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991.
Xu G Searle LL Hughes TV Beck AK Connolly PJ Abad MC Neeper MP Struble GT Springer BA Emanuel SL Gruninger RH Pandey N Adams M Moreno-Mazza S Fuentes-Pesquera AR Middleton SA Greenberger LM 《Bioorganic & medicinal chemistry letters》2008,18(12):3495-3499
We herein disclose a novel series of 4-aminopyrimidine-5-carbaldehyde oximes that are potent and selective inhibitors of both EGFR and ErbB-2 tyrosine kinases, with IC(50) values in the nanomolar range. Structure-activity relationship (SAR) studies elucidated a critical role for the 4-amino and C-6 arylamino moieties. The X-ray co-crystal structure of EGFR with 37 was determined and validated our design rationale. 相似文献
992.
Ueda S Kato M Inuki S Ohno H Evans B Wang ZX Peiper SC Izumi K Kodama E Matsuoka M Nagasawa H Oishi S Fujii N 《Bioorganic & medicinal chemistry letters》2008,18(14):4124-4129
The design and synthesis of novel non-peptide CXCR4 antagonists is described. The peptide backbone of highly potent cyclic peptide-based CXCR4 antagonists was entirely replaced by an indole framework, which was expected to reproduce the disposition of the key pharmacophores consistent with those of potential bioactive conformations of the original peptides. A structure–activity relationship study on a series of modified indoles identified novel small-molecule antagonists having three pharmacophore functional groups through the appropriate linkers. 相似文献
993.
Brent E Hagel I Barry Pless Claude Goulet Robert W Platt Yvonne Robitaille 《BMJ (Clinical research ed.)》2005,330(7486):281
Objective To determine the effect of helmets on the risk of head and neck injuries in skiers and snowboarders.Design Matched case-control and case crossover study.Setting 19 ski areas in Quebec, Canada, November 2001 to April 2002.Participants 1082 skiers and snowboarders (cases) with head and neck injuries reported by the ski patrol and 3295 skiers and snowboarders (controls) with non-head or non-neck injuries matched to cases at each hill.Main outcome measures Estimates of matched odds ratios for the effect of helmet use on the risk of any head or neck injury and for people requiring evacuation by ambulance.Results The adjusted odds ratio for helmet use in participants with any head injury was 0.71 (95% confidence interval 0.55 to 0.92), indicating a 29% reduction in the risk of head injury. For participants who required evacuation by ambulance for head injuries, the adjusted odds ratio for helmet use was 0.44 (0.24 to 0.81). Similar results occurred with the case crossover design (odds ratio 0.43, 0.09 to 1.83). The adjusted odds ratio for helmet use for participants with any neck injury was 0.62 (0.33 to 1.19) and for participants who required evacuation by ambulance for neck injuries it was 1.29 (0.41 to 4.04).Conclusions Helmets protect skiers and snowboarders against head injuries. We cannot rule out the possibility of an increased risk of neck injury with helmet use, but the estimates on which this assumption is based are imprecise. 相似文献
994.
Michael D Carter Katie Southwick Georgi Lukov Barry M Willardson Craig D Thulin 《Journal of biomolecular techniques》2004,15(4):257-264
Post-translational modifications are used by cells to control the functions of proteins. Phosducin-like protein (PhLP) is a regulator of G-protein signaling that is post-translationally modified via phosphorylation. Phosphorylation of PhLP initiates its degradation by the 26S proteasome in serum-stimulated cells. In this report, we show that PhLP is phosphorylated in serum-stimulated Chinese hamster ovary (CHO) cells. Through the use of tandem mass spectrometry (MS/MS), the specific amino acids phosphorylated can be identified. A PhLP-myc-His construct was purified and phosphorylated by serum-stimulated CHO extract. The resulting protein was digested with trypsin and the peptides were identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Automated collison-induced dissociation data acquisition was compared with LC-MS/MS of manually chosen parents. In general, LC-MS/MS is superior for parent ions chosen manually, with the notable exception that automated fragmentation employs dynamic collision energy, which can result in higher quality collison-induced dissociation. Using the LC-MS/MS methods, four phosphorylation sites on PhLP were positively identified. 相似文献
995.
William D-C Man Michael I Polkey Nora Donaldson Barry J Gray John Moxham 《BMJ (Clinical research ed.)》2004,329(7476):1209
Objective To evaluate the effects of an early community based pulmonary rehabilitation programme after hospitalisation for acute exacerbations of chronic obstructive pulmonary disease (COPD).Design A single centre, randomised controlled trial.Setting An inner city, secondary and tertiary care hospital in London.Participants 42 patients admitted with an acute exacerbation of COPD.Intervention An eight week, pulmonary rehabilitation programme for outpatients, started within 10 days of hospital discharge, or usual care.Main outcome measures Incremental shuttle walk distance, disease specific health status (St George''s respiratory questionnaire, SGRQ; chronic respiratory questionnaire, CRQ) and generic health status (medical outcomes short form 36 questionnaire, SF-36) at three months after hospital discharge.Results Early pulmonary rehabilitation, compared with usual care, led to significant improvements in median incremental shuttle walk distance (60 metres, 95% confidence interval 26.6 metres to 93.4 metres, P = 0.0002), mean SGRQ total score (-12.7, -5.0 to -20.3, P = 0.002), all four domains of the CRQ (dyspnoea 5.5, 2.0 to 9.0, P = 0.003; fatigue 5.3, 1.9 to 8.8, P = 0.004; emotion 8.7, 2.4 to 15.0, P = 0.008; and mastery 7.5, 4.2 to 10.7, P < 0.001) and the mental component score of the SF-36 (20.1, 3.3 to 36.8, P = 0.02). Improvements in the physical component score of the SF-36 did not reach significance (10.6, -0.3 to 21.6, P = 0.057).Conclusion Early pulmonary rehabilitation after admission to hospital for acute exacerbations of COPD is safe and leads to statistically and clinically significant improvements in exercise capacity and health status at three months. 相似文献
996.
