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排序方式: 共有350条查询结果,搜索用时 31 毫秒
61.
Maier JA Brugel TA Clark MP Sabat M Golebiowski A Bookland RG Laufersweiler MJ Laughlin SK Vanrens JC De B Hsieh LC Brown KK Juergens K Walter RL Janusz MJ 《Bioorganic & medicinal chemistry letters》2006,16(13):3514-3518
A new class of tumor necrosis factor alpha (TNF-alpha) synthesis inhibitors based on a N-2,4-pyrimidine-N-phenyl-N'-alkyl urea scaffold is described. Many of these compounds showed low-nanomolar activity against lipopolysaccharide stimulated TNF-alpha production. Two analogs were tested in an in vivo rat iodoacetate model of osteoarthritis and shown to be orally efficacious. X-ray co-crystallization studies with mutated p38alpha showed that these trisubstituted ureas interact with the ATP-binding pocket in a pseudo-bicyclic conformation brought about by the presence of an intramolecular hydrogen bonding interaction. 相似文献
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Maier JA Brugel TA Sabat M Golebiowski A Laufersweiler MJ VanRens JC Hopkins CR De B Hsieh LC Brown KK Easwaran V Janusz MJ 《Bioorganic & medicinal chemistry letters》2006,16(14):3646-3650
A new class of lymphocyte specific tyrosine kinase (lck) inhibitors based on an N-4,6-pyrimidine-N-alkyl-N'-phenyl urea scaffold is described. Many of these compounds showed low-nanomolar inhibition of lck kinase activity as well as IL-2 synthesis from Jurkat cells. One of these analogs, 7i, was shown to be orally efficacious by in vivo testing in a rat adjuvant-induced arthritis study. 相似文献
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Meghan Larin David Gallo Laura Tamblyn Jay Yang Hudson Liao Nestor Sabat Grant W. Brown J. Peter McPherson 《Nucleic acids research》2014,42(15):9807-9820
Individuals with Fanconi anemia (FA) are susceptible to bone marrow failure, congenital abnormalities, cancer predisposition and exhibit defective DNA crosslink repair. The relationship of this repair defect to disease traits remains unclear, given that crosslink sensitivity is recapitulated in FA mouse models without most of the other disease-related features. Mice deficient in Mus81 are also defective in crosslink repair, yet MUS81 mutations have not been linked to FA. Using mice deficient in both Mus81 and the FA pathway protein FancC, we show both proteins cooperate in parallel pathways, as concomitant loss of FancC and Mus81 triggered cell-type-specific proliferation arrest, apoptosis and DNA damage accumulation in utero. Mice deficient in both FancC and Mus81 that survived to birth exhibited growth defects and an increased incidence of congenital abnormalities. This cooperativity of FancC and Mus81 in developmental outcome was also mirrored in response to crosslink damage and chromosomal integrity. Thus, our findings reveal that both pathways safeguard against DNA damage from exceeding a critical threshold that triggers proliferation arrest and apoptosis, leading to compromised in utero development. 相似文献
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Andreas Grahnert Tina Richter Daniel Piehler Maria Eschke Bianca Schulze Uwe Müller Martina Protschka Gabriele K?hler Robert Sabat Frank Brombacher Gottfried Alber 《PloS one》2014,9(1)
Cryptococcus neoformans is an opportunistic fungal pathogen that causes lung inflammation and meningoencephalitis in immunocompromised people. Previously we showed that mice succumb to intranasal infection by induction of pulmonary interleukin (IL)-4Rα–dependent type 2 immune responses, whereas IL-12-dependent type 1 responses confer resistance. In the experiments presented here, IL-4Rα−/− mice unexpectedly show decreased fungal control early upon infection with C. neoformans, whereas wild-type mice are able to control fungal growth accompanied by enhanced macrophage and dendritic cell recruitment to the site of infection. Lower pulmonary recruitment of macrophages and dendritic cells in IL-4Rα−/− mice is associated with reduced pulmonary expression of CCL2 and CCL20 chemokines. Moreover, IFN-γ and nitric oxide production are diminished in IL-4Rα−/− mice compared to wild-type mice. To directly study the potential mechanism(s) responsible for reduced production of IFN-γ, conventional dendritic cells were stimulated with C. neoformans in the presence of IL-4 which results in increased IL-12 production and reduced IL-10 production. Together, a beneficial role of early IL-4Rα signaling is demonstrated in pulmonary cryptococcosis, which contrasts with the well-known IL-4Rα-mediated detrimental effects in the late phase. 相似文献
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In lizards, one of the most important behavioral mechanisms to cope with spatial and temporal variations in thermal resources observed is activity time. The longer a lizard can maintain activity, the more time it has to forage and reach larger adult body size. We studied the behavioral adjustments to different climatic regimens on daily and seasonal scales in three natural populations of the lizard Microlophus atacamensis along a latitudinal temperature and rainfall gradient. We also used Niche Mapper to determinate the amount of thermally suitable time for activity for this species. Abundance and daily activity patterns varied greatly over the year for the three populations. In summer and spring, the daily activity times were greater, and were reduced in fall and winter seasons. In summer, when stressful heat loads should prohibit activity over a midday gap, lizards did not show bimodal patterns of activity. Instead, they move to the cooler intertidal habitat. Abundance and thermal quality in the southernmost coolest site was lower, and the potential annual activity time decreases with latitude. Contrary to expectations, lizards from this locality showed the largest body sizes possibly due to diet and/or time to sexual maturation. Our results indicate that the intertidal habitat is a key factor that influences daily and seasonal activity of M. atacamensis lizards. While this habitat is not climatically optimal for lizards, it allows them to behaviorally extend their activity window and gain access to food in the intertidal areas. 相似文献
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Biodegradation of a crude oil by three microbial consortia of different origins and metabolic capabilities 总被引:6,自引:0,他引:6
Viñas M Grifoll M Sabaté J Solanas AM 《Journal of industrial microbiology & biotechnology》2002,28(5):252-260
Microbial consortia were obtained three by sequential enrichment using different oil products. Consortium F1AA was obtained
on a heavily saturated fraction of a degraded crude oil; consortium TD, by enrichment on diesel and consortium AM, on a mixture
of five polycyclic aromatic hydrocarbons [PAHs]. The three consortia were incubated with a crude oil in order to elucidate
their metabolic capabilities and to investigate possible differences in the biodegradation of these complex hydrocarbon mixtures
in relation to their origin. The efficiency of the three consortia in removing the saturated fraction was 60% (F1AA), 48%
(TD) and 34% (AM), depending on the carbon sources used in the enrichment procedures. Consortia F1AA and TD removed 100% of
n-alkanes and branched alkanes, whereas with consortium AM, 91% of branched alkanes remained. Efficiency on the polyaromatic
fraction was 19% (AM), 11% (TD) and 7% (F1AA). The increase in aromaticity of the polyaromatic fraction during degradation
of the crude oil by consortium F1AA suggested that this consortium metabolized the aromatic compounds primarily by oxidation
of the alkylic chains. The 500-fold amplification of the inocula from the consortia by subculturing in rich media, necessary
for use of the consortia in bioremediation experiments, showed no significant decrease in their degradation capability. Journal of Industrial Microbiology & Biotechnology (2002) 28, 252–260 DOI: 10.1038/sj/jim/7000236
Received 12 July 2001/ Accepted in revised form 11 November 2001 相似文献