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Sanchez RM Erhard K Hardwicke MA Lin H McSurdy-Freed J Plant R Raha K Rominger CM Schaber MD Spengler MD Moore ML Yu H Luengo JI Tedesco R Rivero RA 《Bioorganic & medicinal chemistry letters》2012,22(9):3198-3202
A series of 1,2,4-triazolo[1,5-a]pyrimidin-7(3H)-ones with excellent enzyme inhibition, improved isoform selectivity, and excellent inhibition of downstream phosphorylation of AKT has been identified. Several compounds in the series demonstrated potent (~ 0.100 μM IC(50)) growth inhibition in a PTEN deficient cancer cell line. 相似文献
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Francesco Sofi Andrea Capalbo Nicola Pucci Jacopo Giuliattini Francesca Condino Flavio Alessandri Rosanna Abbate Gian Franco Gensini Sergio Califano 《BMJ (Clinical research ed.)》2008,337(7661):88-92
Objective To evaluate the clinical usefulness of complete preparticipation cardiovascular screening in a large cohort of sports participants.Design Cross sectional study of data over a five year period.Setting Institute of Sports Medicine in Florence, Italy.Participants 30 065 (23 570 men) people seeking to obtain clinical eligibility for competitive sports.Main outcome measures Results of resting and exercise 12 lead electrocardiography.Results Resting 12 lead ECG patterns showed abnormalities in 1812 (6%) participants, with the most common abnormalities (>80%) concerning innocent ECG changes. Exercise ECG showed an abnormal pattern in 1459 (4.9%) participants. Exercise ECG showed cardiac anomalies in 1227 athletes with normal findings on resting ECG. At the end of screening, 196 (0.6%) participants were considered ineligible for competitive sports. Among the 159 participants who were disqualified at the end of the screening for cardiac reasons, a consistent proportion (n=126, 79.2%) had shown innocent or negative findings on resting 12 lead ECG but clear pathological alterations during the exercise test. After adjustment for possible confounders, logistic regression analysis showed that age >30 years was significantly associated with an increased risk of being disqualified for cardiac findings during exercise testing.Conclusions Among people seeking to take part in competitive sports, exercise ECG can identify those with cardiac abnormalities. Follow-up studies would show if disqualification of such people would reduce the incidence of CV events among athletes. 相似文献
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Reducing the Native Tropism of Adenovirus Vectors Requires Removal of both CAR and Integrin Interactions 总被引:5,自引:0,他引:5 下载免费PDF全文
David A. Einfeld Rosanna Schroeder Peter W. Roelvink Alena Lizonova C. Richter King Imre Kovesdi Thomas J. Wickham 《Journal of virology》2001,75(23):11284-11291
The development of tissue-selective virus-based vectors requires a better understanding of the role of receptors in gene transfer in vivo, both to rid the vectors of their native tropism and to introduce new specificity. CAR and alphav integrins have been identified as the primary cell surface components that interact with adenovirus type 5 (Ad5)-based vectors during in vitro transduction. We have constructed a set of four vectors, which individually retain the wild-type cell interactions, lack CAR binding, lack alphav integrin binding, or lack both CAR and alphav integrin binding. These vectors have been used to examine the roles of CAR and alphav integrin in determining the tropism of Ad vectors in a mouse model following intrajugular or intramuscular injection. CAR was found to play a significant role in liver transduction. The absence of CAR binding alone, however, had little effect on the low level of expression from Ad in other tissues. Binding of alphav integrins appeared to have more influence than did binding of CAR in promoting the expression in these tissues and was also found to be important in liver transduction by Ad vectors. An effect of the penton base modification was a reduction in the number of vector genomes that could be detected in several tissues. In the liver, where CAR binding is important, combining defects in CAR and alphav integrin binding was essential to effectively reduce the high level of expression from Ad vectors. While there may be differences in Ad vector tropism among species, our results indicate that both CAR and alphav integrins can impact vector distribution in vivo. Disruption of both CAR and alphav integrin interactions may be critical for effectively reducing native tropism and enhancing the efficacy of specific targeting ligands in redirecting Ad vectors to target tissues. 相似文献
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Esteban Grasso Daniel Paparini Vanesa Hauk Gabriela Salamone Claudia Perez Leiros Rosanna Ramhorst 《PloS one》2014,9(5)
