Pepsinogens, progastricsins, and prochymosins: structure, function, evolution, and development

Five types of zymogens of pepsins, gastric digestive proteinases, are known: pepsinogens A, B, and F, progastricsin, and prochymosin. The amino acid and/or nucleotide sequences of more than 50 pepsinogens other than pepsinogen B have been determined to date. Phylogenetic analyses based on these sequences indicate that progastricsin diverged first followed by prochymosin, and that pepsinogens A and F are most closely related. Tertiary structures, clarified by X-ray crystallography, are commonly bilobal with a large active-site cleft between the lobes. Two aspartates in the center of the cleft, Asp32 and Asp215, function as catalytic residues, and thus pepsinogens are classified as aspartic proteinases. Conversion of pepsinogens to pepsins proceeds autocatalytically at acidic pH by two different pathways, a one-step pathway to release the intact activation segment directly, and a stepwise pathway through a pseudopepsin(s). The active-site cleft is large enough to accommodate at least seven residues of a substrate, thus forming S₄ through S₃′ subsites. Hydrophobic and aromatic amino acids are preferred at the P₁ and P₁′ positions. Interactions at additional subsites are important in some cases, for example with cleavage of κ-casein by chymosin. Two potent naturally occurring inhibitors are known: pepstatin, a pentapeptide from Streptomyces, and a unique proteinous inhibitor from Ascaris. Pepsinogen genes comprise nine exons and may be multiple, especially for pepsinogen A. The latter and progastricsin predominate in adult animals, while pepsinogen F and prochymosin are the main forms in the fetus/infant. The switching of gene expression from fetal/infant to adult-type pepsinogens during postnatal development is noteworthy, being regulated by several factors, including steroid hormones. Received 25 May 2001; received after revision 27 August 2001; accepted 30 August 2001     

Physicalism,realization, and structure

In the philosophy of mind and psychology, a central question since the 1960s has been that of how to give a philosophically adequate formulation of mind-body physicalism. A large quantity of work on the topic has been done in the interim. There have been, and continue to be, extensive discussions of the ideas of physicalism, identity, functionalism, realization, and constitution. My aim in this paper is a modest one: it is to get clearer about these ideas and some of their interrelations. After providing some background and history, I shall focus on two related topics: the distinction between a functional property and a structural one and the dispute over whether a realization account of the mental-physical relation provides a better physicalist account than a constitutional account.     

Bird, Kuhn, and positivism

I challenge Alexander Bird’s contention that the divergence between Kuhn’s views and recent philosophy of science is a matter of Kuhn having taken a wrong turn. Bird is right to remind us of Kuhn’s naturalistic tendencies, but these are not clearly an asset, rather than a liability. Kuhn was right to steer clear of extreme referential conceptions of meaning, since these court an unacceptable semantic scepticism. Although he eschewed the concepts of truth and knowledge as philosophers of science have tended to understand them, this doesn’t mean that, as Bird claims, Kuhn was a sceptic about scientific knowledge. Bird’s claim that recent philosophical naturalism represents a rejection of positivism far more thorough than Kuhn’s is problematic since, from a different perspective, this kind of naturalism can be seen to have inherited some equally important positivistic themes. Finally, it’s not clear that Kuhn should have endorsed a computational approach to the philosophy of science, such as connectionism, since such approaches may be more behaviouristic, and thus unacceptably positivistic, than the original cognitive revolution promised.     

Microbes,mathematics, and models

Microbial model systems have a long history of fruitful use in fields that include evolution and ecology. In order to develop further insight into modelling practice, we examine how the competitive exclusion and coexistence of competing species have been modelled mathematically and materially over the course of a long research history. In particular, we investigate how microbial models of these dynamics interact with mathematical or computational models of the same phenomena. Our cases illuminate the ways in which microbial systems and equations work as models, and what happens when they generate inconsistent findings about shared targets. We reveal an iterative strategy of comparative modelling in different media, and suggest reasons why microbial models have a special degree of epistemic tractability in multimodel inquiry.     

