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941.
Qingping Zeng John G. Allen Matthew P. Bourbeau Xianghong Wang Guomin Yao Seifu Tadesse James T. Rider Chester C. Yuan Fang-Tsao Hong Matthew R. Lee Shiwen Zhang Julie A. Lofgren Daniel J. Freeman Suijin Yang Chun Li Elizabeth Tominey Xin Huang Douglas Hoffman Harvey K. Yamane Christopher Fotsch Xiaoling Zhang 《Bioorganic & medicinal chemistry letters》2010,20(5):1559-1564
Through a combination of screening and structure-based rational design, we have discovered a series of N1-(5-(heterocyclyl)-thiazol-2-yl)-3-(4-trifluoromethylphenyl)-1,2-propanediamines that were developed into potent ATP competitive inhibitors of AKT. Studies of linker strand-binding adenine isosteres identified SAR trends in potency and selectivity that were consistent with binding interactions observed in structures of the inhibitors bound to AKT1 and to the counter-screening target PKA. One compound was shown to have acceptable pharmacokinetic properties and to be a potent inhibitor of AKT signaling and of in vivo xenograft tumor growth in a preclinical model of glioblastoma. 相似文献
942.
943.
Y. L. Gu I. C. C. van der Horst Y. L. Douglas T. Svilaas M. A. Mariani F. Zijlstra 《Netherlands heart journal》2010,18(7):348-354
Background/Objectives. We aimed to investigate the incidence and clinical outcome of coronary artery bypass grafting (CABG) performed in contemporary patients with ST-elevation myocardial infarction (STEMI) within 30 days after presentation. Methods. All 1071 patients enrolled in the Thrombus Aspiration during Percutaneous coronary intervention in Acute myocardial infarction Study (TAPAS) were included in this analysis. CABG was indicated for both ischaemic and anatomical reasons according to the current treatment guidelines for STEMI. For all surgical as well as non-surgical patients, clinical outcome was assessed at both 30 days and one year. Results. CABG was performed within 30 days of presentation in 59/1071 (5.5%) patients, in 13 (22%) within 24 hours, in eight (14%) between one and three days, and in 38 (64%) between four and 30 days. Compared with non-surgical patients, surgical patients required more initial intra-aortic balloon pump support (33 vs. 5%, p<0.001) and more often had multi-vessel disease (p<0.001). Overall, rethoracotomy was performed in 9/59 (15%) patients. In patients operated within three days, the rethoracotomy rate was markedly higher than after three days (33 vs. 5%, p=0.004). Cardiac mortality at 30 days and one year was 1.7% in the surgical group and 3.2 and 5.3%, respectively, in the non-surgical group. Conclusion. STEMI patients treated with CABG within three days after presentation are at increased risk of rethoracotomy. However, despite this higher incidence of surgical complications and multiple high-risk features at presentation, surgical management during the acute and subacute phase is associated with excellent 30-day and one-year survival. (Neth Heart J 2010;18:348-54.) 相似文献
944.
Preeti Rajesh Changanamkandath Rajesh Michael D. Wyatt Douglas L. Pittman 《DNA Repair》2010,9(4):458-467
SN1-type methylating agents generate O6-methyl guanine (O6-meG), which is a potently mutagenic, toxic, and recombinogenic DNA adduct. Recognition of O6-meG:T mismatches by mismatch repair (MMR) causes sister chromatid exchanges, which are representative of homologous recombination (HR) events. Although the MMR-dependent mutagenicity and toxicity caused by O6-meG has been studied, the mechanisms of recombination induced by O6-meG are poorly understood. To explore the HR and MMR genetic interactions in mammals, we used the Rad51d and Mlh1 mouse models. Ablation of Mlh1 did not appreciably influence the developmental phenotypes conferred by the absence of Rad51d. Mouse embryonic fibroblasts (MEFs) deficient in Rad51d can only proliferate in p53-deficient background. Therefore, Rad51d?/?Mlh1?/? Trp53?/? MEFs with a combined deficiency of HR and MMR were generated and comparisons between MLH1 and RAD51D status were made. To our knowledge, these MEFs are the first mammalian model system for combined HR and MMR defects. Rad51d-deficient MEFs were 5.3-fold sensitive to N-methyl-N′-nitro-N-nitrosoguanidine (MNNG) compared to the Rad51d-proficient MEFs. A pronounced G2/M arrest in Rad51d-deficient cells was accompanied by an accumulation of γ-H2AX and apoptosis. Mlh1-deficient MEFs were resistant to MNNG and showed no G2/M arrest or apoptosis at the doses used. Importantly, loss of Mlh1 alleviated sensitivity of Rad51d-deficient cells to MNNG, in addition to reducing γ-H2AX, G2/M arrest and apoptosis. Collectively, the data support the hypothesis that MMR-dependent sensitization of HR-deficient cells is specific for O6-meG and suggest that HR resolves DNA intermediates created by MMR recognition of O6-meG:T. This study provides insight into recombinogenic mechanisms of carcinogenesis and chemotherapy resulting from O6-meG adducts. 相似文献
945.
