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     

Abduction, tomography, and other inverse problems

Charles S. Peirce introduced in the late 19^th century the notion of abduction as inference from effects to causes, or from observational data to explanatory theories. Abductive reasoning has become a major theme in contemporary logic, philosophy of science, and artificial intelligence. This paper argues that the new growing branch of applied mathematics called inverse problems deals successfully with various kinds of abductive inference within a variety of scientific disciplines. The fundamental theorem about the inverse reconstruction of plane functions from their line integrals was proved by Johann Radon already in 1917. The practical applications of Radon’s theorem and its generalizations include computerized tomography which became a routine imaging technique of diagnostic medicine in the 1970s.     

Immunochemical identity of dipeptidyl aminopeptidase IV from pig serum, liver, submaxillary gland and kidney.

The enzymes which were extracted by autodigestion from the microsomal fractions of the pig kidney, liver and submaxillary gland and from the serum showed an immunochemical identity by a double immunodiffusion test. But the kidney enzyme had a different pI-value from the pI-values of the enzymes of other organs.     

Immunohistochemical localization fo galactocerebroside in kidney,liver, and lung of golden hamster

Summary Localization of galactocerebroside in kidney, liver, and lung of hamster was studied by the immunoperoxidase method using an affinity-purified specific antibody. Epithelial cells of the following anatomical sites were labelled with the antibody: distal tubuli, ascending limbs of Henle's loops, and collecting tubuli in kidney; periportal bile ducts and hepatic parenchyma in liver; bronchioli and alveoli in lung. The existence of galactocerebroside in these 3 organs was also confirmed by chemical analysis.This study was supported in part by grants from the Ministry of Education, Science and Culture of Japan, a Research Grant for Intractable Diseases from the Ministry of Health and Welfare of Japan, and a grant from the Mitsubishi Foundation.     

James geikie,james croll,and the eventful ice age

James Geikie's Great Ice Age (1874) first presented to the geological public the Pleistocene. modern interpretation of alternating mild and cold periods during the Though it was supported by geological evidence, Geikie's view of the Ice Age was based on a theoretical framework supplied by the climatic physics of James Croll. Mid-nineteenth-century British geologists had encountered great difficulty in making sense out of the varied and complicated glacial deposits, or ‘drift’, and had formulated the ‘iceberg’ theory to account for the apparent chaos of the drift, an explanation which discouraged its stratigraphic study. The reaffirmation of faith in continental glaciation by several Scottish geologists in the 1850s brought with it a belief in an eventful Pleistocene, but it remained difficult to discover the events of Ice Age history from study of the glacial deposits. In 1864 Croll presented a detailed climatic history of the Ice Age deduced from astronomy and physical geography. By 1871 James Geikie was using Croll's scheme of Ice Age history as the basis for his impressive synthesis of Pleistocene data from throughout the world.     

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.     

Immunochemical identity of dipeptidyl aminopeptidase IV from pig serum,liver, submaxillary gland and kidney

Summary The enzymes which were extracted by autodigestion from the microsomal fractions of the pig kidney, liver and submaxillary gland and from the serum showed an immunochemical identity by a double immunodiffusion test. But the kidney enzyme had a different pI-value from the pI-values of the enzymes of other organs.This investigation was supported by a grant from the Ministry of Education, Japan to K. M. F. We would like to thank Dr Toshiharu Nagatsu (Department of Life Chemistry, Graduate School at Nagatsuta, Tokyo Institute of Technology, Yokohama, Japan) for helpful suggestions, Mr Moritoshi Sato (Matsumoto Meat Inspection Station, Matsumoto, Japan) for their generous supply of pig organs and Ajinomoto Co. Inc., Tokyo, Japan, for the gift of Gly-Pro-p-nitroanilide tosylate. Technical assistance of Miss K. Yanagisawa is gratefully acknowledged.     

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.     

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.     