Causation,information, and physics

This work outlines the novel application of the empirical analysis of causation, presented by Kutach, to the study of information theory and its role in physics. The central thesis of this paper is that causation and information are identical functional tools for distinguishing controllable correlations, and that this leads to a consistent view, not only of information theory, but also of statistical physics and quantum information. This approach comes without the metaphysical baggage of declaring information a fundamental ingredient in physical reality and exorcises many of the otherwise puzzling problems that arise from this view-point, particularly obviating the problem of ‘excess baggage’ in quantum mechanics. This solution is achieved via a separation between information carrying causal correlations of a single qubit and the bulk of its state space.     

Flavodoxins: sequence, folding, binding, function and beyond

Flavodoxins are electron-transfer proteins involved in a variety of photosynthetic and non-photosynthetic reactions in bacteria, whereas, in eukaryotes, a descendant of the flavodoxin gene helps build multidomain proteins. The redox activity of flavodoxin derives from its bound flavin mononucleotide cofactor (FMN), whose intrinsic properties are profoundly modified by the host apoprotein. This review covers the very exciting last decade of flavodoxin research, in which the folding pathway, the structure and stability of the apoprotein, the mechanism of FMN recognition, the interactions that stabilize the functional complex and tailor the redox potentials, and many details of the binding and electron transfer to partner proteins have been revealed. The next decade should witness an even deeper understanding of the flavodoxin molecule and a greater comprehension of its many physiological roles. The fact that flavodoxin is essential for the survival of some human pathogens could make it a drug target on its own. Received 26 October 2005; received after revision 20 November 2005; accepted 14 December 2005     

Acceptance,values, and probability

This essay makes a case for regarding personal probabilities used in Bayesian analyses of confirmation as objects of acceptance and rejection. That in turn entails that personal probabilities are subject to the argument from inductive risk, which aims to show non-epistemic values can legitimately influence scientific decisions about which hypotheses to accept. In a Bayesian context, the argument from inductive risk suggests that value judgments can influence decisions about which probability models to accept for likelihoods and priors. As a consequence, if the argument from inductive risk is sound, then non-epistemic values can affect not only the level of evidence deemed necessary to accept a hypothesis but also degrees of confirmation themselves.     

Bile Acids: Chemistry, Pathochemistry, Biology, Pathobiology, and Therapeutics

Bile acids and bile alcohols in the form of their conjugates are amphipathic end products of cholesterol metabolism with multiple physiological functions. The great variety of bile acids and bile alcohols that are present in vertebrates are tabulated. Bile salts have an enterohepatic circulation resulting from efficient vectorial transport of bile salts through the hepatocyte and the ileal enterocyte; such transport leads to the accumulation of a pool of bile salts that cycles between the liver and intestine. Bile salt anions promote lipid absorption, enhance tryptic cleavage of dietary proteins, and have antimicrobial effects. Bile salts are signaling molecules, activating nuclear receptors in the hepatocyte and ileal enterocyte, as well as an increasing number of G-protein coupled receptors. Bile acids are used therapeutically to correct deficiency states, to decrease the cholesterol saturation of bile, or to decrease the cytotoxicity of retained bile acids in cholestatic liver disease.     

Immunofluorescent localization of collagen types I,III, IV,V, fibronectin,laminin, entactin,and heparan sulphate proteoglycan in human immature placenta

The distribution of eight components of the extracellular matrix in immature human placenta was studied by an indirect immunofluorescence method with monospecific antibodies. In the stroma of the term chorionic villi, collagen types I, III, IV, V, and fibronectin formed a mesh of fibers and conglomerates. Heparan sulphate proteoglycan formed multiple conglomerates, whereas laminin comprised small, scanty, discrete granules. Collagen type IV, laminin, entactin, and heparan sulphate proteoglycan were confined to the basement membrane of the trophoblast. Sometimes, only collagen type IV was identified in fetal vascular basement membrane.     

