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1.
Thin Film Thermoelectric Metal–Organic Framework with High Seebeck Coefficient and Low Thermal Conductivity
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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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OA al-Swayeh MS al-Humayyd AA Mustafa AS al-Tuwaijri RS al-Rashed AT Ali 《Canadian Metallurgical Quarterly》1997,12(7):481-489
Recent evidence suggests that oxygen-derived free radicals are involved in mediating gastric microvascular and parenchymal cell injuries induced by ischaemia and reperfusion. Therefore, the effect of the locally acting anti-ulcer drug, sucralfate, was studied on ischaemia and reperfusion (e.g. induced gastric lesions, intraluminal bleeding, changes in vascular permeability and non-protein sulfhydryl levels in the rat stomach). Allopurinol was used as a known standard antioxidant drug. Rats were subjected to 30 min of gastric ischaemia in the presence of 100 mmol/L hydrochloric acid and reperfusion periods of 15, 30 or 60 min duration. The gastric lesions were assessed microscopically under an inverted microscope. The vascular permeability was quantified by measuring the extravasated Evans blue in the stomach. There were significantly greater numbers of gastric lesions, intraluminal bleeding and leakage of Evans blue during all reperfusion periods as compared with those of ischaemia, with maximum effects occurring at 60 min following reperfusion. Pretreatment with sucralfate (31.25-250 mg/kg, p.o.) or allopurinol (12.5-50 mg/kg, i.p.) 30 min before the procedure, dose-dependently reduced the gastric lesions, intraluminal bleeding, and decreased the vascular permeability induced by ischaemia and reperfusion. Furthermore, sucralfate dose-dependently reverses the ischaemia and reperfusion-induced depletion of mucosal non-protein sulfhydryl levels and inhibited the superoxide radical production in both cell-free xanthine-xanthine oxidase and in the stimulated polymorphonuclear cellular systems. These results suggest that the protection produced by sucralfate against gastric injury may be due to its antioxidant effects. 相似文献
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Pigmented vulvar lesions were observed in a child during a sexual abuse evaluation. Gross examination of the lesions appeared most consistent with bowenoid papulosis; however, biopsy confirmed the lesions to be pigmented apocrine hamartomas. To our knowledge, these rare and benign tumors have never been described as pigmented, but should be added to the differential diagnosis of pigmented vulvar lesions. 相似文献
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SA Khotimchenko VM Kodentsova IA Alekseeva SG Vlaskina OA Vrzhesinskaia AA Sokol''nikov LA Kharitonchik IP Aleshko-Ozhevskií LV Sheviakova 《Canadian Metallurgical Quarterly》1997,43(3):158-164
Gamma delta T-Cells represent a minor subpopulation of T-lymphocytes in man and their role in normal and diseased human skin is unknown. This article is a comprehensive review of T-lymphocytes bearing the gamma delta T-cell receptor in normal and pathological human skin. Firstly, we have documented the occurrence of gamma delta T-cells in normal skin and in a range of reactive and malignant skin conditions. We have then discussed the experimental findings regarding the repertoire used by gamma delta T-cells in normal human skin and in cutaneous disorders with an increased percentage of gamma delta T-cells. 相似文献