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排序方式: 共有266条查询结果,搜索用时 140 毫秒
111.
Le Brazidec JY Pasis A Tam B Boykin C Wang D Marcotte DJ Claassen G Chong JH Chao J Fan J Nguyen K Silvian L Ling L Zhang L Choi M Teng M Pathan N Zhao S Li T Taveras A 《Bioorganic & medicinal chemistry letters》2012,22(12):4033-4037
This Letter reports the optimization of a pyrrolopyrimidine series as dual inhibitors of Aurora A/B kinases. This series derived from a pyrazolopyrimidine series previously reported as inhibitors of aurora kinases and CDKs. In an effort to improve the selectivity of this chemotype, we switched to the pyrrolopyrimidine core which allowed functionalization on C-2. In addition, the modeling rationale was based on superimposing the structures of Aurora-A kinase and CDK2 which revealed enough differences leading to a path for selectivity improvement. The synthesis of the new series of pyrrolopyrimidine analogs relied on the development of a different route for the two key intermediates 7 and 19 which led to analogs with both tunable activity against CDK1 and maintained cell potency. 相似文献
112.
Stereocilia, the modified microvilli projecting from the apical surfaces of the sensory hair cells of the inner ear, are essential to the mechanoelectrical transduction process underlying hearing and balance. The actin-filled stereocilia on each hair cell are tethered together by fibrous links to form a highly patterned hair bundle. Although many structural components of hair bundles have been identified, little is known about the signaling mechanisms that regulate their development, morphology, and maintenance. Here, we describe two naturally occurring, allelic mutations that result in hearing and balance deficits in mice, named roundabout (rda) and roundabout-2J (rda(2J)). Positional cloning identified both as mutations of the mouse ELMO domain containing 1 gene (Elmod1), a poorly characterized gene with no previously reported mutant phenotypes. The rda mutation is a 138 kb deletion that includes exons 1-5 of Elmod1, and rda(2J) is an intragenic duplication of exons 3-8 of Elmod1. The deafness associated with these mutations is caused by cochlear hair cell dysfunction, as indicated by conspicuous elongations and fusions of inner hair cell stereocilia and progressive degeneration of outer hair cell stereocilia. Mammalian ELMO-family proteins are known to be involved in complexes that activate small GTPases to regulate the actin cytoskeleton during phagocytosis and cell migration. ELMOD1 and ELMOD2 recently were shown to function as GTPase-activating proteins (GAPs) for the Arf family of small G proteins. Our finding connecting ELMOD1 deficiencies with stereocilia dysmorphologies thus establishes a link between the Ras superfamily of small regulatory GTPases and the actin cytoskeleton dynamics of hair cell stereocilia. 相似文献
113.
Andrea R Tentner Michael J Lee Gerry J Ostheimer Leona D Samson Douglas A Lauffenburger Michael B Yaffe 《Molecular systems biology》2012,8(1)
Following DNA damage, cells display complex multi‐pathway signaling dynamics that connect cell‐cycle arrest and DNA repair in G1, S, or G2/M phase with phenotypic fate decisions made between survival, cell‐cycle re‐entry and proliferation, permanent cell‐cycle arrest, or cell death. How these phenotypic fate decisions are determined remains poorly understood, but must derive from integrating genotoxic stress signals together with inputs from the local microenvironment. To investigate this in a systematic manner, we undertook a quantitative time‐resolved cell signaling and phenotypic response study in U2OS cells receiving doxorubicin‐induced DNA damage in the presence or absence of TNFα co‐treatment; we measured key nodes in a broad set of DNA damage signal transduction pathways along with apoptotic death and cell‐cycle regulatory responses. Two relational modeling approaches were then used to identify network‐level relationships between signals and cell phenotypic events: a partial least squares regression approach and a complementary new technique which we term ‘time‐interval stepwise regression.’ Taken together, the results from these analysis methods revealed complex, cytokine‐modulated inter‐relationships among multiple signaling pathways following DNA damage, and identified an unexpected context‐dependent role for Erk in both G1/S arrest and apoptotic cell death following treatment with this commonly used clinical chemotherapeutic drug. 相似文献
114.
Binh Thanh Nguyen Rochelle Alipio Flores Paula Leona Taymen Cammayo Suk Kim Woo Hyun Kim Wongi Min 《The Korean journal of parasitology》2021,59(4):403
Avian coccidiosis has a major economic impact on the poultry industry, it is caused by 7 species of Eimeria, and has been primarily controlled using chemotherapeutic agents. Due to the emergence of drug-resistant strains, alternative control strategies are needed. We assessed anticoccidial effects of berberine-based diets in broiler chickens following oral infection with 5 Eimeria species (E. acervulina, E. maxima, E. tenella, E. mitis, and E. praecox). When 0.2% berberine, a concentration that does not affect weight gain, was added to the diet, the 4 groups infected with E. acervulina, E. tenella, E. mitis, or E. praecox showed significant reductions in fecal oocyst shedding (P<0.05) compared to their respective infected and untreated controls. In chickens treated 0.5% berberine instead of 0.2% and infected with E. maxima, fecal oocyst production was significantly reduced, but body weight deceased, indicating that berberine treatment was not useful for E. maxima infection. Taken together, these results illustrate the applicability of berberine for prophylactic use to control most Eimeria infections except E. maxima. Further studies on the mechanisms underlying the differences in anticoccidial susceptibility to berberine, particularly E. maxima, are remained. 相似文献
115.
