91 research outputs found

    Conformational Selectivity of ITK Inhibitors: Insights from Molecular Dynamics Simulations

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    Interleukin-2-inducible T-cell kinase (ITK) regulates the response to T-cell receptor signaling and is a drug target for inflammatory and immunological diseases. Molecules that bind preferentially to the active form of ITK have low selectivity between kinases, whereas those that bind preferentially to the inactive form have high selectivity for ITK. Therefore, computational methods to predict the conformational selectivity of compounds are required to design highly selective ITK inhibitors. In this study, we performed absolute binding free-energy perturbation (ABFEP) simulations for 11 compounds on both active and inactive forms of ITK, and the calculated binding free energies were compared with experimental data. The conformational selectivity of 10 of the 11 compounds was correctly predicted using ABFEP. To investigate the mechanism underlying the stabilization of the active and inactive structures by the compounds, we performed extensive, conventional molecular dynamics simulations, which revealed that the compound-induced stabilization of the P-loop and linkage of conformational changes in L489, V419, F501, and M410 upon compound binding were critical factors. A guideline for designing inactive-form binders is proposed based on these key structural factors. The ABFEP and the created guidelines are expected to facilitate the discovery of highly selective ITK inhibitors

    Conformational Selectivity of ITK Inhibitors: Insights from Molecular Dynamics Simulations

    No full text
    Interleukin-2-inducible T-cell kinase (ITK) regulates the response to T-cell receptor signaling and is a drug target for inflammatory and immunological diseases. Molecules that bind preferentially to the active form of ITK have low selectivity between kinases, whereas those that bind preferentially to the inactive form have high selectivity for ITK. Therefore, computational methods to predict the conformational selectivity of compounds are required to design highly selective ITK inhibitors. In this study, we performed absolute binding free-energy perturbation (ABFEP) simulations for 11 compounds on both active and inactive forms of ITK, and the calculated binding free energies were compared with experimental data. The conformational selectivity of 10 of the 11 compounds was correctly predicted using ABFEP. To investigate the mechanism underlying the stabilization of the active and inactive structures by the compounds, we performed extensive, conventional molecular dynamics simulations, which revealed that the compound-induced stabilization of the P-loop and linkage of conformational changes in L489, V419, F501, and M410 upon compound binding were critical factors. A guideline for designing inactive-form binders is proposed based on these key structural factors. The ABFEP and the created guidelines are expected to facilitate the discovery of highly selective ITK inhibitors

    A Transponder Aggregator with Efficient Use of Filtering Function for Transponder Noise Suppression

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    Colorless, directionless, and contentionless reconfigurable optical add/drop multiplexing (CDC-ROADM) provides highly flexible physical layer network configuration. Such CDC-ROADM must operate in multiple wavelength bands which are being increasingly implemented in optical transmission systems. The operation in C+L bands requires switch devices used in CDC-ROADM to also be capable of multiband operation. Recent studies on wavelength division multiplexing (WDM) systems have pointed out the impact of amplified spontaneous emission (ASE) noise generated by signals of different wavelengths, which causes OSNR degradation. Therefore, it is desirable to filter out the ASE noise from different transponders when multiplexing multiple wavelengths at the transmitter side, especially in a system with non-wavelength selective combiners such as directional couplers and multicast switches. The use of transponder aggregators with filtering functions, such as the M x N wavelength selective switch (WSS), is preferable for this filtering. However, the downside of these devices is that it is difficult to provide economical multiband support. Therefore, we propose an economical transponder aggregator configuration by allowing a certain amount of ASE superposition and reducing the number of filtering functions. In this paper, we fabricated a prototype of the proposed transponder aggregator by combining silica-based planar lightwave circuit technology and C+L band WSS, both commercially available, and verified its feasibility through transmission experiments. The novel transponder aggregator is a practical solution for a multiband CDC-ROADM system with improved OSNR performance.Comment: 10 pages, 11 figures. Submitted to IEEE Journal of Lightwave Technology for possible publicatio

    Slow contraction of flash aurora induced by an isolated chorus element ranging from lower-band to upper-band frequencies in the source region

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    Abstract Flash aurora driven by an isolated chorus element can be a useful ionospheric indicator for identifying the source wave properties via wave-particle interactions. Using ground observation and modeling approaches, here we report the temporal characteristics of flash aurora that depend on the chorus frequency width and the sweep rate. We found that the contraction time increases more than the expansion time in patchy auroral variations, due to the difference in the minimum electron energies resonated with the chorus wave packet away from the equatorial source to higher latitudes. Especially, the contraction time strongly depends on the higher-frequency chorus waves due to cyclotron resonance with lower-energy electrons. The model calculations support that the chorus element ranges from lower-band to upper-band frequencies with respect to half the gyrofrequency at the exact generation region. Our study provides the prompt (milliseconds) chorus-driven electron dynamics through the spatiotemporal characteristics of flash aurora in the ionosphere

    Predictors of NOAC versus VKA use for stroke prevention in patients with newly diagnosed atrial fibrillation: Results from GARFIELD-AF

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    Introduction A principal aim of the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) was to document changes in treatment practice for patients with newly diagnosed atrial fibrillation during an era when non-vitamin K antagonist oral anticoagulants (NOACs) were becoming more widely adopted. In these analyses, the key factors which determined the choice between NOACs and vitamin K antagonists (VKAs) are explored

    International trends in clinical characteristics and oral anticoagulation treatment for patients with atrial fibrillation: Results from the GARFIELD-AF, ORBIT-AF I, and ORBIT-AF II registries