Metabolomics in drug target discovery.

Most diseases result in metabolic changes. In many cases, these changes play a causative role in disease progression. By identifying pathological metabolic changes, metabolomics can point to potential new sites for therapeutic intervention. Particularly promising enzymatic targets are those that carry increased flux in the disease state. Definitive assessment of flux requires the use of isotope tracers. Here we present techniques for finding new drug targets using metabolomics and isotope tracers. The utility of these methods is exemplified in the study of three different viral pathogens. For influenza A and herpes simplex virus, metabolomic analysis of infected versus mock-infected cells revealed dramatic concentration changes around the current antiviral target enzymes. Similar analysis of human-cytomegalovirus-infected cells, however, found the greatest changes in a region of metabolism unrelated to the current antiviral target. Instead, it pointed to the tricarboxylic acid (TCA) cycle and its efflux to feed fatty acid biosynthesis as a potential preferred target. Isotope tracer studies revealed that cytomegalovirus greatly increases flux through the key fatty acid metabolic enzyme acetyl-coenzyme A carboxylase. Inhibition of this enzyme blocks human cytomegalovirus replication. Examples where metabolomics has contributed to identification of anticancer drug targets are also discussed. Eventual proof of the value of metabolomics as a drug target discovery strategy will be successful clinical development of therapeutics hitting these new targets.

Computer generated track and field scoring tables: III. Model evaluation and analysis.

An investigation is made into the subject of scoring tables for track and field with emphasis on the application of computers to calculate and output the tables. The resulting scoring tables represent an attempt to describe the effective quality of performance for track and field events. This paper is published in three parts. The first part reviewed the historical development of scoring tables. The second part presented a theoretical foundation and the development of a model which could be utilized for all scoring tables. In this final part, the model is evaluated and an analysis of the model validity is made. Sample computer generated scoring tables are included.

Computer generated track and field scoring tables: II. Theoretical foundation and development of a model.

An investigation is made into the subject of scoring tables for track and field with emphasis on the application of computers to calculate and output the tables. The resulting scoring tables represent an attempt to describe the effective quality of performance for track and field events. This paper is published in three parts. The first portion reviewed the historical development of scoring tables. This part concerns the theoretical foundation and development of a mathematical model. A set of underlying principles and construction guidelines are established as a basis for all scoring tables. In order to satisfy the goals, a model which includes an exponential term is developed. The concept of a zero offset is introduced as a boundary value for the low-level performances. The final part concerns an evaluation of the model and an analysis of the point scores for different events.