Wild-Type U2AF1 Antagonizes the Splicing Program Characteristic of U2AF1-Mutant Tumors and Is Required for Cell Survival.

We have asked how the common S34F mutation in the splicing factor U2AF1 regulates alternative splicing in lung cancer, and why wild-type U2AF1 is retained in cancers with this mutation. A human lung epithelial cell line was genetically modified so that U2AF1S34F is expressed from one of the two endogenous U2AF1 loci. By altering levels of mutant or wild-type U2AF1 in this cell line and by analyzing published data on human lung adenocarcinomas, we show that S34F-associated changes in alternative splicing are proportional to the ratio of S34F:wild-type gene products and not to absolute levels of either the mutant or wild-type factor. Preferential recognition of specific 3' splice sites in S34F-expressing cells is largely explained by differential in vitro RNA-binding affinities of mutant versus wild-type U2AF1 for those same 3' splice sites. Finally, we show that lung adenocarcinoma cell lines bearing U2AF1 mutations do not require the mutant protein for growth in vitro or in vivo. In contrast, wild-type U2AF1 is required for survival, regardless of whether cells carry the U2AF1S34F allele. Our results provide mechanistic explanations of the magnitude of splicing changes observed in U2AF1-mutant cells and why tumors harboring U2AF1 mutations always retain an expressed copy of the wild-type allele.

Building disaster-resilient micro enterprises in the developing world.

Family-owned micro enterprises operating within the informal sector of most developing countries provide millions of citizens with a livelihood and are the economic backbone of many communities. Yet, the turbulence that emanates up or down respective supply chains following a disaster can cause these entities to fail. This study develops a model that recognises the relative weakness of micro enterprises to such disaster-related shocks. The model proposes that micro enterprises can moderate the effect of such shocks by creating resilience through cognitive preparation, continuous learning, and the generation of various forms of social capital (cognitive, relational, and structural). The propositions for the model are established through an extensive literature review, coupled with examples drawn from the documents of humanitarian agencies performing disaster relief work in India. This model also serves as a preliminary basis with which to derive metrics to set benchmarks or to assess the viability of a micro enterprise's ability to survive disaster-related shocks.

A dynamic model for costing disaster mitigation policies.

The optimal level of investment in mitigation strategies is usually difficult to ascertain in the context of disaster planning. This research develops a model to provide such direction by relying on cost of quality literature. This paper begins by introducing a static approach inspired by Joseph M. Juran's cost of quality management model (Juran, 1951) to demonstrate the non-linear trade-offs in disaster management expenditure. Next it presents a dynamic model that includes the impact of dynamic interactions of the changing level of risk, the cost of living, and the learning/investments that may alter over time. It illustrates that there is an optimal point that minimises the total cost of disaster management, and that this optimal point moves as governments learn from experience or as states get richer. It is hoped that the propositions contained herein will help policymakers to plan, evaluate, and justify voluntary disaster mitigation expenditures.