Francine M Perrine Barry G Rolfe Michael F Hynes Charles H Hocart 《Plant Physiology and Biochemistry》2004,42(9):723-729
A new method for preparing alkyl esters of indole-3-acetic acid (IAA) in aqueous solution is adapted from the chloroformate method originally described by Husek for the analysis of amino acids. This method has the significant advantage of avoiding the generation and use of diazomethane, and is done in aqueous solution without the need to dry the sample with concomitant non-specific losses of IAA. The effectiveness of this method is demonstrated by its use in an isotope dilution gas chromatography-mass spectrometry (GC-MS) assay of IAA and L-tryptophan (Trp) in the culture supernatant of a series of Sinorhizobium meliloti and Rhizobium leguminosarum bv. trifolii strains that can interact with rice to either enhance or inhibit rice plant growth. We were testing the hypothesis that the rice growth inhibition was related to the biosynthesis of IAA. It was found that S. meliloti and Rhizobium strains produced high amounts of IAA in Trp supplemented BIII minimal medium compared to BIII media. All the strains produced more than the minimum amount of IAA required to inhibit rice growth and thus IAA is not the major inhibitory factor of rice seedling growth from S. meliloti and Rhizobium strains. 相似文献
997.
998.
Woo J Chae YK Jang SJ Kim MS Baek JH Park JC Trink B Ratovitski E Lee T Park B Park M Kang JH Soria JC Lee J Califano J Sidransky D Moon C 《Biochemical and biophysical research communications》2008,366(2):321-327
Phosphorylation pathway has been identified as an important step in membrane trafficking for AQP5. We generated stably transfected BEAS-2B human bronchial epithelial cells with various over-expression constructs on permeable support. In stable cells with wild-type AQP5 and S156A (AQP5 mutant targeting PKA consensus sequence), AQP5 expression was predominantly polarized to the apical membrane, whereas stable cells with N185D (AQP5 mutant targeting second NPA motif), mainly localized to the cytoplasm. Treatment with H89 and/or chlorophenylthio-cAMP (cpt-cAMP) did not affect membrane expression of AQP5 in any of three stable cells. In cells with wild-type AQP5 and N185D, AQP5s were phosphorylated by PKA, while phosphorylation of AQP5 was not detected in cells with S156A. These results indicate that, in AQP5, serine156 may be phosphorylated by PKA, but membrane expression of AQP5 may not be regulated by PKA phosphorylation. We conclude that AQP5 membrane targeting can include more than one mechanism besides cAMP dependent phosphorylation. 相似文献
999.
Augustine AJ Kragh ME Sarangi R Fujii S Liboiron BD Stoj CS Kosman DJ Hodgson KO Hedman B Solomon EI 《Biochemistry》2008,47(7):2036-2045
The multicopper oxidases catalyze the 4e- reduction of O2 to H2O coupled to the 1e- oxidation of 4 equiv of substrate. This activity requires four Cu atoms, including T1, T2, and coupled binuclear T3 sites. The T2 and T3 sites form a trinuclear cluster (TNC) where O2 is reduced. The T1 is coupled to the TNC through a T1-Cys-His-T3 electron transfer (ET) pathway. In this study the two T3 Cu coordinating His residues which lie in this pathway in Fet3 have been mutated, H483Q, H483C, H485Q, and H485C, to study how perturbation at the TNC impacts the T1 Cu site. Spectroscopic methods, in particular resonance Raman (rR), show that the change from His to Gln to Cys increases the covalency of the T1 Cu-S Cys bond and decreases its redox potential. This study of T1-TNC interactions is then extended to Rhus vernicifera laccase where a number of well-defined species including the catalytically relevant native intermediate (NI) can be trapped for spectroscopic study. The T1 Cu-S covalency and potential do not change in these species relative to resting oxidized enzyme, but interestingly the differences in the structure of the TNC in these species do lead to changes in the T1 Cu rR spectrum. This helps to confirm that vibrations in the cysteine side chain of the T1 Cu site and the protein backbone couple to the Cu-S vibration. These changes in the side chain and backbone provide a possible mechanism for regulating intramolecular T1 to TNC ET in NI and partially reduced enzyme forms for efficient turnover. 相似文献
1000.
Sri Sudaryanti Yulinah Trihadiningrum Barry T Hart Peter E. Davies Chris Humphrey Richard Norris Justen Simpson Lisa Thurtell 《Aquatic Ecology》2001,35(2):135-146
This study aimed to evaluate the applicability of the Australian River Assessment System (AUSRIVAS) bioassessment methodology to assess the biological health of streams in the upper-middle Brantas River catchment, East Java, Indonesia. A total of 84 `minimally disturbed' reference sites were selected and sampled for macroinvertebrates in riffle habitats. Sampling of macroinvertebrates and identification to family level was conducted by local biologists following intensive training, and under supervision. A quality control protocol was introduced to ensure the data were reliable and reproducible. A suite of `potential predictor' and `monitoring' environmental variables were also measured at each site. The macroinvertebrate data were used to develop a predictive AUSRIVAS model for the upper-middle Brantas river, and the model was then used to assess the `health' of 15 test sites in the catchment. Bioassessment outputs – Observed (O)/Expected (E) ratios – were found to be broadly related to measures of physical disturbance from land use and riparian degradation. Through the process of local reference site selection and sampling, model development, validation and subsequent use, the Australian AUSRIVAS rapid bioassessment method was assessed as being highly applicable to the upper-middle catchment sections of Indonesian river systems. 相似文献