Properties of a dehydroalanine analog of glutathione: A reactive electrophilic busulfan metabolite

Gamma-Glutamyldehydroalanylglycine (EdAG) is a dethiolated, electrophilic metabolite of glutathione (GSH) derived from the Phase II conjugation of GSH with busulfan catalyzed by glutathione S-transferase (GST). It was demonstrated in this dissertation that EdAG could be successfully synthesized and shown to be a metabolite of busulfan from in vitro metabolism by enzymes in human liver cytosol. The electrophilic EdAG was reactive toward the cellular thiols cysteine and glutathione (GSH), and toward cysteine residues in reduced bovine insulin B-chain and bovine serum albumin in vitro , as well. EdAG was demonstrated to be a reversible noncompetitive inhibitor of GSTs, specifically GSTA1-1 at micromolar concentrations up to 1 mM. EdAG at high concentration (10 mM) was found to be an irreversible inhibitor of human GSTA1-1, although an EdAG-modified peptide was not observed. Inhibition of GST by a busulfan metabolite has the potential of altering busulfan pharmacokinetics or GSH cellular function. Since conversion of GSH to EdAG represents a loss of thiol-related redox properties and the gain of a captodative radical scavenging dehydroalanine group, the reactivity of EdAG with hydroxyl radical was evaluated. EdAG was shown to scavenge hydroxyl radical generated in the Fenton reaction in a concentration-dependent manner. The results indicate a stabilized carbon-based captodative radical intermediate in the reaction of EdAG with hydroxyl radical. In support of a captodative mechanism was the identification of a dimerized gamma-glutamylserylglycine as a product in the reaction. Conversion of GSH from a redox active nucleophile to an electrophilic dehydroalanine is a significant change in chemical reactivity that may have biological implications for GSH and free radical biochemistry as well as busulfan therapeutics

User data spectrum theory: Collecting, interpreting, and implementing user data in organizations

Organizations interested in increasing their user experience (UX) capacity lack the tools they need to know how to do so. This dissertation addresses this challenge via three major research efforts: 1) the creation of User Data Spectrum theory and a User Data Spectrum survey for helping organizations better invest resources to grow their UX capacity, 2) a new UX method and model for organizations that want to capitalize on spoken words from end users called Rapid Meaningful Scenarios (RMS), and 3) a recommendation for UX education in response to the current ACM SIGCHI education Living Curriculum initiative. The User Data Spectrum work is based on 30 interviews and 110 survey responses from UX stakeholders across 120 companies. These data informed the theory as well as a factor analysis performed to identify the most relevant items in the User Data Spectrum survey. The Rapid Meaningful Scenarios methodology was developed based on iterative UX experience with a real-world organization and refined to aid UX professionals in creating structured results based on end users\u27 words. The UX education recommendation integrates experience with the HCI curriculum at Iowa State University and curriculum discussions within the SIGCHI community over the past 5 years. The overall contribution of this research is a set of tools that will enable UX professionals and organizations to better strategize how to increase their UX capacity

Extraction of Transcript Diversity from Scientific Literature

Transcript diversity generated by alternative splicing and associated mechanisms contributes heavily to the functional complexity of biological systems. The numerous examples of the mechanisms and functional implications of these events are scattered throughout the scientific literature. Thus, it is crucial to have a tool that can automatically extract the relevant facts and collect them in a knowledge base that can aid the interpretation of data from high-throughput methods. We have developed and applied a composite text-mining method for extracting information on transcript diversity from the entire MEDLINE database in order to create a database of genes with alternative transcripts. It contains information on tissue specificity, number of isoforms, causative mechanisms, functional implications, and experimental methods used for detection. We have mined this resource to identify 959 instances of tissue-specific splicing. Our results in combination with those from EST-based methods suggest that alternative splicing is the preferred mechanism for generating transcript diversity in the nervous system. We provide new annotations for 1,860 genes with the potential for generating transcript diversity. We assign the MeSH term “alternative splicing” to 1,536 additional abstracts in the MEDLINE database and suggest new MeSH terms for other events. We have successfully extracted information about transcript diversity and semiautomatically generated a database, LSAT, that can provide a quantitative understanding of the mechanisms behind tissue-specific gene expression. LSAT (Literature Support for Alternative Transcripts) is publicly available at http://www.bork.embl.de/LSAT/

Do South African universities provide the required training platforms for otolaryngology specialist training?

Background. Concern exists about the quality of specialist training platforms at South African universities and teaching hospitals.Method. We conducted an audit of the quality of training at South African otolaryngology (ENT) training institutions from the perspective of the registrars.Results. Some institutions were deficient in terms of supervision, theatre time, access to teaching aids and research tools, and range of surgery, and do not provide the required training platforms for ENT specialist training. Five out of 8 institutions have produced <2 publications in peer-reviewed journals over the past 5 years.Conclusions. The HPCSA fails to adequately police the quality of training in South Africa. Training programme shortcomings must urgently be addressed to ensure proper education and training of otolaryngologists

Sex, grade-level and stream differences in learning environment and attitudes to science in Singapore primary schools

Learning environment research provides a well-established approach for describing and understanding what goes on in classrooms and has attracted considerable interest in Singapore. This article reports the first study of science classroom environments in Singapore primary schools. Ten scales from the What Is Happening In this Class?, Constructivist Learning Environment Survey and Test Of Science Related Attitudes were administered to 1,081 students in 55 classes. Factor and reliability analyses provided strong support for this widely-applicable questionnaire for assessing Involvement, Teacher Support, Investigation, Task Orientation, Cooperation, Personal Relevance, Uncertainty, Student Negotiation, Attitude to Inquiry and Enjoyment of Science Lessons among Singaporean primary-school students. Statistically significant findings of small magnitude emerged for sex differences, grade-level differences, stream differences, the stream–by–sex interaction and the grade–by–stream interaction