Radical catalysis of B12 enzymes: structure,mechanism, inactivation,and reactivation of diol and glycerol dehydratases

Enzymatic radical catalysis is defined as a mechanism of catalysis by which enzymes catalyze chemically difficult reactions by utilizing the high reactivity of free radicals. Adenosylcobalamin (coenzyme B12) serves as a cofactor for enzymatic radical reactions. The recent structural analysis of adenosylcobalamin-dependent diol dehydratase revealed that the substrate 1,2-propanediol and an essential potassium ion are located inside a (beta/alpha)8 barrel. Two hydroxyl groups of the substrate coordinate directly to the potassium ion which binds to the negatively charged inner part of the cavity. Cobalamin bound in the base-on mode covers the cavity to isolate the active site from solvent. Based on the three-dimensional structure and theoretical calculations, a new mechanism for diol dehydratase is proposed in which the potassium ion plays a direct role in the catalysis. The mechanisms for generation of a catalytic radical by homolysis of the coenzyme Co-C bond and for protection of radical intermediates from undesired side reactions during catalysis are discussed based on the structure. The reactivating factors for diol and glycerol dehydratases have been identified. These factors are a new type of molecular chaperone which participate in reactivation of the inactivated holoenzymes by mediating ATP-dependent exchange of the modified coenzyme for free intact coenzyme.     

Kuhn, Popper, and the Superconducting Supercollider

The demise of the Superconducting Supercollider (SSC) is often explained in terms of the strain that it placed on the federal budget of the United States, and change in national security interests with the end of the Cold War. Recent work by Steve Fuller provides a framework to re-examine this episode in epistemological terms using the work of Kuhn and Popper. Using this framework, it is tempting to explain the demise as resulting from the overly Kuhnian character of its proponents, who supposedly argued for its construction by appealing to the importance of testing the predictions of a specific paradigm (i.e. the Standard Model). On this reading, the SSC case appears as an example of how Kuhn’s paradigm-driven view of science was invoked to keep science closed and autonomous from society. I argue that the SSC episode should not be viewed as giving support to the displacement of Kuhn’s view of science for Popper’s, and that such a displacement is detrimental to the project of integrating discussion on science into the public sphere. Drawing upon Rouse and Wimsatt, I argue that understanding paradigms as practices blunts some criticisms against Kuhn’s model, and that his model should play an important epistemological role in the aforementioned project.     

Professional forecasters' expectations,consistency, and international spillovers

This paper focuses on the expectation formation process of professional forecasters by relying on survey data on forecasts regarding gross domestic product growth, consumer price index inflation and 3-month interest rates for a broad set of countries. We examine the interrelation between macroeconomic forecasts and also the impact of uncertainty on forecasts by allowing for cross-country interdependencies and time variation in the coefficients. We find that professional forecasts are often in line with the Taylor rule and identify significant expectation spillovers from monetary policy in the USA.     

Disciplines,models, and computers: The path to computational quantum chemistry

Many disciplines and scientific fields have undergone a computational turn in the past several decades. This paper analyzes this sort of turn by investigating the case of computational quantum chemistry. The main claim is that the transformation from quantum to computational quantum chemistry involved changes in three dimensions. First, on the side of instrumentation, small computers and a networked infrastructure took over the lead from centralized mainframe architecture. Second, a new conception of computational modeling became feasible and assumed a crucial role. And third, the field of computational quantum chemistry became organized in a market-like fashion and this market is much bigger than the number of quantum theory experts. These claims will be substantiated by an investigation of the so-called density functional theory (DFT), the arguably pivotal theory in the turn to computational quantum chemistry around 1990.     

Negotiating history: Contingency,canonicity, and case studies

Objections to the use of historical case studies for philosophical ends fall into two categories. Methodological objections claim that historical accounts and their uses by philosophers are subject to various biases. We argue that these challenges are not special; they also apply to other epistemic practices. Metaphysical objections, on the other hand, claim that historical case studies are intrinsically unsuited to serve as evidence for philosophical claims, even when carefully constructed and used, and so constitute a distinct class of challenge. We show that attention to what makes for a canonical case can address these problems. A case study is canonical with respect to a particular philosophical aim when the features relevant to that aim provide a reasonably complete causal account of the results of the historical process under investigation. We show how to establish canonicity by evaluating relevant contingencies using two prominent examples from the history of science: Eddington’s confirmation of Einstein’s theory of general relativity using his data from the 1919 eclipse and Watson and Crick’s determination of the structure of DNA.     

