排序方式: 共有237条查询结果,搜索用时 15 毫秒
161.
Prat M Buil MA Fernández MD Castro J Monleón JM Tort L Casals G Ferrer M Huerta JM Espinosa S López M Segarra V Gavaldà A Miralpeix M Ramos I Vilella D González M Córdoba M Cárdenas A Antón F Beleta J Ryder H 《Bioorganic & medicinal chemistry letters》2011,21(11):3457-3461
Novel quaternary ammonium derivatives of N,N-disubstituted (3R)-quinuclidinyl carbamates have been identified as potent M3 muscarinic antagonists with long duration of action in an in vivo model of bronchoconstriction. These compounds have also presented a high level of metabolic transformation (human liver microsomes). The synthesis, structure-activity relationships and biological evaluation of these compounds are reported. 相似文献
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Maxwell CA Benítez J Gómez-Baldó L Osorio A Bonifaci N Fernández-Ramires R Costes SV Guinó E Chen H Evans GJ Mohan P Català I Petit A Aguilar H Villanueva A Aytes A Serra-Musach J Rennert G Lejbkowicz F Peterlongo P Manoukian S Peissel B Ripamonti CB Bonanni B Viel A Allavena A Bernard L Radice P Friedman E Kaufman B Laitman Y Dubrovsky M Milgrom R Jakubowska A Cybulski C Gorski B Jaworska K Durda K Sukiennicki G Lubiński J Shugart YY Domchek SM Letrero R Weber BL Hogervorst FB Rookus MA 《PLoS biology》2011,9(11):e1001199
Differentiated mammary epithelium shows apicobasal polarity, and loss of tissue organization is an early hallmark of breast carcinogenesis. In BRCA1 mutation carriers, accumulation of stem and progenitor cells in normal breast tissue and increased risk of developing tumors of basal-like type suggest that BRCA1 regulates stem/progenitor cell proliferation and differentiation. However, the function of BRCA1 in this process and its link to carcinogenesis remain unknown. Here we depict a molecular mechanism involving BRCA1 and RHAMM that regulates apicobasal polarity and, when perturbed, may increase risk of breast cancer. Starting from complementary genetic analyses across families and populations, we identified common genetic variation at the low-penetrance susceptibility HMMR locus (encoding for RHAMM) that modifies breast cancer risk among BRCA1, but probably not BRCA2, mutation carriers: n = 7,584, weighted hazard ratio (wHR) = 1.09 (95% CI 1.02–1.16), ptrend = 0.017; and n = 3,965, wHR = 1.04 (95% CI 0.94–1.16), ptrend = 0.43; respectively. Subsequently, studies of MCF10A apicobasal polarization revealed a central role for BRCA1 and RHAMM, together with AURKA and TPX2, in essential reorganization of microtubules. Mechanistically, reorganization is facilitated by BRCA1 and impaired by AURKA, which is regulated by negative feedback involving RHAMM and TPX2. Taken together, our data provide fundamental insight into apicobasal polarization through BRCA1 function, which may explain the expanded cell subsets and characteristic tumor type accompanying BRCA1 mutation, while also linking this process to sporadic breast cancer through perturbation of HMMR/RHAMM. 相似文献
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In addition to floral senescence and longevity, the control of leaf senescence is a major factor determining the quality of several cut flowers, including Lilium, in the commercial market. To better understand the physiological process underlying leaf senescence in this species, we evaluated: (i) endogenous variation in the levels of phytohormones during leaf senescence, (ii) the effects of leaf darkening in senescence and associated changes in phytohormones, and (iii) the effects of spray applications of abscisic acid (ABA) and pyrabactin on leaf senescence. Results showed that while gibberellin 4 (GA(4)) and salicylic acid (SA) contents decreased, that of ABA increased during the progression of leaf senescence. However, dark-induced senescence increased ABA levels, but did not affect GA(4) and SA levels, which appeared to correlate more with changes in air temperature and/or photoperiod than with the induction of leaf senescence. Furthermore, spray applications of pyrabactin delayed the progression of leaf senescence in cut flowers. Thus, we conclude that (i) ABA plays a major role in the regulation of leaf senescence in Lilium, (ii) darkness promotes leaf senescence and increases ABA levels, and (iii) exogenous applications of pyrabactin inhibit leaf senescence in Lilium, therefore suggesting that it acts as an antagonist of ABA in senescing leaves of cut lily flowers. 相似文献
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Nuria Aguilar Marta Mir Pedro M. Grima Manel López Victor Segarra Laia Esteban Imma Moreno Nuria Godessart Gema Tarrasón Teresa Domenech Dolors Vilella Clara Armengol Mònica Córdoba Mar Sabaté Daniel Casals Maria Domínguez 《Bioorganic & medicinal chemistry letters》2012,22(24):7672-7676
Amido-1,3,4-thiadiazoles have been identified as a novel structural class of potent and selective sphingosine-1-phosphate receptor subtype 1 agonists. Starting from a micromolar HTS hit with the help of an in-house homology model, robust structural–activity relationships were developed to yield compounds with good selectivity and excellent in vivo efficacy in rat models. 相似文献
169.
Mráz P Garcia-Jacas N Gex-Fabry E Susanna A Barres L Müller-Schärer H 《Molecular phylogenetics and evolution》2012,62(2):612-623
Spotted knapweed (Centaurea stoebe) occurs from Western Asia to Western Europe both as diploid and tetraploid cytotypes, predominantly in single-cytotype populations with higher frequency of diploid populations. Interestingly, only tetraploids have been recorded so far from its introduced range in North America where they became highly invasive. We performed phylogenetic and network analyses of more than 40 accessions of the C. stoebe and C. paniculata groups and other related taxa using cloned internal transcribed spacer (ITS) and sequences of the chloroplast trnT-trnL and atpBrbcL regions to (i) assess the evolutionary origin of tetraploid C. stoebe s.l., and (ii) uncover the phylogeny of the C. stoebe group. Both issues have not been studied so far and thus remained controversial. Cloned ITS sequences showed the presence of two slightly divergent ribotypes occurring in tetraploid cytotype, while only one major ribotype was present in diploid C. stoebe s.str. This pattern suggests an allopolyploid origin of tetraploids with contribution of the diploid C. stoebe s.str. genome. Although we were not able to detect the second parental taxon, we hypothesize that hybridization might have triggered important changes in morphology and life history traits, which in turn may explain the colonization success of the tetraploid taxon. Bayesian relaxed clock estimations indicate a relatively recent--Pleistocene origin of the tetraploid C. stoebe s.l. Furthermore, our analyses showed a deep split between the C. paniculata and C. stoebe groups, and a young diversification of the taxa within the C. stoebe group. In contrast to nrDNA analyses, the observed pattern based on two cpDNA regions was inconclusive with respect to the origin and phylogeny of the studied taxa, most likely due to shared ancient polymorphism and frequent homoplasies. 相似文献
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Marcelo L Laia Leandro M Moreira Juliana Dezajacomo Joice B Brigati Cristiano B Ferreira Maria IT Ferro Ana CR Silva Jesus A Ferro Julio CF Oliveira 《BMC microbiology》2009,9(1):12-17