Advances in Applying Computer-Aided Drug Design for Neurodegenerative Diseases

Neurodegenerative diseases (NDs) including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease are incurable and affect millions of people worldwide. The development of treatments for this unmet clinical need is a major global research challenge. Computer-aided drug design (CADD) methods minimize the huge number of ligands that could be screened in biological assays, reducing the cost, time, and effort required to develop new drugs. In this review, we provide an introduction to CADD and examine the progress in applying CADD and other molecular docking studies to NDs. We provide an updated overview of potential therapeutic targets for various NDs and discuss some of the advantages and disadvantages of these tools.     

Constraints on effectiveness of cyanogenic glycosides in herbivore defense

Cyanogenesis is the process by which hydrogen cyanide is released from endogenous cyanide containing compounds. Many cyanogenic plants release HCN in sufficient quantities to be toxic and, as a result, tend to be avoided by herbivores. However, there are many exceptions with some herbivores either immune to the cyanogenic status of the plant, or in some cases attracted to cyanogenic plants. This has led to a certain degree of scepticism regarding the role of cyanogenic glycosides as defense compounds. In this review, we examine evidence showing that differences in the effectiveness of cyanogenic glycosides in deterring herbivory can usually be reconciled when the morphology, physiology, and behavior of the animals, together with the concentration of cyanogenic glycosides in the host plant, are taken into account. Cyanogenic glycosides are not effective against all herbivores, and not all cyanogenic plants release enough cyanide to be considered toxic. Nevertheless, they do form part of the broad spectrum of toxic and distasteful compounds that herbivores must accommodate if they are to feed on cyanogenic plants.     

Identification of c-type heme-containing peptides using nonactivated immobilized metal affinity chromatography resin enrichment and higher-energy collisional dissociation

The c-type cytochromes play essential roles in many biological activities of both prokaryotic and eukaryotic cells, including electron transfer, enzyme catalysis, and induction of apoptosis. We report a novel enrichment strategy for identifying c-type heme-containing peptides that uses nonactivated IMAC resin. The strategy demonstrated at least 7-fold enrichment for heme-containing peptides digested from a cytochrome c protein standard, and quantitative linear performance was also assessed for heme-containing peptide enrichment. Heme-containing peptides extracted from the periplasmic fraction of Shewanella oneidensis MR-1 were further identified using higher-energy collisional dissociation tandem mass spectrometry. The results demonstrated the applicability of this enrichment strategy to identify c-type heme-containing peptides from a highly complex biological sample and, at the same time, confirmed the periplasmic localization of heme-containing proteins during suboxic respiration activities of S. oneidensis MR-1.     

Integrating natural language understanding with document structure analysis

Document understanding, the interpretation of a document from its image form, is a technology area which benefits greatly from the integration of natural language processing with image processing. We have developed a prototype of an Intelligent Document Understanding System (IDUS) which employs several technologies: image processing, optical character recognition, document structure analysis and text understanding in a cooperative fashion. This paper discusses those areas of research during development of IDUS where we have found the most benefit from the integration of natural language processing and image processing: document structure analysis, optical character recognition (OCR) correction, and text analysis. We also discuss two applications which are supported by IDUS: text retrieval and automatic generation of hypertext links     

Prostaglandin E2 stimulates ion transport in prairie dog gallbladder

The effects of progesterone and RU486, a synthetic anti-progesterone, on ovarian 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) activity, a key enzyme of progesterone production, were studied during ovulation in immature 22-day-old rats primed with pregnant mares' serum gonadotrophin (PMSG) and human chorionic gonadotrophin (hCG). Ovarian 3 beta-HSD activities had increased significantly 4 h after hCG injection. These increases were inhibited at 4 and 6 h after hCG when 20 mg RU486 kg-1 was administered 2 h before hCG. However, RU486 had no influence on the activity of 3 beta-HSD when administered at the same time as hCG injection. A histochemical study revealed that 3 beta-HSD activities in the granulosa cell layer, but not in the theca cell layer, were inhibited when RU486 was given 2 h before hCG. Serum progesterone concentrations, but not oestradiol concentrations, were significantly suppressed by RU486 treatment 4 and 6 h after hCG. The effect of progesterone on ovarian 3 beta-HSD activity was tested by administering graded doses of progesterone exogenously to rats 2 h before hCG injection. Ovarian 3 beta-HSD activity was increased in a dose-dependent manner, and more than 20 mg progesterone kg-1 significantly stimulated the activity. Although 10 mg progesterone kg-1 did not stimulate ovarian 3 beta-HSD activities, the RU486-inhibited activities were recovered by the concomitant administration of 10 mg progesterone kg-1 with RU486. These results indicate that ovarian 3 beta-HSD activity depends on progesterone concentrations, and suggest an autocrine regulation of progesterone production during ovulation in immature rat ovaries stimulated with PMSG and hCG.     

