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.     

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.     

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.     

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.     

Structures of maridomycin I,III, IV,V and VI,macrolide antibiotics

Zusammenfassung Strukturaufklärung einer Gruppe von Antibiotika aus der Reihe der Makrolide.     

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.     

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.     

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.     

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.     

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     

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.     

Ecotype,ecospecies, and macroevolution

Summary Der Autor tritt erneut der Ansicht der Neodarwinisten entgegen, daß geographische, erbliche Varianten Vorstufen neuer Arten seien. Für deren Entstehung sowie für Merkmale höherer Einheiten kommen nur plötzlich große und nicht einzelne summierende Mutationsschritte in Betracht. Mikromutationen liefern lediglich das Material für die Entstehung von Rassen und Unterarten. Nicht nur größere systematische Unterschiede, sondern auch Anpassungsmerkmale kommen durch Großmutationen zustande. Als Beispiele werden unter anderem zwei Mutationen beiDrosphila melanogaster angeführt. Bei der einen sind die Flügel in Halteren, oder umgekehrt, diese in Flügel, umgebildet. Bei der anderen, vom Autor aufgefundenen, sind aus den Flügeln beinartige Organe geworden. Diese Mutante ist außerdem deswegen von Bedeutung, weil sich nach Kreuzung mit anderen Mutationen Merkmale entwickeln, die an den letzteren nicht erscheinen.Paper read at the closing session of the International Congress of Zoology, Paris, July, 1948.