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71.
72.
Angell RM Atkinson FL Brown MJ Chuang TT Christopher JA Cichy-Knight M Dunn AK Hightower KE Malkakorpi S Musgrave JR Neu M Rowland P Shea RL Smith JL Somers DO Thomas SA Thompson G Wang R 《Bioorganic & medicinal chemistry letters》2007,17(5):1296-1301
The identification and exploration of a novel, potent and selective series of N-(3-cyano-4,5,6,7-tetrahydro-1-benzothien-2-yl)amide inhibitors of JNK2 and JNK3 kinases is described. Compounds 5a and 11a were identified as potent inhibitors of JNK3 (pIC50 6.7 and 6.6, respectively), with essentially equal potency against JNK2 (pIC50 6.5). Selectivity within the mitogen-activated protein kinase (MAPK) family, against JNK1, p38alpha and ERK2, was observed for the series. X-ray crystallography of 5e and 8a in JNK3 revealed a unique binding mode, with the 3-cyano substituent forming an H-bond acceptor interaction with the hinge region of the ATP-binding site. 相似文献
73.
The dynamics of axonal transport are often colloquially described using highway traffic as a model system. Examination of the physics of traffic patterns, with emphasis on traffic jams and accidents, provides unique and perhaps counterintuitive insight into the aberrant accumulation of neurofilaments that accompanies amyotrophic lateral sclerosis/motor neuron disease. 相似文献
74.
Tassilo?Gleede Barbara?Riehl Colleen?Shea Lena?Kersting Aylin?Sibel?Cankaya David?Alexoff Michael?Schueller Joanna?S.?Fowler Wenchao?QuEmail author 《Amino acids》2015,47(3):525-533
Carbon-11 (β+ emitter, t 1/2 = 20.4 min) radiolabeled l-glutamine is a potentially useful molecular imaging agent that can be utilized with positron emission tomography for both human oncological diagnosis and plant imaging research. Based upon a previously reported [11C]cyanide end-capping labeling method, a systematic investigation of nucleophilic cyanation reactions and acidic hydrolysis reaction parameters, including base, metal ion source, phase transfer catalyst, solvent, reaction temperature and reaction time, was conducted. The result was a milder, more reliable, two-step method which provides l-[5-11C]-glutamine with a radiochemical yield of 63.8 ± 8.7 % (range from 51 to 74 %, n = 10) with >90 % radiochemical purity and >90 % enantiomeric purity. The total synthesis time was 40–50 min from the end of bombardment. In addition, an Fmoc derivatization method was developed to measure the specific activity of this radiotracer. 相似文献
75.
The aggregation of soluble proteins into fibrillar species is a complex process that spans many lengths and time scales, and that involves the formation of numerous on-pathway and off-pathway intermediate species. Despite this complexity, several elements underlying the aggregation process appear to be universal. The kinetics typically follows a nucleation-growth process, and proteins with very different sequences aggregate to form similar fibril structures, populating intermediates with sufficient structural similarity to bind to a common antibody. This review focuses on a computational approach that exploits the common features of aggregation to simplify or 'coarse-grain' the representation of the protein. We highlight recent developments in coarse-grained modeling and illustrate how these models have been able to shed new light into the mechanisms of protein aggregation and the nature of aggregation intermediates. The roles of aggregation prone conformations in the monomeric state and the influence of inherent β-sheet and aggregation propensities in modulating aggregation pathways are discussed. 相似文献
76.
Jason A Roberts Michael S Roberts Andrew Semark Andrew A Udy Carl MJ Kirkpatrick David L Paterson Matthew J Roberts Peter Kruger Jeffrey Lipman 《BMC anesthesiology》2011,11(1):1-7
Background
Critical illness, mediated by trauma or sepsis, can lead to physiological changes that alter the pharmacokinetics of antibiotics and may result in sub-therapeutic concentrations at the sites of infection. The first aim of this project is to identify the clinical characteristics of critically ill patients with significant trauma that have been recently admitted to ICU that may predict the dosing requirements for the antibiotic, cefazolin. The second aim of this is to identify the clinical characteristics of critically ill patients with sepsis that may predict the dosing requirements for the combination antibiotic, piperacillin-tazobactam.Methods/Design
This is an observational pharmacokinetic study of patients with trauma (cefazolin) or with sepsis (piperacillin-tazobactam). Participants will have samples from blood and urine, collected at different intervals. Patients will also have a microdialysis catheter inserted into subcutaneous tissue to measure interstitial fluid penetration of the antibiotic. Participants will be administered sinistrin, indocyanine green and sodium bromide as well as have cardiac output monitoring performed and tetrapolar bioimpedance to determine physiological changes resulting from pathology. Analysis of samples will be performed using validated liquid chromatography tandem mass-spectrometry. Pharmacokinetic analysis will be performed using non-linear mixed effects modeling to determine individual and population pharmacokinetic parameters of antibiotics.Discussion
The study will describe cefazolin and piperacillin-tazobactam concentrations in plasma and the interstitial fluid of tissues in trauma and sepsis patients respectively. The results of this study will guide clinicians to effectively dose these antibiotics in order to maximize the concentration of antibiotics in the interstitial fluid of tissues. 相似文献77.