Olfactory ensheathing cells are attracted to, and can endocytose, bacteria

Olfactory ensheathing cells (OECs) have been shown previously to express Toll-like receptors and to respond to bacteria by translocating nuclear factor-kappaB from the cytoplasm to the nucleus. In this study, we show that OECs extended significantly more pseudopodia when they were exposed to Escherichia coli than in the absence of bacteria (p=0.019). Co-immunoprecipitation showed that E. coli binding to OECs was mediated by Toll-like receptor 4. Lyso-Tracker, a fluorescent probe that accumulates selectively in lysosomes, and staining for type 1 lysosome-associated membrane proteins demonstrated that endocytosed FITC-conjugated E. coli were translocated to lysosomes. They appeared to be subsequently broken down, as shown by transmission electron microscopy. No obvious adherence to the membrane and less phagocytosis was observed when OECs were incubated with inert fluorescent microspheres. The ability of OECs to endocytose bacteria supports the notion that OECs play an innate immune function by protecting olfactory tissues from bacterial infection.     

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     

Isolation,characterization, and determination of human liver (copper/zinc) metallothionein

Summary A copper-containing protein was purified from the liver of a patient with primary biliary cirrhosis by a combination of gel filtration and anion exchange chromatography. This copper-protein had UV absorption and emission spectra, an amino acid composition, and a molecular mass which were characteristic for metallothionein (MT).From 8 livers (3 control, 1 fetal and 4 primary biliary cirrhosis) MT was extracted with non-reducing buffer and centrifuged, and the pellets were re-extracted with a 1% 2-mercaptoethanol-containing buffer. The non-reducing buffer extracted a predominantly copper-containing MT from the livers of patients with primary biliary cirrhosis and a predominantly zinc-containing MT from control lives and the fetal liver. Only from the fetal liver was a copper/zinc containing MT solubilized during the re-extraction with 2-mercaptoethanol-containing buffer. These results indicate that human MT is a unique metalloprotein with age and disease-dependent characteristics.     

Isolation, characterization, and determination of human liver (copper/zinc) metallothionein

A copper-containing protein was purified from the liver of a patient with primary biliary cirrhosis by a combination of gel filtration and anion exchange chromatography. This copper-protein had UV absorption and emission spectra, an amino acid composition, and a molecular mass which were characteristic for metallothionein (MT). From 8 livers (3 control, 1 fetal and 4 primary biliary cirrhosis) MT was extracted with non-reducing buffer and centrifuged, and pellets were re-extracted with a 1% 2-mercaptoethanol-containing buffer. The non-reducing buffer extracted a predominantly copper-containing MT from the livers of patients with primary biliary cirrhosis and a predominantly zinc-containing MT from control livers and the fetal liver. Only from the fetal liver was a copper/zinc containing MT solubilized during the re-extraction with 2-mercaptoethanol-containing buffer. These results indicate that human MT is a unique metalloprotein with age and disease-dependent characteristics.     

Conservation,evolution, and specificity in cellular control by protein phosphorylation

The glycolytic control enzyme phosphofructokinase from the parasitic nematodeAscaris lumbricodies is regulated by reversible phosphorylation. The enzyme is phosphorylated by an atypical cyclic adenosine monophosphate (cAMP)-dependent protein kinase whose substrate specificity deviates from that of the mammalian protein kinase. This variation is explained by structural peculiarities on the surface part of the catalytic groove of the protein kinase. Also, the protein phosphatases responsible for the reversal of phosphorylation appear to act specifically in glycolysis and are different from those participating in regulation of glycogenolysis.