Combined Experimental and Simulation Studies Suggest a Revised Mode of Action of the Anti‐Alzheimer Disease Drug NQ‐Trp

Inhibition of the aggregation of the monomeric peptide β‐amyloid (Aβ) into oligomers is a widely studied therapeutic approach in Alzheimer’s disease (AD). Many small molecules have been reported to work in this way, including 1,4‐naphthoquinon‐2‐yl‐L ‐tryptophan (NQ‐Trp). NQ‐Trp has been reported to inhibit aggregation, to rescue cells from Aβ toxicity, and showed complete phenotypic recovery in an in vivo AD model. In this work we investigated its molecular mechanism by using a combined approach of experimental and theoretical studies, and obtained converging results. NQ‐Trp is a relatively weak inhibitor and the fluorescence data obtained by employing the fluorophore widely used to monitor aggregation into fibrils can be misinterpreted due to the inner filter effect. Simulations and NMR experiments showed that NQ‐Trp has no specific “binding site“‐type interaction with mono‐ and dimeric Aβ, which could explain its low inhibitory efficiency. This suggests that the reported anti‐AD activity of NQ‐Trp‐type molecules in in vivo models has to involve another mechanism. This study has revealed the potential pitfalls in the development of aggregation inhibitors for amyloidogenic peptides, which are of general interest for all the molecules studied in the context of inhibiting the formation of toxic aggregates.     

On-line delta(18)O measurement of organic and inorganic substances

A method for the automated sample conversion and on-line oxygen isotope ratio (delta(18)O) determination for organic and inorganic substances is presented. The samples are pyrolytically decomposed at 1400 degrees C in the presence of nickelized graphite. With the system presented organic as well as inorganic samples such as nitrates, sulphates and phosphates of 50-100 &mgr;g O can be analyzed for their delta(18)O values with a standard deviation usually better than 0.5 per thousand. Additionally, carbon isotope ratios of organic substances and nitrogen isotope ratios of inorganic nitrogenous compounds are available in the same sample run. Data for international and some inter-laboratory reference materials are presented to show the accuracy and reliability of the method. The effect of some additives on the CO yield was checked for substances which do not pyrolyze completely. Copyright 1999 John Wiley & Sons, Ltd.     

Wave scattering effects in elastic percolation models

The study of the propagation of waves in randomly diluted models is presented. Porosity (crack-like) models are simulated by constructing typical elastic percolation networks with random microscopic heterogeneities in order to resemble rock media. Central and bond-bending forces (Born Hamiltonian) models are considered. For each experimental case, the elastic energy of the system is relaxed in equilibrium and then the model is excited by a pulse source in order to produce wave propagation. First, a review is presented of the well established velocity-porosity relationship from rock physics, which shows a linear trend from small porosities up to the critical porosity (percolation threshold) where the rocks fall apart. From the wave propagation analysis a general trend is observed for the attenuation of waves, from the small to the large porosity models, suggesting multiple scattering effects similar to those reported from effective-medium approximations of wave scattering due to random heterogeneities. Finally, the results are compared with those obtained from laboratory experiments on dry rocks with different porosities and different applied stress regimes.     

High-performance liquid chromatographic separation of caffeine, theophylline, theobromine and paraxanthine in rat brain and serum.

Caffeine and its metabolites theophylline, theobromine and paraxanthine have been determined in rat brain and serum samples by high-performance liquid chromatography with ultraviolet detection. The recovery, 85-103%, allowed quantification by external standard methods. The variability was found to be less than 3 and 7% for intra-day and inter-day assays, respectively. The detection limit, 1.57 ng of methylxanthines on column, allowed the determination of 62.5 ng/g or ml in biological material. Rats treated with 30 mg/kg caffeine (subcutaneously) were sacrificed at different times (1, 6, 12 and 24 h). Higher concentrations of methylxanthines (specially paraxanthine) were observed in the striatum than in the rest of the brain, and it was also observed that the clearance of methylxanthines was faster in serum than in brain structures.     

FEATURES OF BIOECONOMICS MODELS FOR THE OPTIMAL MANAGEMENT OF A FISHERY EXPLOITED BY TWO DIFFERENT FLEETS

ABSTRACT. After the extension of the Exclusive Economic Zone, in 1977, to 200 miles, most fish stocks came under jurisdiction of the adjacent coastal states. This development opened prospects of effective management of the open sea fisheries. Coastal states have the right to plan out the operation of so-called by Clarke and Munro “distant water fishing nations” from their Exclusive Economic Zone. Under some arrangements, a foreign fleet is allowed to harvest the resource in the Exclusive Economic Zone area. Clarke and Munro, in [1987] and [1991], focus on the issue of optimum terms and conditions of access and, in doing so, built a multiobjective model. The main goal of the present work is the development of a more general model including more variables and parameters related to the presence of a domestic fleet as well as a distant water fishing nation. The main difficulty resides in sharing the harvesting between the two fleets. The study responds to the realistic problemof coastal states who own enough resource stocks to allow harvesting by several kinds of fleets. Two optimal scenarios are developed, in each of them a solution is given.     

