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Thin Film Thermoelectric Metal–Organic Framework with High Seebeck Coefficient and Low Thermal Conductivity 下载免费PDF全文
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Dr. Hui Qiu Richard Caldwell Dr. Lesley Liu-Bujalski Dr. Andreas Goutopoulos Reinaldo Jones Justin Potnick Dr. Brian Sherer Dr. Andrew Bender Dr. Roland Grenningloh Dr. Daigen Xu Dr. Anna Gardberg Dr. Igor Mochalkin Dr. Theresa Johnson Dr. Ariele Viacava Follis Jared Head Dr. Federica Morandi 《ChemMedChem》2019,14(2):217-223
Bruton's tyrosine kinase (Btk) is an attractive target for the treatment of a wide array of B-cell malignancies and autoimmune diseases. Small-molecule covalent irreversible Btk inhibitors targeting Cys481 have been developed for the treatment of such diseases. In clinical trials, probe molecules are required in occupancy studies to measure the level of engagement of the protein by these covalent irreversible inhibitors. The result of this pharmacodynamic (PD) activity provides guidance for appropriate dosage selection to optimize inhibition of the drug target and correlation of target inhibition with disease treatment efficacy. This information is crucial for successful evaluation of drug candidates in clinical trials. Based on the pyridine carboxamide scaffold of a novel solvent-accessible pocket (SAP) series of covalent irreversible Btk inhibitors, we successfully developed a potent and selective affinity-based biotinylated probe 12 (2-[(4-{4-[5-(1-{5-[(3aS,4S,6aR)-2-oxo-hexahydro-1H-thieno[3,4-d]imidazol-4-yl]pentanamido}-3,6,9,12-tetraoxapentadecan-15-amido)pentanoyl]piperazine-1-carbonyl}phenyl)amino]-6-[1-(prop-2-enoyl)piperidin-4-yl]pyridine-3-carboxamide). Compound 12 has been used in Btk occupancy assays for preclinical studies to determine the therapeutic efficacy of Btk inhibition in two mouse lupus models driven by TLR7 activation and type I interferon. 相似文献
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MA Nowak AL Lloyd GM Vasquez TA Wiltrout LM Wahl N Bischofberger J Williams A Kinter AS Fauci VM Hirsch JD Lifson 《Canadian Metallurgical Quarterly》1997,71(10):7518-7525
Mathematical modeling of viral replication dynamics, based on sequential measurements of levels of virion-associated RNA in plasma during antiretroviral treatment, has led to fundamental new insights into human immunodeficiency virus type 1 pathogenesis. We took advantage of the simian immunodeficiency virus (SIV)-infected macaque model to perform detailed measurements and mathematical modeling during primary infection and during treatment of established infection with the antiretroviral drug (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA). The calculated clearance half-life for productively infected cells during resolution of the peak viremia of primary infection was on the order of 1 day, with slightly shorter clearance half-lives calculated during PMPA treatment. Viral reproduction rates upon discontinuation of PMPA treatment after 2 weeks were approximately twofold greater than those obtained just prior to initiation of treatment in the same animals, likely reflecting accumulation of susceptible target cells during treatment. The basic reproductive ratio (R0) for the spread of SIV infection in vivo, which represents the number of productively infected cells derived from each productively infected cell at the beginning of infection, was also estimated. This parameter quantifies the extent to which antiviral therapy or vaccination must limit the initial spread of virus to prevent establishment of chronic disseminated infection. The results thus provide an important guide for efforts to develop vaccines against SIV and, by extension, human immunodeficiency virus. 相似文献
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S Ziebe B Bech K Petersen AL Mikkelsen A Gabrielsen AN Andersen 《Canadian Metallurgical Quarterly》1998,13(1):178-181
A new oxidative pathway for the degradation of caffeine(1,3,7-Trimethylxanthine, I) by a mixed culture consisting of strains belonging to the genera Klebsiella and Rhodococcus is presented. The mixed culture does not initiate degradation by N-demethylation either complete or partial, but instead carries out oxidation at the C-8 position resulting in the formation of 1,3,7-trimethyluric acid (TMU, II) which further gets degraded to 3,6,8-trimethylallantoin (TMA, III). Both TMU and TMA are hitherto not shown to be formed in the microbial system. Further degradation of TMA (III) by caffeine grown cells yields dimethylurea (VII) as one of the metabolites. Oxygen uptake studies indicated that caffeine(I) grown cells oxidized TMU(II), TMA (III), glyoxalic acid (VI), dimethylurea(VII), and monomethylurea(V), but not monomethyl and dimethyluric acids. The mixed culture does not accept theophylline(1,3-dimethylxanthine), theobromine(3,7-dimethylxanthine), and paraxanthine(1,7-dimethylxanthine) as the carbon source. 相似文献
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BF Habbick JL Nanson RE Snyder RE Casey AL Schulman 《Canadian Metallurgical Quarterly》1996,87(3):204-207
Ethers and thioethers of monosaccharides have been synthesised which show potent toxicity to mouse (LD50 > or = 4 g.kg-1 O.W. and 0.2 to 1.5 g.kg-1 I.P.W.). A study of calcium antagonist activity for the full series of compounds indicated that the activity was similar for both O- and S- ethers and maximum activities were observed for monoacetoneglucose ethers possessing carbon chain close to 8 carbons. 相似文献
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Reactive oxygen species may participate in development of neurological toxicity resulting from hyperbaric oxygen exposure. To explore the possibility that increased reactive O2 metabolite generation may result in oxidative modification of lipids and proteins, rats were exposed to five atmospheres (gauge pressure) of O2 until development of an electroencephalographic seizure. Lipid peroxidation (as thiobarbituric acid-reactive substances) and protein oxidation (as 2,4-dinitrophenyl-hydrazones) were measured in five brain regions. Oxidized and reduced glutathione were also determined because of their role in regulating lipid peroxidation. Lipid peroxidation was confined to the frontal cortex and hippocampus, while protein oxidation (in both cytoplasmic and membranous fractions) and increased oxidized glutathione was evident throughout the brain. These results support a role for formation of reactive O2 metabolites from hyperbaric O2 exposure and suggest that protein oxidation, especially in soluble proteins, may be one of the most sensitive measures. 相似文献
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