Macrophages at the maternal-placental interface coordinate opposite demands under the control of trophoblast cells such as the response against pathogens on one hand, and apoptotic cell clearance and wound healing with the production of suppressor cytokines. Here, we investigated whether trophoblast cells induce maternal monocyte activation towards an alternative activated macrophage profile and whether bacterial or viral stimuli modulate their migratory properties. We used an in vitro model of the maternal-placental interface represented by co-cultures of CD14+ cells isolated from fertile women with first trimester trophoblast cell line (Swan-71 cells) in the presence or absence of pathogen associated molecular pattern (PAMP) stimuli lipopolysaccharide (LPS), peptidoglycan (PGN) or poly [I:C]). Maternal CD14+ cells showed increased CD16 and CD39 expression, both markers associated to an alternative activation profile, with no changes in CD80 expression after trophoblast cell interaction. These changes were accompanied by increased IL-10 and decreased IL-12 production by CD14+ cells. After stimulation with LPS, PGN or poly [I:C], monocytes co-cultured with trophoblast cells had lower production of TNF-α and IL-1β compared with non co-cultured monocytes. Interestingly, monocyte migration towards trophoblast cells was prevented in the presence of LPS or PGN but not after 24h of stimulation with poly [I:C]. LPS or PGN also decreased CCR5, CXCL-8 and CCL5 expression. Finally, trophoblast cells co-cultured with monocytes in the presence of pathological stimuli failed to increase chemokine expression, indicating a bidirectional effect. In conclusion, trophoblast might ‘instruct’ maternal monocytes to express an alternative activation profile and restrain their early recruitment under pathological threats as one of the first strategies to avoid potential tissue damage at the maternal-placental interface. 相似文献
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Stream detritus and Tipula (Diptera) feces were wet-sieved to a 63–250 µm particle size range and mixed in three proportions with ashed sand of the same size to yield food substrates of varying quality. Growth of fourth-instar Stictochironomus annulicrus (Townes) (Diptera: Chironomidae) larvae was used to indicate whether the more nutritious particles were selected from these mixtures. Respective mean relative growth rates on the substrates, in order of decreasing percentage organic matter (i.e. food quality), were: 0.0229, 0.0104 and 0.0004 mg·mg–1d–1. Replicates of the relatively high quality substrate consistently elicited the highest growth rates; animals grew at intermediate rates on medium quality, and slowest on low quality substrates. Thus, this collector does not appear to have selected for food quality under the described experimental conditions. 相似文献
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Phospholipase D (PLD) hydrolyzes the phosphodiester bond of the predominant membrane phospholipid, phosphatidylcholine producing phosphatidic acid and free choline. This activity can participate in signal transduction pathways and impact on vesicle trafficking for secretion and endocytosis, as well as receptor signalling. Phospholipids can regulate PLD activity directly, through specific intermolecular interactions, or indirectly, through their effect on the localization or activity of PLD's protein effectors. This short review highlights these various phospholipid inputs into the regulation of PLD activity and also reviews potential roles for PLD-generated phosphatidic acid, particularly a mechanism by which the phospholipid may participate in the process of vesicular trafficking. 相似文献
120.
Nano FE Zhang N Cowley SC Klose KE Cheung KK Roberts MJ Ludu JS Letendre GW Meierovics AI Stephens G Elkins KL 《Journal of bacteriology》2004,186(19):6430-6436
Francisella tularensis is a gram-negative, facultative intracellular pathogen that causes the highly infectious zoonotic disease tularemia. We have discovered a ca. 30-kb pathogenicity island of F. tularensis (FPI) that includes four large open reading frames (ORFs) of 2.5 to 3.9 kb and 13 ORFs of 1.5 kb or smaller. Previously, two small genes located near the center of the FPI were shown to be needed for intramacrophage growth. In this work we show that two of the large ORFs, located toward the ends of the FPI, are needed for virulence. Although most genes in the FPI encode proteins with amino acid sequences that are highly conserved between high- and low-virulence strains, one of the FPI genes is present in highly virulent type A F. tularensis, absent in moderately virulent type B F. tularensis, and altered in F. tularensis subsp. novicida, which is highly virulent for mice but avirulent for humans. The G+C content of a 17.7-kb stretch of the FPI is 26.6%, which is 6.6% below the average G+C content of the F. tularensis genome. This extremely low G+C content suggests that the DNA was imported from a microbe with a very low G+C-containing chromosome. 相似文献