Sustainability in metal mining: from exploration, over processing to mine waste management 总被引:1,自引:0,他引:1
Bernhard Dold 《Reviews in Environmental Science and Biotechnology》2008,7(4):275-285
Metal mining or more general mineral mining, is the base industry of the economic wealth and development of numerous countries.
However, mining has a negative reputation due to the complex problems of environmental contamination like SO2 and CO2 emissions and acid mine drainage (AMD) formation, which endangers vital limited resources, like air, water, and soils. This
view paper highlights the environmental problems of todays metal mining operations and explores possibilities of future more
sustainable mining operations with focus on enhanced and optimized metal recovery systems in combination with a minimization
of the environmental impact. These changes depend on a change in mentality and in the mining operation process, which can
nowadays yet be observed in some modern mining operations. The goal for the future will be to implement these changes as standard
for all future mining operations. 相似文献
116.
DNA bases carrying an exocyclic amino group, namely adenine (A), guanine (G) and cytosine (C), encounter deamination under nitrosative stress. Oxanine (O), derived from deamination of guanine, is a cytotoxic and potentially mutagenic lesion and studies of its enzymatic repair are limited. Previously, we reported that the murine alkyladenine glycosylase (Aag) acts as an oxanine DNA glycosylase (JBC (2004), 279: 38177). Here, we report our recent findings on additional oxanine DNA glycosylase (ODG) activities in Aag knockout mouse tissues and other mammalian tissues. Analysis of the partially purified proteins from the mammalian cell extracts indicated the existence of ODG enzymes in addition to Aag. Data obtained from oxanine DNA cleavage assays using purified human glycosylases demonstrated that two known glycosylases, hNEIL1 and hSMUG1, contained weak but detectable ODG activities. ODG activity was the highest in hAAG and lowest in hSMUG1. 相似文献
117.
A female weanling northern elephant seal (Mirounga angustirostris) presented to The Marine Mammal Center in Sausalito, California, USA, in poor body condition. An esophageal obstruction was diagnosed by contrast radiography and esophagoscopy, but despite extensive diagnostics and supportive care, the seal died 6 days later. On postmortem examination, the right aortic arch was persistent, forming a vascular ring anomaly with a patent ductus arteriosus that compressed the distal esophagus. Aplasia of the right cribiform plate and hypoplasia of the right olfactory nerve was also identified. A review of necropsy reports from January 1988 to December 2003 revealed 16 severe congenital anomalies in 454 juvenile northern elephant seals that stranded in northern California. 相似文献
118.
Singh J Chuaqui CE Boriack-Sjodin PA Lee WC Pontz T Corbley MJ Cheung HK Arduini RM Mead JN Newman MN Papadatos JL Bowes S Josiah S Ling LE 《Bioorganic & medicinal chemistry letters》2003,13(24):4355-4359
We describe the discovery, using shape-based virtual screening, of a potent, ATP site-directed inhibitor of the TβRI kinase, an important and novel drug target for fibrosis and cancer. The first detailed report of a TβRI kinase small molecule co-complex confirms the predicted binding interactions of our small molecule inhibitor, which stabilizes the inactive kinase conformation. Our results validate shape-based screening as a powerful tool to discover useful leads against a new drug target. 相似文献
119.
Sobol RW Kartalou M Almeida KH Joyce DF Engelward BP Horton JK Prasad R Samson LD Wilson SH 《The Journal of biological chemistry》2003,278(41):39951-39959
DNA alkylation damage is primarily repaired by the base excision repair (BER) machinery in mammalian cells. In repair of the N-alkylated purine base lesion, for example, alkyl adenine DNA glycosylase (Aag) recognizes and removes the base, and DNA polymerase beta (beta-pol) contributes the gap tailoring and DNA synthesis steps. It is the loss of beta-pol-mediated 5'-deoxyribose phosphate removal that renders mouse fibroblasts alkylation-hypersensitive. Here we report that the hypersensitivity of beta-pol-deficient cells after methyl methanesulfonate-induced alkylation damage is wholly dependent upon glycosylase-mediated initiation of repair, indicating that alkylated base lesions themselves are tolerated in these cells and demonstrate that beta-pol protects against accumulation of toxic BER intermediates. Further, we find that these intermediates are initially tolerated in vivo by a second repair pathway, homologous recombination, inducing an increase in sister chromatid exchange events. If left unresolved, these BER intermediates trigger a rapid block in DNA synthesis and cytotoxicity. Surprisingly, both the cytotoxic and genotoxic signals are independent of both the p53 response and mismatch DNA repair pathways, demonstrating that p53 is not required for a functional BER pathway, that the observed damage response is not part of the p53 response network, and that the BER intermediate-induced cytotoxic and genotoxic effects are distinct from the mechanism engaged in response to mismatch repair signaling. These studies demonstrate that, although base damage is repaired by the BER pathway, incomplete BER intermediates are shuttled into the homologous recombination pathway, suggesting possible coordination between BER and the recombination machinery. 相似文献
120.
This study presents a nonlinear system of delay differential equations to model the concentrations of five hormones important
for regulation and maintenance of the menstrual cycle. Linear model components for the ovaries and pituitary were previously
analyzed and reported separately. Results for the integrated model are now presented here. This model predicts serum levels
of ovarian and pituitary hormones which agree with data in the literature for normally cycling women. In addition, the model
indicates the existence and stability of an abnormal cycle. Hence, the model may be used to simulate the effects of external
hormone therapies on abnormally cycling women as well as the effects of exogenous compounds on normally cycling women. Such
simulations may be helpful in understanding the role of xenobiotics in fertility problems, in predicting successful hormone
therapies, and for testing hormonal methods of birth control. 相似文献