Synthesis, characterization, and metal coordinating ability of multifunctional carbohydrate-containing compounds for Alzheimer's therapy

Dysfunctional interactions of metal ions, especially Cu, Zn, and Fe, with the amyloid-beta (A beta) peptide are hypothesized to play an important role in the etiology of Alzheimer's disease (AD). In addition to direct effects on A beta aggregation, both Cu and Fe catalyze the generation of reactive oxygen species (ROS) in the brain further contributing to neurodegeneration. Disruption of these aberrant metal-peptide interactions via chelation therapy holds considerable promise as a therapeutic strategy to combat this presently incurable disease. To this end, we developed two multifunctional carbohydrate-containing compounds N,N'-bis[(5-beta-D-glucopyranosyloxy-2-hydroxy)benzyl]-N,N'-dimethyl-ethane-1,2-diamine (H2GL1) and N,N'-bis[(5-beta-D-glucopyranosyloxy-3-tert-butyl-2-hydroxy)benzyl]-N,N'-dimethyl-ethane-1,2-diamine (H2GL2) for brain-directed metal chelation and redistribution. Acidity constants were determined by potentiometry aided by UV-vis and 1H NMR measurements to identify the protonation sites of H2GL1,2. Intramolecular H bonding between the amine nitrogen atoms and the H atoms of the hydroxyl groups was determined to have an important stabilizing effect in solution for the H2GL1 and H2GL2 species. Both H2GL1 and H2GL2 were found to have significant antioxidant capacity on the basis of an in vitro antioxidant assay. The neutral metal complexes CuGL1, NiGL1, CuGL2, and NiGL2 were synthesized and fully characterized. A square-planar arrangement of the tetradentate ligand around CuGL2 and NiGL2 was determined by X-ray crystallography with the sugar moieties remaining pendant. The coordination properties of H2GL1,2 were also investigated by potentiometry, and as expected, both ligands displayed a higher affinity for Cu2+ over Zn2+ with H2GL1 displaying better coordinating ability at physiological pH. Both H2GL1 and H2GL2 were found to reduce Zn2+- and Cu2+- induced Abeta1-40 aggregation in vitro, further demonstrating the potential of these multifunctional agents as AD therapeutics.     

Stable carbon ((12/13)C) and nitrogen ((14/15)N) isotopes as a tool for identifying the sources of cyanide in wastes and contaminated soils--a method development

The occurrence of iron-cyanide complexes in the environment is of concern, since they are potentially hazardous. In order to determine the source of iron-cyanide complexes in contaminated soils and wastes, we developed a method based on the stable isotope ratios ¹³C/¹²C and ¹⁵N/¹⁴N of the complexed cyanide-ion (CN⁻). The method was tested on three pure chemicals and two industrials wastes: blast-furnace sludge (BFS) and gas-purifier waste (GPW). The iron-cyanide complexes were converted into the solid cupric ferrocyanide, Cu₂[Fe(CN)₆]·7H₂O, followed by combustion and determination of the isotope-ratios by continuous flow isotope ratio mass spectrometry. Cupric ferrocyanide was obtained from the materials by (i) an alkaline extraction with 1 M NaOH and (ii) a distillate digestion. The [Fe(CN)₆]⁴⁻ of the alkaline extraction was precipitated after adding Cu²⁺. The CN⁻ of the distillate digestion was at first complexed with Fe²⁺ under inert conditions and then precipitated after adding Cu²⁺. The δ¹³C-values obtained by the two methods differed slightly up to 1-3‰ for standards and BFS. The difference was larger for alkaline-extracted GPW (4-7‰), since non-cyanide C was co-extracted and co-precipitated. Therefore the distillate digestion technique is recommended when determining the C isotope ratios in samples rich in organic carbon. Since the δ¹³C-values of BFS are in the range of −30 to −24‰ and of −17 to −5‰ for GPW, carbon seems to be a suitable tracer for identifying the source of cyanide in both wastes. However, the δ¹⁵N-values overlapped for BFS and GPW, making nitrogen unsuitable as a tracer.     

