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- Orellana, Laura, et al.
(författare)
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Oncogenic mutations at the EGFR ectodomain structurally converge to remove a steric hindrance on a kinase-coupled cryptic epitope
- 2019
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : NATL ACAD SCIENCES. - 0027-8424 .- 1091-6490. ; 116:20, s. 10009-10018
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Tidskriftsartikel (refereegranskat)abstract
- Epidermal growth factor receptor (EGFR) signaling is initiated by a large ligand-favored conformational change of the extracellular domain (ECD) from a closed, self-inhibited tethered monomer, to an open untethered state, which exposes a loop required for strong dimerization and activation. In glioblastomas (GBMs), structurally heterogeneous missense and deletion mutations concentrate at the ECD for unclear reasons. We explore the conformational impact of GBM missense mutations, combining elastic network models (ENMs) with multiple molecular dynamics (MD) trajectories. Our simulations reveal that the main missense class, located at the I-II interface away from the self-inhibitory tether, can unexpectedly favor spontaneous untethering to a compact intermediate state, here validated by small-angle X-ray scattering (SAXS). Significantly, such intermediate is characterized by the rotation of a large ECD fragment (N-TR1), deleted in the most common GBM mutation, EGFRvIII, and that makes accessible a cryptic epitope characteristic of cancer cells. This observation suggested potential structural equivalence of missense and deletion ECD changes in GBMs. Corroborating this hypothesis, our FACS, in vitro, and in vivo data demonstrate that entirely different ECD variants all converge to remove N-TR1 steric hindrance from the 806-epitope, which we show is allosterically coupled to an intermediate kinase and hallmarks increased oncogenicity. Finally, the detected extraintracellular coupling allows for synergistic cotargeting of the intermediate with mAb806 and inhibitors, which is proved herein.
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- Timmons, D., et al.
(författare)
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Cost minimization for fully renewable electricity systems : A Mauritius case study
- 2019
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Ingår i: Energy Policy. - : Elsevier Ltd. - 0301-4215 .- 1873-6777. ; 133
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Tidskriftsartikel (refereegranskat)abstract
- Climate change is the world's most prominent environmental problem, and fossil-fuel combustion is its primary cause. To set carbon reduction goals, policy makers require information on feasibility and cost of renewable energy systems. In this study, we describe an economic approach to modeling a national electricity system based entirely on renewable sources, using the island-nation of Mauritius as a case study. Many renewable electricity studies consider levelized costs of electricity (LCOE), which represents average cost of electricity, but cost minimization requires equalizing marginal costs. With variable sources, marginal costs change over time. Minimizing cost thus requires a model incorporating variability at high time resolution (daily or hourly), with the objective of minimizing the levelized cost of electricity for an entire electricity system (LCOES). In Mauritius, the minimum-cost renewable electricity portfolio includes roughly equal proportions of solar, wind, and biomass electricity, along with electricity storage. Policy issues include setting renewable energy targets, selecting policy instruments to incentivize optimum renewable energy portfolios, incorporating energy efficiency, determining appropriate discount rates, ensuring land availability, and accounting for non-cost considerations. Many of the economic and policy issues identified apply universally, and methods demonstrated in this study could be used anywhere in the world.
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