Inventing paradigms,monopoly, methodology,and mythology at ‘Chicago’: Nutter,Stigler, and Milton Friedman

This paper aims to contribute to a better understanding of the formation of the so-called Chicago-school of economics; it does so by focusing on (i) previously unpublished correspondence between George Stigler and Thomas Kuhn as well as (ii) Warren Nutter’s The Extent of Enterprise Monopoly in the United States, 1899–1939. Nutter’s book started out as a (1949) doctoral dissertation at The University of Chicago, part of Aaron Director’s Free Market Study. Besides Director, O.H. Brownlee and Milton Friedman were closely involved with supervising it. It was published by The University of Chicago Press in 1951. The book was explicitly understood as belonging to the “Chicago School” (Dow & Abernathy, 1963). But by the time of Reder’s well known (1982) review paper Nutter does not figure at all. I argue that the Stigler-Kuhn correspondence helps us better understand why Nutter disappeared from sight. More important, by contrasting the work of Nutter with that of Harberger, the episode reveals how Milton Friedman’s methodological statements became the rhetoric for a paradigm that was committed to a very different approach than the one advocated by Nutter or Friedman.     

Understanding,explanation, and unification

In this article I argue that there are two different types of understanding: the understanding we get from explanations, and the understanding we get from unification. This claim is defended by first showing that explanation and unification are not as closely related as has sometimes been thought. A critical appraisal of recent proposals for understanding without explanation leads us to discuss the example of a purely classificatory biology: it turns out that such a science can give us understanding of the world through unification of the phenomena, even though it does not give us any explanations. The two types of understanding identified in this paper, while strictly separate, do have in common that both consist in seeing how the individual phenomena of the universe hang together. Explanations give us connections between the phenomena through the asymmetric, ‘vertical’ relation of determination; unifications give us connections through the symmetric, ‘horizontal’ relation of kinship. We then arrive at a general definition of understanding as knowledge of connections between the phenomena, and indicate that there might be more than two types of understanding.     

Deflationary representation,inference, and practice

This paper defends the deflationary character of two recent views regarding scientific representation, namely RIG Hughes' DDI model and the inferential conception. It is first argued that these views' deflationism is akin to the homonymous position in discussions regarding the nature of truth. There, we are invited to consider the platitudes that the predicate “true” obeys at the level of practice, disregarding any deeper, or more substantive, account of its nature. More generally, for any concept X, a deflationary approach is then defined in opposition to a substantive approach, where a substantive approach to X is an analysis of X in terms of some property P, or relation R, accounting for and explaining the standard use of X. It then becomes possible to characterize a deflationary view of scientific representation in three distinct senses, namely: a “no-theory” view, a “minimalist” view, and a “use-based” view—in line with three standard deflationary responses in the philosophical literature on truth. It is then argued that both the DDI model and the inferential conception may be suitably understood in any of these three different senses. The application of these deflationary ‘hermeneutics’ moreover yields significant improvements on the DDI model, which bring it closer to the inferential conception. It is finally argued that what these approaches have in common—the key to any deflationary account of scientific representation—is the denial that scientific representation may be ultimately reduced to any substantive explanatory property of sources, or targets, or their relations.     

Simultaneity,convention, and gauge freedom

As is well known from Einstein (1905) the choice of a criterion for distant simultaneity is equivalent to stipulating one-way speeds for the transit of light. It is shown that any choice of non-standard synchrony is equivalent to a Lorentz local time boost. From this and considerations from the hole argument, it follows that there is a non-trivial sense in which distant simultaneity is conventional, at least to the extent that the “gauge freedom” arising in the hole argument is non-trivial.     

Melatonin,mitochondria, and the skin

The skin being a protective barrier between external and internal (body) environments has the sensory and adaptive capacity to maintain local and global body homeostasis in response to noxious factors. An important part of the skin response to stress is its ability for melatonin synthesis and subsequent metabolism through the indolic and kynuric pathways. Indeed, melatonin and its metabolites have emerged as indispensable for physiological skin functions and for effective protection of a cutaneous homeostasis from hostile environmental factors. Moreover, they attenuate the pathological processes including carcinogenesis and other hyperproliferative/inflammatory conditions. Interestingly, mitochondria appear to be a central hub of melatonin metabolism in the skin cells. Furthermore, substantial evidence has accumulated on the protective role of the melatonin against ultraviolet radiation and the attendant mitochondrial dysfunction. Melatonin and its metabolites appear to have a modulatory impact on mitochondrion redox and bioenergetic homeostasis, as well as the anti-apoptotic effects. Of note, some metabolites exhibit even greater impact than melatonin alone. Herein, we emphasize that melatonin–mitochondria axis would control integumental functions designed to protect local and perhaps global homeostasis. Given the phylogenetic origin and primordial actions of melatonin, we propose that the melatonin-related mitochondrial functions represent an evolutionary conserved mechanism involved in cellular adaptive response to skin injury and repair.     

