A threshold model for receptor tyrosine kinase signaling specificity and cell fate determination [version 1; referees: 4 approved]

Upon ligand engagement, the single-pass transmembrane receptor tyrosine kinases (RTKs) dimerize to transmit qualitatively and quantitatively different intracellular signals that alter the transcriptional landscape and thereby determine the cellular response. The molecular mechanisms underlying these fundamental events are not well understood. Considering recent insights into the structural biology of fibroblast growth factor signaling, we propose a threshold model for RTK signaling specificity in which quantitative differences in the strength/longevity of ligand-induced receptor dimers on the cell surface lead to quantitative differences in the phosphorylation of activation loop (A-loop) tyrosines as well as qualitative differences in the phosphorylation of tyrosines mediating substrate recruitment. In this model, quantitative differences on A-loop tyrosine phosphorylation result in gradations in kinase activation, leading to the generation of intracellular signals of varying amplitude/duration. In contrast, qualitative differences in the pattern of tyrosine phosphorylation on the receptor result in the recruitment/activation of distinct substrates/intracellular pathways. Commensurate with both the dynamics of the intracellular signal and the types of intracellular pathways activated, unique transcriptional signatures are established. Our model provides a framework for engineering clinically useful ligands that can tune receptor dimerization stability so as to bias the cellular transcriptome to achieve a desired cellular output

Superior radiation-resistant nanoengineered austenitic 304L stainless steel for applications in extreme radiation environments

Nuclear energy provides more than 10% of electrical power internationally, and the increasing engagement of nuclear energy is essential to meet the rapid worldwide increase in energy demand. A paramount challenge in the development of advanced nuclear reactors is the discovery of advanced structural materials that can endure extreme environments, such as severe neutron irradiation damage at high temperatures. It has been known for decades that high dose radiation can introduce significant void swelling accompanied by precipitation in austenitic stainless steel (SS). Here we report, however, that through nanoengineering, ultra-fine grained (UFG) 304L SS with an average grain size of ~100 nm, can withstand Fe ion irradiation at 500°C to 80 displacements-per-atom (dpa) with moderate grain coarsening. Compared to coarse grained (CG) counterparts, swelling resistance of UFG SS is improved by nearly an order of magnitude and swelling rate is reduced by a factor of 5. M(23)C(6) precipitates, abundant in irradiated CG SS, are largely absent in UFG SS. This study provides a nanoengineering approach to design and discover radiation tolerant metallic materials for applications in extreme radiation environments

Higher temperature reactor materials workshop sponsored by the Department of Energy Office of Nuclear Energy, Science, and Technology (NE) and the Office of Basic Energy Sciences (BES).

On March 18-21, 2002, the Department of Energy, Office of Nuclear Energy, Science, and Technology (NE) and the Office of Basic Energy Sciences (BES) sponsored a workshop to identify needs and opportunities for materials research aimed at performance improvements of structural materials in higher temperature reactors. The workshop focused discussion around the reactor concepts proposed as part of the Generation IV Nuclear Energy System Roadmap. The goal of the Generation IV initiative is to make revolutionary improvements in nuclear energy system design in the areas of sustainability, economics, safety and reliability. The Generation IV Nuclear Energy Systems Roadmap working groups have identified operation at higher temperature as an important step in improving economic performance and providing a means for nuclear energy to support thermochemical production of hydrogen. However, the move to higher operating temperatures will require the development and qualification of advanced materials to perform in the more challenging environment. As part of the process of developing advanced materials for these reactor concepts, a fundamental understanding of materials behavior must be established and the data-base defining critical performance limitations of these materials under irradiation must be developed. This workshop reviewed potential reactor designs and operating regimes, potential materials for application in high-temperature reactor environments, anticipated degradation mechanisms, and research necessary to understand and develop reactor materials capable of satisfactory performance while subject to irradiation damage at high temperature. The workshop brought together experts from the reactor materials and fundamental materials science communities to identify research and development needs and opportunities to provide optimum high temperature nuclear energy system structural materials