Bakker MF Verstappen SM Welsing PM Jacobs JW Jahangier ZN van der Veen MJ Bijlsma JW Lafeber FP;Utrecht Arthritis Cohort study group 《Arthritis research & therapy》2011,13(3):R70
Introduction
The aim of this study was to investigate whether serum biomarker levels of C2C, C1,2C, CS846, and CPII can predict the long-term course of disease activity and radiographic progression early in the disease course of rheumatoid arthritis (RA). 相似文献78.
Kunte K Shea C Aardema ML Scriber JM Juenger TE Gilbert LE Kronforst MR 《PLoS genetics》2011,7(9):e1002274
Hybrid speciation, or the formation of a daughter species due to interbreeding between two parental species, is a potentially important means of diversification, because it generates new forms from existing variation. However, factors responsible for the origin and maintenance of hybrid species are largely unknown. Here we show that the North American butterfly Papilio appalachiensis is a hybrid species, with genomic admixture from Papilio glaucus and Papilio canadensis. Papilio appalachiensis has a mosaic phenotype, which is hypothesized to be the result of combining sex-linked traits from P. glaucus and P. canadensis. We show that P. appalachiensis' Z-linked genes associated with a cooler thermal habitat were inherited from P. canadensis, whereas its W-linked mimicry and mitochondrial DNA were inherited from P. glaucus. Furthermore, genome-wide AFLP markers showed nearly equal contributions from each parental species in the origin of P. appalachiensis, indicating that it formed from a burst of hybridization between the parental species, with little subsequent backcrossing. However, analyses of genetic differentiation, clustering, and polymorphism based on molecular data also showed that P. appalachiensis is genetically distinct from both parental species. Population genetic simulations revealed P. appalachiensis to be much younger than the parental species, with unidirectional gene flow from P. glaucus and P. canadensis into P. appalachiensis. Finally, phylogenetic analyses, combined with ancestral state reconstruction, showed that the two traits that define P. appalachiensis' mosaic phenotype, obligatory pupal diapause and mimicry, evolved uniquely in P. canadensis and P. glaucus, respectively, and were then recombined through hybridization to form P. appalachiensis. These results suggest that natural selection and sex-linked traits may have played an important role in the origin and maintenance of P. appalachiensis as a hybrid species. In particular, ecological barriers associated with a steep thermal cline appear to maintain the distinct, mosaic genome of P. appalachiensis despite contact and occasional hybridization with both parental species. 相似文献
79.
Documentation of insect diversity is an important component of the study of biodiversity, community dynamics, and global change. Accurate identification of insects usually requires catching individuals for close inspection. However, because insects are so diverse, most trapping methods are specifically tailored to a particular taxonomic group. For scientists interested in the broadest possible spectrum of insect taxa, whether for long term monitoring of an ecosystem or for a species inventory, the use of several different trapping methods is usually necessary. We describe a novel composite method for capturing a diverse spectrum of insect taxa. The Composite Insect Trap incorporates elements from four different existing trapping methods: the cone trap, malaise trap, pan trap, and flight intercept trap. It is affordable, resistant, easy to assemble and disassemble, and collects a wide variety of insect taxa. Here we describe the design, construction, and effectiveness of the Composite Insect Trap tested during a study of insect diversity. The trap catches a broad array of insects and can eliminate the need to use multiple trap types in biodiversity studies. We propose that the Composite Insect Trap is a useful addition to the trapping methods currently available to ecologists and will be extremely effective for monitoring community level dynamics, biodiversity assessment, and conservation and restoration work. In addition, the Composite Insect Trap will be of use to other insect specialists, such as taxonomists, that are interested in describing the insect taxa in a given area. 相似文献
80.