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.     

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.     

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.     

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

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

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     

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.     

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.