Hierarchical Modeling of Activation Mechanisms in the ABL and EGFR Kinase Domains: Thermodynamic and Mechanistic Catalysts of Kinase Activation by Cancer Mutations

Structural and functional studies of the ABL and EGFR kinase domains have recently suggested a common mechanism of activation by cancer-causing mutations. However, dynamics and mechanistic aspects of kinase activation by cancer mutations that stimulate conformational transitions and thermodynamic stabilization of the constitutively active kinase form remain elusive. We present a large-scale computational investigation of activation mechanisms in the ABL and EGFR kinase domains by a panel of clinically important cancer mutants ABL-T315I, ABL-L387M, EGFR-T790M, and EGFR-L858R. We have also simulated the activating effect of the gatekeeper mutation on conformational dynamics and allosteric interactions in functional states of the ABL-SH2-SH3 regulatory complexes. A comprehensive analysis was conducted using a hierarchy of computational approaches that included homology modeling, molecular dynamics simulations, protein stability analysis, targeted molecular dynamics, and molecular docking. Collectively, the results of this study have revealed thermodynamic and mechanistic catalysts of kinase activation by major cancer-causing mutations in the ABL and EGFR kinase domains. By using multiple crystallographic states of ABL and EGFR, computer simulations have allowed one to map dynamics of conformational fluctuations and transitions in the normal (wild-type) and oncogenic kinase forms. A proposed multi-stage mechanistic model of activation involves a series of cooperative transitions between different conformational states, including assembly of the hydrophobic spine, the formation of the Src-like intermediate structure, and a cooperative breakage and formation of characteristic salt bridges, which signify transition to the active kinase form. We suggest that molecular mechanisms of activation by cancer mutations could mimic the activation process of the normal kinase, yet exploiting conserved structural catalysts to accelerate a conformational transition and the enhanced stabilization of the active kinase form. The results of this study reconcile current experimental data with insights from theoretical approaches, pointing to general mechanistic aspects of activating transitions in protein kinases

Renewable, ethical? Assessing the energy justice potential of renewable electricity

Energy justice is increasingly being used as a framework to conceptualize the impacts of energy decision making in more holistic ways and to consider the social implications in terms of existing ethical values. Similarly, renewable energy technologies are increasingly being promoted for their environmental and social benefits. However, little work has been done to systematically examine the extent to which, in what ways and in what contexts, renewable energy technologies can contribute to achieving energy justice. This paper assesses the potential of renewable electricity technologies to address energy justice in various global contexts via a systematic review of existing studies analyzed in terms of the principles and dimensions of energy justice. Based on publications including peer reviewed academic literature, books, and in some cases reports by government or international organizations, we assess renewable electricity technologies in both grid integrated and off-grid use contexts. We conduct our investigation through the rubric of the affirmative and prohibitive principles of energy justice and in terms of its temporal, geographic, socio-political, economic, and technological dimensions. Renewable electricity technology development has and continue to have different impacts in different social contexts, and by considering the different impacts explicitly across global contexts, including differences between rural and urban contexts, this paper contributes to identifying and understanding how, in what ways, and in what particular conditions and circumstances renewable electricity technologies may correspond with or work to promote energy justice

Phenolic Compounds in Wheat Kernels: Genetic and Genomic Studies of Biosynthesis and Regulations

Whole wheat grains are an important source of bioactive components, particularly of phenolic acids and flavonoids. Due to the health-promoting effects of these phenolics, nowadays, the increase of their content in mature kernels is of great interest and a potential target for wheat breeding programs. The biogenesis of phenolics occurs through the general phenylpropanoid pathway, which is ubiquitous in plant cell walls and leads to the synthesis of secondary metabolites that are involved in plant defence and structural support. This chapter reviews the current knowledge in phenylpropanoid chemistry, and the genetic and molecular basis for the biosynthesis of phenolic acids and anthocyanins in wheat grains. Also, advances in assessing genetic variation in the content and composition of these components in wheat germplasm are reviewed, including the effects of different environmental conditions on their accumulation in mature kernels. The recent, ongoing genomic studies are reviewed providing updates on quantitative trait loci and genes involved in the synthesis and accumulation of phenolics in wheat kernels. Finally, the promise and limitations of breeding programs to potentially develop wheat cultivars rich in phenolic components are discussed

A New Boson with a Mass of 125 GeV Observed with the CMS Experiment at the Large Hadron Collider

The Higgs boson was postulated nearly five decades ago within the framework of the standard model of particle physics and has been the subject of numerous searches at accelerators around the world. Its discovery would verify the existence of a complex scalar field thought to give mass to three of the carriers of the electroweak force-the W+, W-, and Z 0 bosons-as well as to the fundamental quarks and leptons. The CMS Collaboration has observed, with a statistical significance of five standard deviations, a new particle produced in proton-proton collisions at the Large Hadron Collider at CERN. The evidence is strongest in the diphoton and four-lepton (electrons and/or muons) final states, which provide the best mass resolution in the CMS detector. The probability of the observed signal being due to a random fluctuation of the background is about 1 in 3 x 106. The new particle is a boson with spin not equal to 1 and has a mass of about 1.25 giga-electron volts. Although its measured properties are, within the uncertainties of the present data, consistent with those expected of the Higgs boson, more data are needed to elucidate the precise nature of the new particle