Investigation of analytical variation in metabonomic analysis using liquid chromatography/mass spectrometry

Sources of analytical variation in high-performance liquid chromatography/mass spectrometry (HPLC/MS), such as changes in retention, mass accuracy or signal intensity, have been investigated to assess their importance as a variable in the metabonomic analysis of human urine. In this study chromatographic retention and mass accuracy were found to be quite reproducible with the most significant source of analytical variation in the data sets obtained being the result of changes in detector response. Depending on the signal intensity threshold used to define the presence of a peak a sample component could be present in some replicate injections and absent in others within the same run. The implementation of a more sophisticated data software analysis package was found to greatly reduce the impact of detector response variability resulting in improved data analysis.     

Explanation for the apparent absence of collapse of polyelectrolyte brushes in the presence of bulky ions

The conformational behavior of poly[2-(methacryloyloxy)ethyltrimethylammonium chloride] (PMETAC) brushes with different chain density in the presence of large benzyltributylammonium chloride (BTBAC) ions has been studied by a Quartz Crystal Microbalance with Dissipation (QCM-D) and Scanning Force Microscopy. Dense brushes do not collapse in the presence of BTBAC solutions of increasing ionic strength, contrary to what is observed in the presence of NaCl. Brush collapse can be observed for low-ionic-strength solutions of BTBAC when the brush density has been reduced. These phenomena can be explained by considering the Hofmeister series as well as ion size and free space in the brush.     

Enantioselective synthesis of P-stereogenic benzophospholanes via palladium-catalyzed intramolecular cyclization

Enantioselective or diastereoselective intramolecular cyclization of functionalized secondary phosphines or their borane adducts catalyzed by chiral Pd(diphosphine) complexes gave P-stereogenic benzophospholanes in up to 70% ee. These results provide a new method for the synthesis of chiral phospholanes, which are valuable ligands in asymmetric catalysis. [reaction: see text]     

Enhancement of temporal periodicity cues in cochlear implants: effects on prosodic perception and vowel identification

Standard continuous interleaved sampling processing, and a modified processing strategy designed to enhance temporal cues to voice pitch, were compared on tests of intonation perception, and vowel perception, both in implant users and in acoustic simulations. In standard processing, 400 Hz low-pass envelopes modulated either pulse trains (implant users) or noise carriers (simulations). In the modified strategy, slow-rate envelope modulations, which convey dynamic spectral variation crucial for speech understanding, were extracted by low-pass filtering (32 Hz). In addition, during voiced speech, higher-rate temporal modulation in each channel was provided by 100% amplitude-modulation by a sawtooth-like wave form whose periodicity followed the fundamental frequency (F0) of the input. Channel levels were determined by the product of the lower- and higher-rate modulation components. Both in acoustic simulations and in implant users, the ability to use intonation information to identify sentences as question or statement was significantly better with modified processing. However, while there was no difference in vowel recognition in the acoustic simulation, implant users performed worse with modified processing both in vowel recognition and in formant frequency discrimination. It appears that, while enhancing pitch perception, modified processing harmed the transmission of spectral information.     

Structure elucidation of a novel family of mycolactone toxins from the frog pathogen Mycobacterium sp. MU128FXT by mass spectrometry

Structures are proposed, based on LC-ion trap MSn analysis and high-resolution FTICR MS/MS analysis, for a novel family of mycolactone toxins isolated from the frog pathogen MU128FXT and differing from those produced by the human pathogen M. ulcerans MUAgy99 in having an altered polyketide side chain.     

Synthetic Wisdom: The Design of a Mixed-Mode Modelling System for Organizational Decision Making

This paper discusses some of the early thinking about the development of a conference-based decision support system. It presents a scheme for the practical development of the mapping of argumentation (‘cognitive mapping’), particularly in the field of strategic planning. The objective is to redesign software (COPE) so that it may become both an effective conferencing system for the collection of ‘synthetic wisdom’ and yet also facilitate the analysis of the qualitative and quantitative features of the models so constructed. It stresses the need for the system to be able to cope with both the political and the behavioural aspects of the decision-making arena.