Lys(9) for Glu(9) substitution in glucagon-like peptide-1(7-36)amide confers dipeptidylpeptidase IV resistance with cellular and metabolic actions similar to those of established antagonists glucagon-like peptide-1(9-36)amide and exendin (9-39)

The incretin hormone glucagon-like peptide-1(7-36)amide (GLP-1) has been deemed of considerable importance in the regulation of blood glucose. Its effects, mediated through the regulation of insulin, glucagon, and somatostatin, are glucose-dependent and contribute to the tight control of glucose levels. Much enthusiasm has been assigned to a possible role of GLP-1 in the treatment of type 2 diabetes. GLIP-l's action unfortunately is limited through enzymatic inactivation caused by dipeptidylpeptidase IV (DPP IV). It is now well established that modifying GLP-1 at the N-terminal amino acids, His(7) and Ala(8), can greatly improve resistance to this enzyme. Little research has assessed what effect Glu(9)-substitution has on GLP-1 activity and its degradation by DPP IV. Here, we report that the replacement of Glu(9) of GLP-1 with Lys dramatically increased resistance to DPP IV. This analogue, (Lys(9))GLP-1, exhibited a preserved GLP-1 receptor affinity, but the usual stimulatory effects of GLP-1 were completely eliminated, a trait duplicated by the other established GLP-1-antagonists, exendin (9-39) and GLP-1 (9-36)amide. We investigated the in vivo antagonistic actions of (Lys(9))GLP-1 in comparison with GLP-1(9-36)amide and exendin (9-39) and revealed that this novel analogue may serve as a functional antagonist of the GLP-1 receptor. (C) 2004 Elsevier Inc. All rights reserved.

On the complexity of the water-gas shift reaction mechanism over a Pt/CeO2 catalyst: Effect of the temperature on the reactivity of formate surface species studied by operando DRIFT during isotopic transient at chemical steady-state

The present report investigates the role of formate species as potential reaction intermediates for the WGS reaction (CO + H2O -> CO2 + H-2) over a Pt-CeO2 catalyst. A combination of operando techniques, i.e., in situ diffuse reflectance FT-IR (DRIFT) spectroscopy and mass spectrometry (MS) during steady-state isotopic transient kinetic analysis (SSITKA), was used to relate the exchange of the reaction product CO2 to that of surface formate species. The data presented here suggest that a switchover from a non-formate to a formate-based mechanism could take place over a very narrow temperature range (as low as 60 K) over our Pt-CeO2 catalyst. This observation clearly stresses the need to avoid extrapolating conclusions to the case of results obtained under even slightly different experimental conditions. The occurrence of a low-temperature mechanism, possibly redox or Mars van Krevelen-like, that deactivates above 473 K because of ceria over-reduction is suggested as a possible explanation for the switchover, similarly to the case of the CO-NO reaction over Cu, I'd and Rh-CeZrOx (see Kaspar and co-workers [1-3]). (c) 2006 Elsevier B.V. All rights reserved.

Determination of absolute configuration of conformationally flexible cis-dihydrodiol metabolites: Effect of diene substitution pattern on the circular dichroism spectra and optical rotations

Absolute configurations of a number of cis-dihydrodiols (cis-1,2-dihydroxy-3,5-cyclohexadienes), synthetically useful products of TDO-catalyzed dihydroxylations of 1,2- and 1,3-disubstituted benzene derivatives, have been determined by a comparison of calculated and experimental CD spectra and optical rotations and by methods involving X-ray crystallography, H-1 NMR spectra of diastereoisomeric derivatives, and by stereochemical correlations. The computations disclosed a significant effect of the substituents on conformational equilibria of cis-dihydrodiols and chiroptical properties of individual conformers. The assigned absolute configurations of cis-dihydrodiols have allowed the validity of a simple predictive model for TDO-catalyzed arene dihydroxylations to be extended.

Substitution of pseudokinase domain residue Val-617 by large non-polar amino acids causes activation of JAK2

Explaining the uniqueness of the acquired somatic JAK2 V617F mutation, which is present in more than 95% of polycythemia vera patients, has been a challenge. The V617F mutation in the pseudokinase domain of JAK2 renders the unmutated kinase domain constitutively active. We have performed random mutagenesis at position 617 of JAK2 and tested each of the 20 possible amino acids for ability to induce constitutive signaling in Ba/F3 cells expressing the erythropoietin receptor. Four JAK2 mutants, V617W, V617M, V617I, and V617L, were able to induce cytokine independence and constitutive downstream signaling. Only V617W induced a level of constitutive activation comparable with V617F. Also, only V617W stabilized tyrosine-phosphorylated suppressor of cytokine signaling 3 ( SOCS3), a mechanism by which JAK2 V617F overcomes inhibition by SOCS3. The V617W mutant induced a myeloproliferative disease in mice, mainly characterized by erythrocytosis and megakaryocytic proliferation. Although JAK2 V617W would predictably be pathogenic in humans, the substitution of the Val codon, GTC, by TTG, the codon for Trp, would require three base pair changes, and thus it is unlikely to occur. We discuss how the predicted conformations of the activated JAK2 mutants can lead to better screening assays for novel small molecule inhibitors.

Identifying the influence of geology, land use, and anthropogenic activities on riverine sulfate on a watershed scale by combining hydrometric, chemical and isotopic approaches

Throughout the last few decades, sulfate concentrations in streamwater have received considerable attention due to their dominant role in anthropogenic acidification of surface waters. The objectives of this study conducted in the Oldman River Basin in Alberta (Canada) were to determine the influence of geology, land use and anthropogenic activities on sources, concentrations and fluxes of riverine sulfate on a watershed scale. This was achieved by combining hydrological, chemical and isotopic techniques. Surface water samples were collected from the main stem and tributaries of the Oldman River on a monthly basis between December 2000 and March 2003 and analyzed for chemical and isotopic compositions. At a given sampling site, sulfate sources were primarily dependent on geology and did not vary with time or flow condition. With increasing flow distance a gradual shift from ?34S values > 10 ‰ and ?18O values > 0 ‰ of riverine sulfate indicating evaporite dissolution and soil-derived sulfate in the predominantly forested headwaters, to negative ?34S and ?18O values suggested that sulfide oxidation was the predominant sulfate source in the agriculturally used downstream part of the watershed. Significant increases in sulfate concentrations and fluxes with downstream distance were observed, and were attributed to anthropogenically enhanced sulfide oxidation due to the presence of an extensive irrigation drainage network with seasonally varying water levels. Sulfate-S exports in an artificially drained subbasin (64 kg S/ha/yr) were found to exceed those in a naturally drained subbasin (4 kg S/ha/yr) by an order of magnitude. Our dataset suggests that the naturally occurring process of sulfide oxidation has been enhanced in the Oldman River Basin by the presence of an extensive network of drainage and irrigation canals.

Capital substitutability and weak sustainability revisited: The conditions for capital substitution in the presence of risk

The capital approach is frequently used to model sustainability. A development is deemed to be sustainable when capital is not reduced. There are different definitions of sustainability, based on whether or not they allow that different forms of capital may be substituted for each other. A development that allows for the substitution of different forms of capital is called weakly sustainable. This article shows that in a risky world and a risk-averse society even under the assumptions of weak sustainability the circumstances under which different forms of capital may be substituted are limited. This is due to the risk-reducing effect of diversification. Using Modern Portfolio Theory this article shows under which conditions substitution of different forms of capital increases risk for future generations.