The Nf2 Tumor Suppressor, Merlin, Functions in Rac-Dependent Signaling

Mutations in the neurofibromatosis type II (NF2) tumor suppressor predispose humans and mice to tumor development. The study of Nf2+/- mice has demonstrated an additional effect of Nf2 loss on tumor metastasis. The NF2-encoded protein, merlin, belongs to the ERM (ezrin, radixin, and moesin) family of cytoskeleton:membrane linkers. However, the molecular basis for the tumor- and metastasis- suppressing activity of merlin is unknown. We have now placed merlin in a signaling pathway downstream of the small GTPase Rac. Expression of activated Rac induces phosphorylation and decreased association of merlin with the cytoskeleton. Furthermore, merlin overexpression inhibits Rac-induced signaling in a phosphorylation-dependent manner. Finally, Nf2-/- cells exhibit characteristics of cells expressing activated alleles of Rac. These studies provide insight into the normal cellular function of merlin and how Nf2 mutation contributes to tumor initiation and progression

Why the Derivation of Nutrient Reference Values Should be Harmonized and How It Can be Accomplished

The adoption of a panel of Nutrient Reference Values (NRVs) in place of a single recommended intake allowed for assessment of nutritional adequacy and safe upper intake levels for nutrients on a population level and for individuals. The Average Requirement (AR) and Tolerable Upper Intake Level (UL) comprise 2 core NRVs needed to obtain accurate, comparable estimates of population-level nutrient intakes, which are necessary to plan and evaluate nutrition support programs globally. Harmonizing the derivation of NRVs, particularly the AR and UL, is essential to ensure inclusion of all countries, whether high-, middle-, or low-income, in the process and to improve access for all users to the tools and data needed to carry it out. The NRV process today is more rigorous and transparent than the first derivation of DRIs because of adoption of systematic reviews and bias assessment methodologies, updated food and nutrient databases, data on cultural and context-specific dietary patterns, and better metabolic markers of nutritional status. A proposed framework for the derivation of NRVs builds on available methodologies to support the NRV process; however, this is not sufficient to achieve harmonization of the process. Fundamental to moving forward toward harmonization is removing existing barriers, including limited access to resources and databases and variance in terminology used to identify specific NRVs; adoption of more rigorous and transparent methodologies, including chronic disease endpoints, in the review process; and creating a central repository for easily accessible evidence. Chief among the barriers to harmonization is a willingness of global bodies to support an agreed-upon approach to the derivation process. Improving access to tools and data resources and providing guidance and support to encourage their adoption are critical to achieving harmonization of the NRV process. The factorial approach for calculating a nutrient requirement is described as the sum of total endogenous nutrient loss (endogenous fecal, urinary, integumental, seminal, menstrual) divided by its bioavailability or fractional absorption