ул. Победы, д. 34., каб. 809
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Лось Алексей Борисович
Single-point mutations in the transmembrane (TM) region of receptor tyrosine kinases (RTKs) can lead to abnormal ligand-independent activation. We use a combination of computational modeling, NMR spectroscopy and cell experiments to analyze in detail the mechanism of how TM domains contribute to the activation of wild-type (WT) PDGFRA and its oncogenic V536E mutant. Using a computational framework, we scan all positions in PDGFRA TM helix for identification of potential functional mutations for the WT and the mutant and reveal the relationship between the receptor activity and TM dimerization via different interfaces. This strategy also allows us design a novel activating mutation in the WT (I537D) and a compensatory mutation in the V536E background eliminating its constitutive activity (S541G). We show both computationally and experimentally that single-point mutations in the TM region reshape the TM dimer ensemble and delineate the structural and dynamic determinants of spontaneous activation of PDGFRA via its TM domain. Our atomistic picture of the coupling between TM dimerization and PDGFRA activation corroborates the data obtained for other RTKs and provides a foundation for developing novel modulators of the pathological activity of PDGFRA.
The article investigates one‐dimensional (1D) suspension‐colloidal transport of size distributed particles with particle attachment. A population balance approach is presented for computing the particle transport and capture by porous media. The occupied area of each attached particle is particle‐size dependent. The main model assumption is the retention‐rate dependency of the overall vacancy concentration for all particle sizes. For the first time, we derive an exact averaging (upscaling) procedure resulting in a closed system of large‐scale equations for average concentrations of suspended and retained particles, and of occupied rock surface area. The resulting large‐scale 3x3 system significantly differs from the traditional 2x2 deep bed filtration model. However, the traditional model becomes a particular case that corresponds to an equal occupied area for all particles. The averaging yields the appearance of two empirical suspension and site‐occupation functions, which govern the kinetics of particle retention and site occupation, respectively. 1D flow problems for the averaged equations are essentially non‐linear. However, they allow for exact solutions. We derive novel exact solutions for three 1D problems: continuous injection of particulate colloidal suspension, injection of colloidal suspension bank with particle‐free chase drive, and fines migration induced by high‐rate flows. The analytical model for continuous injection closely matches three series of laboratory tests on nano‐fluid transport.