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Immobilized enzymes as on-line probes in biochemistry and new drug discovery : biosynthesis of catecholamines
No full textThe use of immobilized enzymes has steadily increased in recent years. Based upon the advantages that immobilized enzymes possess over soluble enzymes, numerous applications have emerged in medical and analytical fields. This work demonstrates the applicability of a liquid chromatographic system based upon coupled on-line immobilized enzyme reactors (IMERs) to organic synthesis, biochemistry and pharmacology. It is envisioned that the model system will grow into a modular process where synthetic chemists can add or subtract the enzymes necessary for their particular synthetic goal. The system allows for on-line chromatographic purification and structural identification of products and could greatly reduce time required to discover new synthetic pathways. In addition, the construction of a coupled enzyme system provides a number of approaches to basic research into synthetic and metabolic pathways as well as a rapid method for the discovery of new pharmaceutical substances.A coupled system using extremely different enzymes with incompatible cofactors and reaction conditions has been constructed. The significance of the proposed project not only lies in the development of the liquid chromatographic on-line enzyme cascade but also in the biosynthetic pathway chosen for this study. The biosynthetic pathway involving dopamine beta-hydroxylase and phenylethanolamine N-methyltransferase encompass the synthesis of the key transmitters, norepinephrine and epinephrine. The results demonstrate for the first time the immobilization of dopamine beta-hydroxylase and phenylethanolamine N-methyltransferase. The IMERs are active and can be used in a liquid chromatographic format for qualitative and quantitative determinations. Studies with the IMER-HPLC systems have also shown that the activity of the immobilized enzymes reflects the non-immobilized enzymes. Thus, the IMER-HPLC system can be used to carry out standard Michaelis-Menten enzyme kinetic studies and to quantitatively determine enzyme kinetic constants, identify specific enzyme inhibitors, provide information regarding the mode of inhibition and the inhibitor constants (Ki). The immobilized enzyme reactors used independently or as a combination will provide a unique opportunity to explore the interrelationships between these enzymes, to investigate the source of catecholamine-related disorders and to design new drug entities for identified clinical syndromes
Prediction and description of enantioselective separations on amylose based HPLC chiral stationary phases
No full textAmylose based chromatographic chiral stationary phases (CSPs) are widely used throughout liquid chromatography to separate enantiomers, although little is known about the interaction processes operating on these phases.This thesis describes a systematic study into the retention and enantioselective separation capabilities of the tris (3,5-dimethylphenylcarbmate), tris (R-phenylethylcarbamate) and tris (S-phenylethylcarbamate) stationary phases.The underlying aim of this work was to obtain an understanding of the solute-stationary phase interactions which are responsible for the chromatographic retention and separation of enantiomers. By development of quantitative structure-enantioselective retention relationships (QSERR), it was possible to identify the primary components involved in the molecular interaction process and describe those interactions in terms of non-empirical solute descriptors.Results for several different series of racemic compounds indicate that multiple mechanisms are possible and that retention may be described by combinations of several key classes of interaction including hydrogen bonding, electrostatic, lipophilic, charge transfer and steric interactions. Progressive development of these properties from classical point interactions to molecular interactions, supports a proposed theory of chiral recognition which extends from the basic three-point model to a more complex dynamic molecular model. This new model, derived to explain obtained experimental results, addresses issues in chirality which are not adequately covered by previous theory. It is proposed that the original theory is a static model which does not authentically reflect real systems and as such, cannot account for all experimentally observed molecular interactions of an enantiospecific nature. A modified and improved theory of chiral recognition has been fashioned, which includes the vital aspects of conformational adjustment and molecular fit.Finally, the first reported application of artificial neural networks in chiral chromatography is documented. Multi-layer feed forward neural networks, with error back propagation, have been used in combination with QSERR as a basis to development of chiral chromatographic expert systems. Resulting networks contained cross validated predictive ability ranging from 94 to 97%
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Are basal D-serine plasma levels a predictive biomarker for the rapid antidepressant effects of ketamineand ketamine metabolites?
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