £3.75.

1. Marxism and totalitarian democracy, 1818-1850.--v. 2. Classical Marxism, 1850-1895.

The topic of the present essay is the proper understanding of Donald Davidson’s version of the publicity requirement for the determinants of linguistic meaning. On the understanding I promote, the requirement is very strict indeed. My narrow aim is to show how such a strict conception of the publicity requirement can be maintained despite the evident need for interpreters to go beyond what is public on that conception in the process of constructing Davidsonian theories of meaning. Towards that aim, I (...) engage dialectically with treatments of Davidson’s principle of charity owing to Lepore and Ludwig and to Bar-On and Risjord, each of which, in different ways, recommend a more permissive approach to the publicity requirement than the one I recommended here. A broader aim is to shed some light on what would be required to take seriously the larger ambitions of Davidson’s semantic program. (shrink)