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A series of tetrahydroisoquinoline derivatives were designed, synthesized, and evaluated for their potential as novel orally efficacious retinoic acid receptor-related orphan receptor-gamma t (RORγt) inverse agonists for the treatment of Th17-driven autoimmune diseases. We carried out cyclization of the phenylglycinamide core by structure-based drug design and successfully identified a tetrahydroisoquinoline carboxylic acid derivative 14 with good biochemical binding and cellular reporter activity. Interestingly, the combination of a carboxylic acid tether and a central fused bicyclic ring was crucial for optimizing PK properties, and the compound 14 showed significantly improved PK profile. Successive optimization of the carboxylate tether led to the discovery of compound 15 with increased inverse agonistic activity and an excellent PK profile. Oral treatment of mice with compound 15 robustly and dose-dependently inhibited IL-17A production in an IL23-induced gene expression assay.  相似文献   
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A review of East Asian frog flounders, genus Pleuronichthys (family Pleuronectidae), recognized Pleuronichthys japonicus sp. nov. and P. cornutus (Temminck and Schlegel 1846). Pleuronichthys japonicus sp. nov. is characterized by small, dark, rounded spots or marbled markings on the ocular side of the body, rounded cycloid scales somewhat irregularly arranged, usually 12 abdominal vertebrae, 67–80 (modally 75) dorsal-fin rays, 48–59 (modally 55) anal-fin rays, and a short branch of the supratemporal lateral line usually present on both sides. Pleuronichthys cornutus is characterized by densely distributed small, dark, irregular spots on the ocular side of the body, elongate cycloid scales somewhat regularly arranged, usually 13 abdominal vertebrae, 72–88 (modally 77) dorsal-fin rays, 52–65 (modally 58) anal-fin rays, and a branch of the supratemporal lateral line usually absent on both sides. Whereas P. cornutus is distributed from Miyagi Prefecture (Tohoku District) southward along the Pacific coast of Japan to the Bungo Channel, from Akita Prefecture (Tohoku District) southward along the Sea of Japan coast through the Tsushima Strait to the East China Sea, Yellow and Bohai Seas, the Taiwan Strait, and northern Chinese coast of the South China Sea, P. japonicus is distributed from southern Hokkaido southward along the Sea of Japan and Pacific coasts of Japan to the southern East China Sea. Geographic variations were found in caudal vertebrae and anal-fin ray counts, and caudal-peduncle depth in P. cornutus, and in ocular side body coloration, body depth, and head length in P. japonicus. Pleuronichthys lighti Wu 1929 was regarded as a junior synonym of P. cornutus.  相似文献   
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Candida albicans is one of the main species able to form a biofilm on almost any surface, causing both skin and superficial mucosal infections. The worldwide increase in antifungal resistance has led to a decrease in the efficacy of standard therapies, prolonging treatment time and increasing health care costs. Therefore, the aim of this work was to demonstrate the applicability of atmospheric plasma at room temperature for inactivating C. albicans growing in biofilms without thermally damaging heat-sensitive materials. This so-called cold atmospheric plasma is produced by applying high voltage to accelerate electrons, which ionize the surrounding air, leading to the production of charged particles, reactive species, and photons. A newly developed plasma device was used, which exhibits a large plasma-generating surface area of 9 by 13 cm (117 cm(2)). Different time points were selected to achieve an optimum inactivation efficacy range of ≥3 log(10) to 5 log(10) reduction in CFU per milliliter, and the results were compared with those of 70% ethanol. The results obtained show that contact-free antifungal inactivation of Candida biofilms by cold atmospheric plasma is a promising tool for disinfection of surfaces (and items) in both health care settings and the food industry, where ethanol disinfection should be avoided.  相似文献   
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Summary The proximate cholesterol precursors lathosterol, 7-dehydrocholesterol and desmosterol supported the growth of NS-1 and X63 mouse myeloma cells. These cells and X63.653 cells are cholesterol auxotrophs, yet each was able to convert [3H]lathosterol to [3H]cholesterol. These results are consistent with the conclusion that cholesterol auxotrophy in these myeloma cells is due to a deficiency in 3-ketosteroid reductase activity. The steroid hormones testosterone, progesserone and hydrocortisone could not replace cholesterol as a medium supplement. These results provide a greater understanding of the cholesterol auxotrophy characteristic of cell lines clonally-derived from the MOPC 21 myeloma tumor, and they provide a rational basis for the use of sterols in defined culture medium for mouse myeloma cells. This work was supported by National Institute of Health grants CA40294 and CA37589 to G. H. Sato and by a grant from RJR nabisco Inc. Editor's Statement These results help identify the defect in myeloma cells leading to cholesterol auxotrophy. The use of these cells in hybridoma derivation adds practical utility to a detailed appreciation of cholesterol metabolism in these cultures.  相似文献   
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Lack of tissue-specific differentiated functions of cells in tissue culture, once thought to be due to “dedifferentiation”, was shown to be due to selective overgrowth of fibroblasts by a series of simple experiments that challenged the prevailing dogma. Following this insight, enrichment culture techniques (alternate animal and culture passage) were designed to give functionally differentiated tumor cells selective advantage over the fibroblasts. These experiments resulted in the derivation of a large number of functionally differentiated clonal strains of a range of cell types, providing the final point of destruction of the dogma of “dedifferentiation.” Instead, the hypothesis was proposed that cells in culture accurately represent cells in vivo, but without the complex in vivo environment. With the development of hormonally defined media and its combination with functionally differentiated clonal cell lines, this concept has been strengthened and the potential of tissue culture studies has been greatly augmented. Hormonally defined media allow the culture of cell types that cannot be grown in conventional, serum-supplemented media. These approaches demonstrate that hormonal responses and dependencies can be discovered in culture. Following this thinking and the discovery of hormonal dependencies of cancer cells has led to a new rationale for therapy. Tissue culture and cell technology continue to play an important role in solving human health problems.  相似文献   
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