Systems and chemical biology approaches to study cell function and response to toxins

Toxicity is one of the main causes of failure during drug discovery, and of withdrawal once drugs reached the market. Prediction of potential toxicities in the early stage of drug development has thus become of great interest to reduce such costly failures. Since toxicity results from chemical perturbation of biological systems, we combined biological and chemical strategies to help understand and ultimately predict drug toxicities. First, we proposed a systematic strategy to predict and understand the mechanistic interpretation of drug toxicities based on chemical fragments. Fragments frequently found in chemicals with certain toxicities were defined as structural alerts for use in prediction. Some of the predictions were supported with mechanistic interpretation by integrating fragmentchemical, chemical-protein, protein-protein interactions and gene expression data. Next, we systematically deciphered the mechanisms of drug actions and toxicities by analyzing the associations of drugs’ chemical features, biological features and their gene expression profiles from the TG-GATEs database. We found that in vivo (rat liver) and in vitro (rat hepatocyte) gene expression patterns were poorly overlapped and gene expression responses in different species (rat and human) and different tissues (liver and kidney) varied widely. Eventually, for further understanding of individual differences in drug responses, we reviewed how genetic polymorphisms influence the individual's susceptibility to drug toxicity by deriving chemical-protein interactions and SNP variations from Mechismo database. Such a study is also essential for personalized medicine. Overall, this study showed that, integrating chemical and biological in addition to genetic data can help assess and predict drug toxicity at system and population levels

Entrepreneurship in a Transition Economy : Life Insurance in Meiji Japan

Along many dimensions, Meiji Japan represented a transition economy. It was transformed from a closed to an open, from a feudal to a capitalist and from an agricultural to an industrial economy. Entrepreneurship played a crucial role in the transformation. This paper analyzes the role of entrepreneurship in the establishment of Japan’s life insurance industry. Life insurance has received little attention in research on Japanese industrialization and entrepreneurship. Japan’s domestic life insurance industry had been successfully established by the end of the Meiji period, which constitutes an impressive achievement. This paper analyzes the profiles of 15 entrepreneurs who played key roles in the establishment of 11 life insurance companies between 1881 and 1912. Many of them share characteristics typical of early Japanese entrepreneurs in other industries in terms of family background and patriotic motivation. Their wide scope of activities and networks beyond the insurance industry helped them to cope with the institutional uncertainty characteristic of transition economies. Their high social standing and cross-sectional networks provided them with the credibility needed to found an insurance company, whose business success was heavily dependent on gaining the trust of potential policyholders