Changes in Nutritional Value of Cyanogenic <Emphasis Type="Italic">Trifolium repens</Emphasis> Grown at Elevated Atmospheric CO<Subscript>2</Subscript>

Global food security in a changing climate depends on both the nutritive value of staple crops as well as their yields. Here, we examined the direct effect of atmospheric carbon dioxide on the toxicity of the important pasture crop, Trifolium repens L. (clover). Shoots of T. repens contain cyanogenic glycosides that break down to release toxic hydrogen cyanide when damaged. The ability of animals to tolerate cyanogenic compounds is dependent, in part, on their overall protein intake. We grew T. repens communities at ambient and approximately twice-ambient CO₂ in a controlled environment greenhouse experiment. We found that the ratio of total cyanogenic glycosides to total protein ratio was nearly two times higher in leaves of T. repens grown at elevated CO₂. This study highlights the importance of assessing the nutritive value of this and other plants in response to rising CO₂ so that steps can be taken to address any adverse consequences for herbivores.     

Electrical Conductivity Breakthrough Curves

The factors affecting the applicability of electrical conductivity (EC) breakthrough curves as an indicator of chemical equilibrium between effluent and influent solutions in compatibility tests are illustrated. The shapes of EC breakthrough curves are shown to be a function of the flow rate, the solute retardation factor, the species of cation and anion in the permeant liquid, and the cation initially occupying the exchange complex of the clay. Measured data show that the magnitude of the EC in the soil due to the existence of soluble salts relative to the EC of the influent solution (permeant liquid) affects significantly the observed shapes of the EC breakthrough curves. Comparison between theoretically predicted and measured EC breakthrough curves varies from good to excellent, depending on the initial conditions for the test. The results indicate that chemical equilibrium can not be attained before complete EC breakthrough is attained, regardless of the shape of the EC breakthrough curve. Thus, EC breakthrough curves offer a potentially simple, practical, and inexpensive method for determining chemical equilibrium in laboratory compatibility tests involving permeation with electrolyte solutions.     

Reaction of Aliphatic Amines with 49% Formic Acid. 1-Hexylamine,di-1-hexylamine,N,N-dimethyl-1-hexylamine, 1-dodecylamine,N,N-dimethyl-1-dodecylamine and N,N-dimethyl-1-butylamine

Two primary amines, 1-hexylamine 2 , 1-dodecylamine 19 , one secondary amine, di-1-hexylamine 18 , and three tertiary amines, N,N-dimethyl-1-hexylamine 6 , N,N-dimethyl-1-butylamine 3 , and N,N-dimethyl-1-dodecylamine 22 were each heated at 150 °C, 250 °C or 350 °C with 49% aqueous formic acid for varying periods of time. The aliphatic primary amines underwent easy N-formylation and subsequent reduction to give N-methyl- and N,N-dimethylalkylamines. Especially at higher temperatures, other reactions intervened including elimination of NH₃ to the corresponding alkenes followed by partial double bond isomerization. Tertiary amines were more reactive at higher temperatures undergoing hydrolysis and reductive cleavages to secondary and primary amines, which subsequently followed the reaction sequences seen for primary amines. This series of saturated amines showed none of the cleavage into smaller fragments that was observed in the reductive alkylation of pyridine and 4-methylpyridine to a series of N-alkylpiperdines. This result reinforces the bis-aza-retro-Aldol-fragmentation mechanism postulated for the formation of the N-alkylpiperidines.