Melatonin,mitochondria, and the metabolic syndrome

A number of risk factors for cardiovascular disease including hyperinsulinemia, glucose intolerance, dyslipidemia, obesity, and elevated blood pressure are collectively known as metabolic syndrome (MS). Since mitochondrial activity is modulated by the availability of energy in cells, the disruption of key regulators of metabolism in MS not only affects the activity of mitochondria but also their dynamics and turnover. Therefore, a link of MS with mitochondrial dysfunction has been suspected since long. As a chronobiotic/cytoprotective agent, melatonin has a special place in prevention and treatment of MS. Melatonin levels are reduced in diseases associated with insulin resistance like MS. Melatonin improves sleep efficiency and has antioxidant and anti-inflammatory properties, partly for its role as a metabolic regulator and mitochondrial protector. We discuss in the present review the several cytoprotective melatonin actions that attenuate inflammatory responses in MS. The clinical data that support the potential therapeutical value of melatonin in human MS are reviewed.     

QFT, antimatter, and symmetry

A systematic analysis is made of the relations between the symmetries of a classical field and the symmetries of the one-particle quantum system that results from quantizing that field in regimes where interactions are weak. The results are applied to gain a greater insight into the phenomenon of antimatter.     

Effect of latent iron deficiency on the levels of iron, calcium, zinc, copper, manganese, cadmium and lead in liver, kidney and spleen of growing rats

Feeding a marginally low iron content diet (18-20 mg iron/kg diet) to weaned (21-day-old) rats for 8 weeks produced a significant decrease in liver non-heme iron (66%, p less than 0.001) but no change in blood hemoglobin. Total iron contents of liver (56%, p less than 0.01), spleen (20%, p less than 0.05), and kidney (19%, p less than 0.05) were also found to decrease along with increased zinc, copper, calcium, manganese lead and cadmium in various organs. The magnitude of alteration of a metal was different in different organs. However, liver was found to be the most affected organ. Two weeks of rehabilitation with iron-sufficient diet (390 mg iron/kg diet) normalized these altered levels.     

Effect of latent iron deficiency on the levels of iron,calcium, zinc,copper, manganese,cadmium and lead in liver,kidney and spleen of growing rats

Summary Feeding a marginally low iron content diet (18–20 mg iron/kg diet) to weaned (21-day-old) rats for 8 weeks produced a significant decrease in liver non-heme iron (66%, p<0.001) but no change in blood hemoglobin. Total iron contents of liver (56%, p<0.01), spleen (20%, p<0.05), and kidney (19%, p<0.05) were also found to decrease along with increased zinc, copper, calcium, manganese lead and cadmium in various organs. The magnitude of alteration of a metal was different in different organs. However, liver was found to be the most affected organ. Two weeks of rehabilitation with iron-sufficient diet (390 mg iron/kg diet) normalized these altered levels.     

Perspectivism, inconsistent models, and contrastive explanation

It is widely recognized that scientific theories are often associated with strictly inconsistent models, but there is little agreement concerning the epistemic consequences. Some argue that model inconsistency supports a strong perspectivism, according to which claims serving as interpretations of models are inevitably and irreducibly perspectival. Others argue that in at least some cases, inconsistent models can be unified as approximations to a theory with which they are associated, thus undermining this kind of perspectivism. I examine the arguments for perspectivism, and contend that its strong form is defeasible in principle, not merely in special cases. The argument rests on the plausibility of scientific knowledge concerning non-perspectival, dispositional facts about modelled systems. This forms the basis of a novel suggestion regarding how to understand the knowledge these models afford, in terms of a contrastive theory of what-questions.