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911.
Ray P Wright J Adam J Bennett J Boucharens S Black D Cook A Brown AR Epemolu O Fletcher D Haunso A Huggett M Jones P Laats S Lyons A Mestres J de Man J Morphy R Rankovic Z Sherborne B Sherry L van Straten N Westwood P Zaman GZ 《Bioorganic & medicinal chemistry letters》2011,21(1):97-101
Fragment-based NMR screening of a small literature focused library led to identification of a historical thrombin/FactorXa building block, 17A, that was found to be a ROCK-I inhibitor. In the absence of an X-ray structure, fragment growth afforded 6-substituted isoquinolin-1-amine derivatives which were profiled in the primary ROCK-I IMAP assay. Compounds 23A and 23E were selected as fragment optimized hits for further profiling. Compound 23A has similar ROCK-1 affinity, potency and cell based efficacy to the first generation ROCK inhibitors, however, it has a superior PK profile in C57 mouse. Compound 23E demonstrates the feasibility of improving ROCK-1 affinity, potency and cell based efficacy for the series, however, it has a poor PK profile relative to 23A. 相似文献
912.
913.
Ping Ouyang Mohammad Arif Jacqueline Fletcher Ulrich Melcher Francisco Manuel Ochoa Corona 《PloS one》2013,8(11)
A reliable, accurate and rapid multigene-based assay combining real time quantitative PCR (qPCR) and a Razor Ex BioDetection System (Razor Ex) was validated for detection of Xylella fastidiosa subsp. pauca (Xfp, a xylem-limited bacterium that causes citrus variegated chlorosis [CVC]). CVC, which is exotic to the United States, has spread through South and Central America and could significantly impact U.S. citrus if it arrives. A method for early, accurate and sensitive detection of Xfp in plant tissues is needed by plant health officials for inspection of products from quarantined locations, and by extension specialists for detection, identification and management of disease outbreaks and reservoir hosts. Two sets of specific PCR primers and probes, targeting Xfp genes for fimbrillin and the periplasmic iron-binding protein were designed. A third pair of primers targeting the conserved cobalamin synthesis protein gene was designed to detect all possible X. fastidiosa (Xf) strains. All three primer sets detected as little as 1 fg of plasmid DNA carrying X. fastidiosa target sequences and genomic DNA of Xfp at as little as 1 - 10 fg. The use of Razor Ex facilitates a rapid (about 30 min) in-field assay capability for detection of all Xf strains, and for specific detection of Xfp. Combined use of three primer sets targeting different genes increased the assay accuracy and broadened the range of detection. To our knowledge, this is the first report of a field-deployable rapid and reliable bioforensic detection and discrimination method for a bacterial phytopathogen based on multigene targets. 相似文献
914.
Babcock Russell C. Plagányi Éva E. Condie Scott A. Westcott David A. Fletcher Cameron S. Bonin Mary C. Cameron Darren 《Coral reefs (Online)》2020,39(5):1233-1244
Coral Reefs - Crown-of-thorns starfish (COTS) outbreaks are a globally significant driver of coral mortality in the Indo-Pacific and work synergistically with other disturbances. We argue that our... 相似文献
915.
916.
Christopher W. Coyne Karan Patel Johanna Heureaux Jeanne Stachowiak Daniel A. Fletcher Allen P. Liu 《Journal of visualized experiments : JoVE》2014,(84)
Bottom-up synthetic biology presents a novel approach for investigating and reconstituting biochemical systems and, potentially, minimal organisms. This emerging field engages engineers, chemists, biologists, and physicists to design and assemble basic biological components into complex, functioning systems from the bottom up. Such bottom-up systems could lead to the development of artificial cells for fundamental biological inquiries and innovative therapies1,2. Giant unilamellar vesicles (GUVs) can serve as a model platform for synthetic biology due to their cell-like membrane structure and size. Microfluidic jetting, or microjetting, is a technique that allows for the generation of GUVs with controlled size, membrane composition, transmembrane protein incorporation, and encapsulation3. The basic principle of this method is the use of multiple, high-frequency fluid pulses generated by a piezo-actuated inkjet device to deform a suspended lipid bilayer into a GUV. The process is akin to blowing soap bubbles from a soap film. By varying the composition of the jetted solution, the composition of the encompassing solution, and/or the components included in the bilayer, researchers can apply this technique to create customized vesicles. This paper describes the procedure to generate simple vesicles from a droplet interface bilayer by microjetting. 相似文献
917.
