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排序方式: 共有84条查询结果,搜索用时 15 毫秒
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Xue Zhi Zhao Evgeny Kiselev George T. Lountos Wenjie Wang Joseph E. Tropea Danielle Needle Thomas A. Hilimire John S. Schneekloth Jr David S. Waugh Yves Pommier Terrence R. Burke Jr 《Chemical science》2021,12(11):3876
Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a member of the phospholipase D family of enzymes, which catalyzes the removal of both 3′- and 5′-DNA phosphodiester adducts. Importantly, it is capable of reducing the anticancer effects of type I topoisomerase (TOP1) inhibitors by repairing the stalled covalent complexes of TOP1 with DNA. It achieves this by promoting the hydrolysis of the phosphodiester bond between the Y723 residue of human TOP1 and the 3′-phosphate of its DNA substrate. Blocking TDP1 function is an attractive means of enhancing the efficacy of TOP1 inhibitors and overcoming drug resistance. Previously, we reported the use of an X-ray crystallographic screen of more than 600 fragments to identify small molecule variations on phthalic acid and hydroxyquinoline motifs that bind within the TDP1 catalytic pocket. Yet, the majority of these compounds showed limited (millimolar) TDP1 inhibitory potencies. We now report examining a 21 000-member library of drug-like Small Molecules in Microarray (SMM) format for their ability to bind Alexa Fluor 647 (AF647)-labeled TDP1. The screen identified structurally similar N,2-diphenylimidazo[1,2-a]pyrazin-3-amines as TDP1 binders and catalytic inhibitors. We then explored the core heterocycle skeleton using one-pot Groebke–Blackburn–Bienayme multicomponent reactions and arrived at analogs having higher inhibitory potencies. Solving TDP1 co-crystal structures of a subset of compounds showed their binding at the TDP1 catalytic site, while mimicking substrate interactions. Although our original fragment screen differed significantly from the current microarray protocol, both methods identified ligand–protein interactions containing highly similar elements. Importantly inhibitors identified through the SMM approach show competitive inhibition against TDP1 and access the catalytic phosphate-binding pocket, while simultaneously providing extensions into both the substrate DNA and peptide-binding channels. As such, they represent a platform for further elaboration of trivalent ligands, that could serve as a new genre of potent TDP1 inhibitors.Using small molecule microarray TDP1 inhibitors have been identified that bind in a trivalent mode. 相似文献
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Kuramitsu Y Sakawa Y Morita T Gregory CD Waugh JN Dono S Aoki H Tanji H Koenig M Woolsey N Takabe H 《Physical review letters》2011,106(17):175002
We investigated the time evolution of a strong collisionless shock in counterstreaming plasmas produced using a high-power laser pulse. The counterstreaming plasmas were generated by irradiating a CH double-plane target with the laser. In self-emission streaked optical pyrometry data, steepening of the self-emission profile as the two-plasma interaction evolved indicated shock formation. The shock thickness was less than the mean free path of the counterstreaming ions. Two-dimensional snapshots of the self-emission and shadowgrams also showed very thin shock structures. The Mach numbers estimated from the flow velocity and the brightness temperatures are very high. 相似文献
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Bhachu DS Waugh MR Zeissler K Branford WR Parkin IP 《Chemistry (Weinheim an der Bergstrasse, Germany)》2011,17(41):11613-11621
The use of an aerosol delivery system enabled fluorine-doped tin dioxide films to be formed from monobutyltin trichloride methanolic solutions at 350-550 °C with enhanced functional properties compared with commercial standards. It was noted that small aerosol droplets (0.3 μm) gave films with better figures of merit than larger aerosol droplets (45 μm) or use of a similar precursor set using atmospheric pressure chemical vapour deposition (CVD) conditions. Control over the surface texturing and physical properties of the thin films were investigated by variation in the deposition temperature and dopant concentration. Optimum deposition conditions for low-emissivity coatings were found to be at a substrate temperature of about 450 °C with a dopant concentration of 1.6 atm% (30 mol% F:Sn in solution), which resulted in films with a low visible light haze value (1.74%), a high charge-carrier mobility (25 cm(2) V s(-1)) and a high charge-carrier density (5.7×10(20) cm(-3)) resulting in a high transmittance across the visible (≈80%), a high reflectance in the IR (80% at 2500 nm) and plasma-edge onset at 1400 nm. Optimum deposition conditions for coatings with applications as top electrodes in thin film photovoltaics were found to be a substrate temperature of about 500 °C with a dopant concentration of 2.2 atm% (30 mol% F:Sn in solution), which resulted in films with a low sheet resistance (3 Ω sq(-1)), high charge-carrier density (6.4×10(20) cm(-3)), a plasma edge onset of 1440 nm and the films also showed pyramidal surface texturing on the micrometer scale which corresponded to a high visible light haze value (8%) for light scattering and trapping within thin film photovoltaic devices. 相似文献
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Jane Yang Nicole Maronian Victoria Reyes Pat Waugh Teresa Brentnall Allen Hillel MD 《Journal of voice》2002,16(2):278-282
Laryngeal and other otolaryngologic manifestations of Crohn's disease are uncommon and may be subtle. Crohn's disease is a well-known inflammatory bowel disease of unknown etiology marked by relapsing and remitting granulomatous inflammation of the alimentary tract. Extraintestinal manifestations of Crohn's disease may appear anytime during the course of the disease process and may be the initial symptom. Findings are nonspecific, primarily edema and ulcerations, and may be confused with a multitude of other disease processes. Awareness of these manifestations in the head and neck will prevent misdiagnosis or a delay in diagnosis. 相似文献
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The spin temperature hypothesis is extended to a system of nuclear spins with internal magnetic dipolar interactions and subject to periodic external perturbation in the form of intense radiofrequency pulses. Preliminary results are described for the case of phase-alternated irradiation at resonance. 相似文献
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A new approach to variable selection in least squares problems 总被引:9,自引:0,他引:9
The title Lasso has been suggested by Tibshirani (1996) as acolourful name for a technique of variable selection which requiresthe minimization of a sum of squares subject to an l1 bound on the solution. This forces zero components in the minimizingsolution for small values of . Thus this bound can functionas a selection parameter. This paper makes two contributionsto computational problems associated with implementing the Lasso:(1) a compact descent method for solving the constrained problemfor a particular value of is formulated, and (2) a homotopymethod, in which the constraint bound becomes the homotopyparameter, is developed to completely describe the possibleselection regimes. Both algorithms have a finite terminationproperty. It is suggested that modified Gram-Schmidt orthogonalizationapplied to an augmented design matrix provides an effectivebasis for implementing the algorithms. 相似文献