Douglas B. Craig Allison M. Haslam Harlyn J. Silverstein Miki Chikamatsu Elnaz Shadabi Ellert R. Nichols 《The protein journal》2010,29(6):398-406
Single enzyme molecule assays were performed using capillary electrophoresis-based protocols on β-galactosidase from Lactobacillus delbrueckii, Lactobacillus reuteri, Lactobacillus helveticus
and Bacillus circulans. The enzyme was found to show static heterogeneity with respect to catalytic rate and the variance in rate increased with
protein size. This is consistent with the proposal that random errors in translation may be an important underlying component
of enzyme heterogeneity. Additionally these enzymes were found to show static heterogeneity with respect to electrophoretic
mobility. Comparison of wild-type and rpsL E. coli β-galactosidase expressed in the presence and absence of streptomycin suggested that increases in error do not result in
detectable increases in the dynamic heterogeneity of activity with increasing temperature. Finally, a method was developed
to measure the dynamic heterogeneity in electrophoretic mobility. 相似文献
946.
We present MassSieve, a Java‐based platform for visualization and parsimony analysis of single and comparative LC‐MS/MS database search engine results. The success of mass spectrometric peptide sequence assignment algorithms has led to the need for a tool to merge and evaluate the increasing data set sizes that result from LC‐MS/MS‐based shotgun proteomic experiments. MassSieve supports reports from multiple search engines with differing search characteristics, which can increase peptide sequence coverage and/or identify conflicting or ambiguous spectral assignments. 相似文献
947.
Sheqing Zhang Jon Salemi Hauyan Hou Takashi Mori Brian Giunta Demian Obregon Jun Tan 《Biochemical and biophysical research communications》2010,398(3):337-341
Rapamycin is a well known immunosuppressant drug for rejection prevention in organ transplantation. Numerous clinical trials using rapamycin analogs, involving both children and adults with various disorders are currently ongoing worldwide. Most recently, rapamycin gained much attention for what appears to be life-span extending properties when administered to mice. The risk for Alzheimer disease (AD) is strongly and positively correlated with advancing age and is characterized by deposition of β-amyloid peptides (Aβ) as senile plaques in the brain. We report that rapamycin (2.5 μM), significantly increases Aβ generation in murine neuron-like cells (N2a) transfected with the human “Swedish” mutant amyloid precursor protein (APP). In concert with these observations, we found rapamycin significantly decreases the neuroprotective amino-terminal APP (amyloid precursor protein) cleavage product, soluble APP-α (sAPP-α) while increasing production of the β-carboxyl-terminal fragment of APP (β-CTF). These cleavage events are associated with decreased activation of a disintegrin and metallopeptidase domain-10 (ADAM-10), an important candidate α-secretase which opposes Aβ generation. To validate these findings in vivo, we intraperitoneal (i.p.) injected Tg2576 Aβ-overproducing transgenic mice with rapamycin (3 mg/kg/day) for 2 weeks. We found increased Aβ levels associated with decreased sAPP-α at an average rapamycin plasma concentration of 169.7 ± 23.5 ng/mL by high performance liquid chromatography (HPLC). These data suggest that although rapamycin may increase the lifespan in some mouse models, it may not decrease the risk for age-associated neurodegenerative disorders such as AD. 相似文献
948.
949.
950.
Fine roots play an important part in forest carbon, nutrient and water cycles. The turnover of fine roots constitutes a major carbon input to soils. Estimation of fine root turnover is difficult, labour intensive and is often compounded by artefacts created by soil disturbance. In this work, an alternative approach of using inclusion nets installed in an undisturbed soil profile was used to measure fine root production and was compared to the in-growth core method. There was no difference between fine root production estimated by the two methods in three southern taiga sites with contrasting soil conditions and tree species compositions in the Central Forest State Biosphere Reserve, Russia. Expressed as annual production over standing biomass, Norway spruce fine root turnover was in the region of 0.10 to 0.24 y-1. The inclusion net technique is suitable for field based assessment of fine root production. There are several advantages over the in-growth core method, due to non-disturbance of the soil profile and its potential for very high rate of replication. 相似文献