Production Factors Controlling the Physical Characteristics of Biochar Derived from Phytoremediation Willow for Agricultural Applications 总被引:1,自引:0,他引:1
Ashleigh J. Fletcher Malcolm A. Smith Andreas Heinemeyer Richard Lord Christopher J. Ennis Edward M. Hodgson Kerrie Farrar 《Bioenergy Research》2014,7(1):371-380
Willow, a leading bioenergy feedstock, may be planted for bioremediation and has been used, more recently, as the biomass feedstock in the manufacture of biochar for agricultural applications. Here, we present a detailed study of the physical and chemical factors affecting willow char properties, where the feedstock is a by-product of bioremediation, potentially transferring pollutants such as heavy metals to the wood feed. Biochar samples were produced via pyrolysis of short-rotation coppice willow, grown on contaminated land, using several treatment times at heat treatment temperatures (HTTs) in the range 350–650 °C, under a constant flow of argon, set at either 100 or 500 mL min?1. The samples were analysed for yield, elemental analysis and structural characteristics, including surface area and pore size distribution, surface functionality and metal content. All chars obtained have high fixed carbon contents but vary in surface characteristics with a marked increase in basic character with increasing HTT, ascribed to the removal of surface oxygen moieties. Results indicate a minimum pyrolysis temperature of 450 °C is required to produce a defined mesoporous structure, as required to facilitate oxygen transport, HTT?≥?550 °C produces total surface area of >170 m2 g?1 and, more importantly, an appreciable external surface area suitable for microbial colonisation. The data show that selection and optimisation of char properties is possible; however, the interplay of factors may mean some compromise is required. 相似文献
918.
Tight junctions (TJs) link adjacent cells and are critical for maintenance of apical-basolateral polarity in epithelial monolayers. The TJ protein occludin functions in disparate processes, including wound healing and Hepatitis C Virus infection. Little is known about steady-state occludin trafficking into and out of the plasma membrane. Therefore, we determined the mechanisms responsible for occludin turnover in confluent Madin-Darby canine kidney (MDCK) epithelial monolayers. Using various biotin-based trafficking assays we observed continuous and rapid endocytosis of plasma membrane localised occludin (the majority internalised within 30 minutes). By 120 minutes a significant reduction in internalised occludin was observed. Inhibition of lysosomal function attenuated the reduction in occludin signal post-endocytosis and promoted co-localisation with the late endocytic system. Using a similar method we demonstrated that ∼20% of internalised occludin was transported back to the cell surface. Consistent with these findings, significant co-localisation between internalised occludin and recycling endosomal compartments was observed. We then quantified the extent to which occludin synthesis and transport to the plasma membrane contributes to plasma membrane occludin homeostasis, identifying inhibition of protein synthesis led to decreased plasma membrane localised occludin. Significant co-localisation between occludin and the biosynthetic secretory pathway was demonstrated. Thus, under steady-state conditions occludin undergoes turnover via a continuous cycle of endocytosis, recycling and degradation, with degradation compensated for by biosynthetic exocytic trafficking. We developed a mathematical model to describe the endocytosis, recycling and degradation of occludin, utilising experimental data to provide quantitative estimates for the rates of these processes. 相似文献
919.
Fletcher DA 《Molecular biology of the cell》2011,22(7):909-910
In theory, the combination of mathematical modeling with experimental studies can be a powerful and compelling approach to understanding cell biology. In practice, choosing appropriate problems, identifying willing and able collaborators, and publishing the resulting research can be remarkably challenging. To provide perspective on the question of whether and when to combine modeling and experiments, a panel of experts at the 2010 ASCB Annual Meeting shared their personal experiences and advice on how to use modeling effectively. 相似文献
920.