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     

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.     

Phylogeography of crossbills, bullfinches, grosbeaks, and rosefinches

Mitochondrial cytochrome b (cyt b) from 24 Carduelini species including crossbills, bullfinches, grosbeaks, rosefinches, and other related, but not conclusively classified species, was sequenced. These sequences were also compared with all the available sequences from the genera Carduelis, Serinus, and Passer. Phylogenetic analyses consistently gave the same groups of finches and the calculated divergence times suggest that speciation of the studied species occurred between 14 and 3 million years ago (Miocene-Pliocene), appearing before the Passer, Carduelis, and Serinus genera. Pleistocene glaciations may have been important in sub-speciation. Crossbills are integrated within the genus Carduelis, and within redpolls; the common crossbill shows subspeciation with Loxia japonica in the Pleistocene epoch. Pinicola enucleator groups together with bullfinches and is probably the ancestor of the group. Hawfinch is only distantly related to the studied groups, and might either represent an isolated genus or be related to the New World genus Hesperiphona. The grosbeak genera Eophona and Mycerobas are clearly sister groups, and species belonging to the former might have given rise to Mycerobas species. The isolated (in classification) Uragus sibiricus and Haematospiza sipahi are included within the genus Carpodacus (rosefinches); Carpodacus nipalensis is outside the genus Carpodacus in the molecular analyses and might be an isolated species or related to the genus Montifringilla.     

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.     

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.     

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.     

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.     

Forecasting technique familiarity,satisfaction, usage,and application

A ten-year retrospective study of Mentzer and Cox (1984) was undertaken to answer the question 'Have sales forecasting practices changed over the past ten years?' A mail survey of 207 forecasting executives was employed to investigate this important question. Findings revealed both discrepancies and similarities between today's sales forecasting practices and those of ten years ago. One particular finding indicated greater reliance on and satisfaction with quantitative forecasting techniques today versus ten years ago. Another indicated that forecasting accuracy has not improved over the past ten years, even though the familiarity and usage of various sophisticated sales forecasting techniques have increased. Future research and managerial implications are discussed based on these and other findings.     

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.     

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.     

Anticonvulsant,antiepileptogenic, and antiictogenic pharmacostrategies

Pharmacological concepts tailored to status epilepticus, to epileptogenesis following acquired brain insults, and to ictogenesis in established epilepsy vary considerably and should ideally be directed at those pathophysiological mechanisms that presumably underly these conditions. Currently known important molecular targets include voltage-gated sodium and calcium channels, the γ-aminobutyric acid (GABA) system and ionotropic glutamate receptors. Metabotropic glutamate receptors, potassium channels, and neurotransmitters such as acetylcholine, glycine, and monoamines are beyond the scope of this review. In status epilepticus, immediate failure of GABAergic inhibition occurs, and administration of benzodiazepines and barbiturates displays the pharmacostrategic mainstay. In epileptogenesis within limbic structures, the most important underlying pathophysiological mechanisms currently discussed are transient loss of inhibition and aberrant mossy fiber sprouting. Both processes may be facilitated by N-methy-d-aspartat (NMDA) receptor regulation. NMDA antagonists may exhibit antiepileptogenic properties in experimental animals, but reliable data in humans are lacking. In established epilepsy, voltage-gated ion channels and impairment of GABAergic functions contribute to mechanisms facilitating ictogenesis. Blockade of sodium and calcium channels and enhancement of GABAergic inhibition are currently the most important tools to prevent the occurrence of seizures. Received 16 January 2007; received after revision 7 March 2007; accepted 17 April 2007     

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.     

Cartilage biology, pathology, and repair

Osteoarthritis is one of the most common forms of musculoskeletal disease and the most prominent type of arthritis encountered in all countries. Although great efforts have been made to investigate cartilage biology and osteoarthritis pathology, the treatment has lagged behind that of other arthritides, as there is a lack of effective disease-modifying therapies. Numerous approaches for dealing with cartilage degradation have been tried, but enjoyed very little success to develop approved OA treatments with not only symptomatic improvement but also structure-modifying effect. In this review we discuss the most recent findings regarding the regulation of cartilage biology and pathology and highlight their potential therapeutic values.     

Reactions of cysteine,its derivatives,glutathione, coenzyme A,and dihydrolipoic acid with isothiocyanates

Summary Isothiocyanates react with deprotonated SH groups of investigated compounds to give the esters of N-monosubstituted dithiocarbamic acid. In the presence of the SH and NH₂ groups (Cys, GSH), isothiocyanates react primarily with the SH groups. The reactions are dependent on the pK_aSH values.     

Explanation,understanding, and unrealistic models

How can false models be explanatory? And how can they help us to understand the way the world works? Sometimes scientists have little hope of building models that approximate the world they observe. Even in such cases, I argue, the models they build can have explanatory import. The basic idea is that scientists provide causal explanations of why the regularity entailed by an abstract and idealized model fails to obtain. They do so by relaxing some of its unrealistic assumptions. This method of ‘explanation by relaxation’ captures the explanatory import of some important models in economics. I contrast this method with the accounts that Daniel Hausman and Nancy Cartwright have provided of explanation in economics. Their accounts are unsatisfactory because they require that the economic model regularities obtain, which is rarely the case. I go on to argue that counterfactual regularities play a central role in achieving ‘understanding by relaxation.’ This has a surprising implication for the relation between explanation and understanding: Achieving scientific understanding does not require the ability to explain observed regularities.     

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