As a member of the bromodomain and extra terminal domain (BET) protein family, bromodomain-containing protein 4 (BRD4) is an epigenetic reader and can recognize acetylated lysine residues in histones. BRD4 has been re...
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As a member of the bromodomain and extra terminal domain (BET) protein family, bromodomain-containing protein 4 (BRD4) is an epigenetic reader and can recognize acetylated lysine residues in histones. BRD4 has been regarded as an essential drug target for cancers, inflammatory diseases and acute heart failure, and therefore the discovery of potent BRD4 inhibitors with novel scaffolds is highly desirable. In this study, the crystalline water molecules in BRD4 involved in ligand binding were analyzed first, and the simulation results suggest that several conserved crystalline water molecules are quite essential to keep the stability of the crystalline water network and therefore they need to be reserved in structure-based drug design. Then, a docking-based virtual screening workflow with the consideration of the conserved crystalline water network in the binding pocket was utilized to identify the potential inhibitors of BRD4. The in vitro fluorescence resonance energy transfer (HTRF) binding assay illustrates that 4 hits have good inhibitory activity against BRD4 in the micromolar regime, including three compounds with IC50 values below 5 mu M and one below 1 mu M (0.37 mu M). The structural analysis demonstrates that three active compounds possess novel scaffolds. Moreover, the interaction patterns between the hits and BRD4 were characterized by molecular dynamics simulations and binding free energy calculations, and then several suggestions for the further optimization of these hits were proposed.
In recent years, considerable attention has been paid in time-frequency analysis (TFA) methods, which is an effective technology in processing the vibration signal of rotating machinery. However, TFA techniques are no...
In recent years, considerable attention has been paid in time-frequency analysis (TFA) methods, which is an effective technology in processing the vibration signal of rotating machinery. However, TFA techniques are not sufficient to handle signals having a strong non-stationary characteristic. To overcome this drawback, taking short-time Fourier transform as a link, a TFA methods that using the generalized Warblet transform (GWT) in combination with the second order synchroextracting transform (SSET) is proposed in this study. Firstly, based on the GWT and SSET theories, this paper proposes a method combining the two TFA methods to improve the TFA concentration, named GWT-SSET. Secondly, the method is verified numerically with single-component and multi-component signals, respectively. Quantized indicators, Renyi entropy and mean relative error (MRE) are used to analyze the concentration of TFA and accuracy of instantly frequency (IF) estimation, respectively. Finally, the proposed method is applied to analyze nonstationary signals in variable speed. The numerical and experimental results illustrate the effectiveness of the GWT-SSET method.
Metabolic interactions between different cell types in the tumor microenvironment (TME) often result in reprogramming of the metabolism to be totally different from their normal physiological processes in order to sup...
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Metabolic interactions between different cell types in the tumor microenvironment (TME) often result in reprogramming of the metabolism to be totally different from their normal physiological processes in order to support tumor growth. Many studies have attempted to inhibit tumor growth and activate tumor immunity by regulating the metabolism of tumors and other cells in TME. However, metabolic inhibitors often suffer from the heterogeneity of tumors, since the favorable metabolic regulation of malignant cells and other cells in TME is often inconsistent with each other. Therefore, we reported the design of a pH-sensitive drug delivery system that targets different cells in TME successively. Outer membrane vesicles (OMVs) derived from Gram-negative bacteria were applied to coload paclitaxel (PTX) and regulated in development and DNA damage response 1 (Redd1)-siRNA and regulate tumor metabolism microenvironment and suppress tumor growth. Our siRNA@M-/PTX-CA-OMVs could first release PTX triggered by the tumor pH (pH 6.8). Then the rest of it would be taken in by M2 macrophages to increase their level of glycolysis. Great potential was observed in TAM repolarization, tumor suppression, tumor immune activation, and TME remolding in the triple-negative breast cancer model. The application of the OMV provided an insight for establishing a codelivery platform for chemical drugs and genetic medicines.
The Cu(OAc)(2)-catalyzed three-component reactions of o-aminophenols, acyl chlorides and 1,2-dichloroethane (DCE) have been established for the efficient synthesis of 3,4-dihydro-2H-benzo[b][1,4] oxazines (3,4-dihydro...
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The Cu(OAc)(2)-catalyzed three-component reactions of o-aminophenols, acyl chlorides and 1,2-dichloroethane (DCE) have been established for the efficient synthesis of 3,4-dihydro-2H-benzo[b][1,4] oxazines (3,4-dihydro-1,4-benzoxazines). This method features advantages of the one-pot operation enabling N-acylation, C-Cl bond amidation and etherification, as well as the structural divergence of the synthesized products. (C) 2018 Elsevier Ltd. All rights reserved.
Composite carbon-based nano-zero-valent iron materials not only have excellent characteristics of nano materials, but also solve the difficulty of recycling nano materials after use, and overcome the shortcomings of t...
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Composite carbon-based nano-zero-valent iron materials not only have excellent characteristics of nano materials, but also solve the difficulty of recycling nano materials after use, and overcome the shortcomings of the nano materials. The introduction of copper increases the redox reaction activity of the micro-electrolytic material and expands the applicable pH range of the reaction environment. In the range of pH = 3-9, the removal efficiency of dichloromethanesulfonic acid (Cl-2-MSA) was maintained at 95.5-99.7% after 30 min. Continuous dynamic simulation experiments verified that the composite carbon-based nano zero-valent iron material has a stable removal effect on the target pollutants.
The present invention provides a concentrated winding axial cooling motor stator and a motor. The above concentrated winding axial cooling motor stator includes barriers and an axial oil feeding device, the barriers a...
标准号:
EP4044404(A4)
The present invention provides a concentrated winding axial cooling motor stator and a motor. The above concentrated winding axial cooling motor stator includes barriers and an axial oil feeding device, the barriers are in contact with stator windings and plug notches of a stator core, and the barrier and coils of two adjacent groups of the stator windings in slots of the stator core constitute a cooling medium communication cavity;the axial oil feeding device is arranged at any end part of the stator cores or is connected with a casing, and a location of the axial oil feeding device corresponds to any end of the stator cores;a side of the axial oil feeding device close to the stator windings is provided with a spray hole, an axis of the spray hole and an axis of the stator winding are intersected obliquely, a cooling medium is sprayed to the barrier and/or the stator winding and thus flows along an axial inner surface of the stator winding towards two ends of the stator winding. The present invention has the beneficial effect that the axial oil feeding device is arranged at a leading-out terminal or a non-leading-out terminal of a motor stator, thereby improving a heat exchange contact area between the cooling medium and the winding, and increasing heat dissipation capability.
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