Purification of guanosine triphosphate cyclohydrolase I from Escherichia coli. The use of competitive inhibitors versus substrate as ligands in affinity chromatography

Different affinity chromatography ligands have been compared for the purification of guanosine triphosphate (GTP) cyclohydrolase I, an enzyme that catalyses the transformation of GTP into formate and dihydroneopterin triphosphate, the first metabolite in the biosynthetic pathway of the pterins. When this enzyme is purified by affinity chromatography on GTP-Sepharose a major fraction of the activity is lost and the yield of enzyme decreases as the amount of enzyme applied to the column decreases. The use of nucleotide competitive inhibitors (UTP and ATP) as ligands in the affinity column has shown that the extent of inactivation of the enzyme is related to the affinity of the enzyme for the ligand. Further, the extent of inactivation was reduced by reducing the length of the columns when using the same volume of GTP-Sepharose. Dihydrofolate-Sepharose gave consistently higher yields of GTP cyclohydrolase I regardless of the amount of enzyme applied, but several other proteins were also obtained. For a high purification of GTP cyclohydrolase I the best yield may be obtained with UTP as the affinity ligand and with the shortest length possible of the affinity column, and the purity of enzyme is comparable with that obtained with GTP-Sepharose.     

Erratum: On the numerical stability of two widely used PLS algorithms

The above article (DOI: 10.1002/cem.1112) was published online on 14 February 2008. An error was subsequently identified: the captions for Figures 1 and 2 were omitted; they should read as follows: Figure 1. Orthogonality criterion (θ_A) for the octane data as a function of number of components (A) calculated using the standard PLS algorithm and SIMPLS. Figure 2. Orthogonality criterion (θ_A) for the wines data as a function of number of components (A) calculated using the standard PLS algorithm and SIMPLS.     

Experimental, Theoretical and Biological Activity Study on the Acyl-Substituted Benzo-18-crown-6, Dibenzo-18-crown-6 and Dibenzo-24-crown-8

Hexadecanoyl, dihexadecanoyl, dioctadecaneoyl, di-10-undecenoyl, and dicis-9-octadecenoyl derivatives of benzo[18]crown-6, dibenzo[18]crown-6 and dibenzo[24]-8 were synthesized by the condensation of carboxylic acids (palmitic, stearic, oleic and undecenoic acid) with benzo and dibenzo crown ethers in the presence of zinc chloride. The extraction equilibrium constants of such macrocyclic ethers with long side chains were estimated using chloroform/water and dichloromethane/water membranes transfer of Na-PAR (4-(2-pyridylazo)-resorcinol mono sodium monohydrate) with UV–Vis spectroscopy. It was found that they were in the range of 10.88–11.71 in dichloromethane and 8.04–11.77 in chloroform. These results actually show that the Na+ binding effect of macrocyclic ethers depends on the type and the length of side chains. The geometrical properties of the molecules were studied employing semi-empirical calculations by simulated annealing technique. The frontier molecular orbital energies and dipole moments were also examined. The biological activity results showed that the synthesized crown ethers have no activity against the studied microorganisms.     

Alkali Metal- and Ammonium Picrate Extraction and Complex Forming Capabilities of d-Glucose and d-Mannose-based Lariat Ethers

The alkali metal- and ammonium picrate extracting ability of d-glucose- and d-mannose-based 15-crown-5 ethers and related lariat ethers was investigated in dichloromethane – water system. A heteroatom was waried in the crown ether containing a 4,6-O-benzylidene-α-d-glucopyranoside unit 6, (X=O), 2 (X=S) and 8a (X=NH). Extracting ability of the latter species (8a) was excellent (97–99%) in regard of all cations (Li⁺, Na⁺, K⁺, Rb⁺, Cs⁺ and NH₄⁺) examined, it was not, howewer, selective. Introduction of a side arm on the nitrogen atom of 8a decreased the extracting ability, but increased the selectivity. In this series of compounds (8b–f, 4), 4 with a pyridylethyl substituent allowed the extraction of sodium picrate in 72%. The glucose-based macrocycles 8a, 8e and 8f formed a stronger complex with the cations examined than the mannose-based analogues 9a, 9e and 9f, that can be explained by the all-gauche conformation of the former ones. It was pointed out that in the case of crowns with tertiary amine moieties, the basicity increases the quantity of the picrates extracted. According to complex forming measurements by FAB-MS, the best sodium ion selectivity was achieved by the γ-hydroxypropyl substituted lariat ether (8e). Possible structures of the complexes formed by the two types of monosacharides with sodium cation were evaluated by molecule modelling calculations.