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1.
Bruton's tyrosine kinase (Btk) is an attractive target for the treatment of a wide array of B-cell malignancies and autoimmune diseases. Small-molecule covalent irreversible Btk inhibitors targeting Cys481 have been developed for the treatment of such diseases. In clinical trials, probe molecules are required in occupancy studies to measure the level of engagement of the protein by these covalent irreversible inhibitors. The result of this pharmacodynamic (PD) activity provides guidance for appropriate dosage selection to optimize inhibition of the drug target and correlation of target inhibition with disease treatment efficacy. This information is crucial for successful evaluation of drug candidates in clinical trials. Based on the pyridine carboxamide scaffold of a novel solvent-accessible pocket (SAP) series of covalent irreversible Btk inhibitors, we successfully developed a potent and selective affinity-based biotinylated probe 12 (2-[(4-{4-[5-(1-{5-[(3aS,4S,6aR)-2-oxo-hexahydro-1H-thieno[3,4-d]imidazol-4-yl]pentanamido}-3,6,9,12-tetraoxapentadecan-15-amido)pentanoyl]piperazine-1-carbonyl}phenyl)amino]-6-[1-(prop-2-enoyl)piperidin-4-yl]pyridine-3-carboxamide). Compound 12 has been used in Btk occupancy assays for preclinical studies to determine the therapeutic efficacy of Btk inhibition in two mouse lupus models driven by TLR7 activation and type I interferon.  相似文献   
2.
The optical properties of gold nanoparticles have been known for a number of years and recent advances in laser power have now allowed the non-linear optical properties to be studied. In this short review paper, the various theories that have been used to describe the optical properties of gold nanoparticles are presented. Methods of preparing gold nanoparticles in glasses are explained briefly, as well as characterization techniques. The optical properties of gold nanoparticles are reviewed, as well as the effects of particle size, shape, concentration and c.  相似文献   
3.
α-BaO.Al2O3.4H2O has been synthesised and studied by infrared, X-ray and thermal analytical techniques. The compound of approximate formula BaO.Al2O3.0.5H2O, described in Part III, forms as a dehydration product, and appears to be identical with the compound β-BAH2 described by other workers. A possible explanation for the discrepancy in water content is discussed.  相似文献   
4.
31P Nuclear magnetic resonance (NMR) spectra of human erythrocyte lysates dissolved in sodium cholate were acquired. The narrow resonances of phospholipids were mostly well resolved, allowing identification and accurate quantitative analysis of phospholipid classes of the erythrocyte membranes. The ether-linked phosphatidylethanolamine components of the erythrocyte membranes were identified, based on the removal of plasmalogens by acidolysis and of diacyl phospholipid species by degradation using phospholipase A1. It was also shown that the introduction of double bonds on the acyl chains of phosphatidylcholine shifted the31P NMR resonances to lower frequencies. Quantitative analyses of phospholipids from the spectra were based on their apparent molar concentrations. The recoveries of phospholipids from erythrocytes were significantly higher than those using conventional extraction procedures.  相似文献   
5.
The effect of trap design, trap color, and a mixture of isothiocyanates on the capture of Ceutorhynchus assimilis (Paykull) was studied in a series of field experiments. Unbaited yellow water traps, a yellow sticky box trap, and a yellow sticky card trap, mounted vertically, or at 45° to the vertical with the yellow card facing upwards were effective for capturing seed weevils, but a horizontal yellow sticky card trap caught few. White, green, and black traps were unattractive. During migratory periods, trap catch could be enhanced two to four times with a lure consisting of a mixture of allyl, 3-butenyl, 4-pentenyl, and 2-phenylethyl isothiocyanates, but this bait did not attract in a trap with ineffective design. The sticky card trap, mounted at 45° to the vertical and baited with the isothiocyanate mixture, may be useful for monitoring movement of C. assimilis during migratory periods. However, during the colonization phase, lures of either a mixture of isothiocyanates or of allyl isothiocyanate alone were not attractive.  相似文献   
6.
Purified Brassica napus enoyl acyl carrier protein reductase (ENR) was used to select specific antibodies from a library of antibody fragments, single-chain Fv (scFv), displayed on filamentous phage. Analysis of the selected clones by BstNl fingerprinting and nucleotide sequencing showed that the scFv were derived from three different human VH germline genes. The binding specificities were confirmed by Western blots and ELISA. The scFv preparations reacted with B. napus ENR, but not with β-keto reductase, nor enoyl reductase from Escherichia coli. Analysis of fragments generated by CNBr treatment indicates that the scFv 3.13 recognizes an epitope located within the n-terminal 80 amino acids of the enzyme molecule. The scFv were used to detect ENR directly in extracts of B. napus seeds.  相似文献   
7.
Prior research has shown that people are likely to skim information presented digitally with the resultant deleterious effect on accurate mental models of the text. Teaching monitoring strategies and presenting text with adjunct questions are effective strategies for improving the mental models of readers of scientific text, but the two strategies have not been directly compared for studying text read from a computer screen. In the present study, participants were individually tested in two experiments in which they studied computer-based text on the heart and circulatory system while either reading the text with no interruption, answering adjunct inference questions, answering adjunct factual questions, or answering prompts for global or specific monitoring. Reading time was untimed but looking back was not available. Prompting for global monitoring was most effective for improvement of mental models as measured by scores in diagram drawing, concept map construction, factual memory, and generating inferences. Further, global monitoring did not require more time-on-task than the other methods.  相似文献   
8.
9.
Self‐assembling peptide amphiphiles (PAs) can form hierarchically ordered membranes when brought in contact with aqueous polyelectrolytes of the opposite charge by rapidly creating a diffusion barrier composed of filamentous nanostructures parallel to the plane of the incipient membrane. Following this event, osmotic forces and charge complexation template nanofiber growth perpendicular to the plane of the membrane in a dynamic self‐assembly process. In this work, we show that this hierarchical structure requires massive interfacial aggregation of PA molecules, suggesting the importance of rapid diffusion barrier formation. Strong PA aggregation is induced here through the use of heparin‐binding PAs with heparin and also with polyelectrolytes of varying charge density. Small angle X‐ray scattering shows that in the case of weak PA‐polyelectrolyte interaction, membranes formed display a cubic phase ordering on the nanoscale that likely results from clusters of PA nanostructures surrounded by polyelectrolyte chains.  相似文献   
10.
Native tissues are typically heterogeneous and hierarchically organized, and generating scaffolds that can mimic these properties is critical for tissue engineering applications. By uniquely combining controlled radical polymerization (CRP), end‐functionalization of polymers, and advanced electrospinning techniques, a modular and versatile approach is introduced to generate scaffolds with spatially organized functionality. Poly‐ε‐caprolactone is end functionalized with either a polymerization‐initiating group or a cell‐binding peptide motif cyclic Arg‐Gly‐Asp‐Ser (cRGDS), and are each sequentially electrospun to produce zonally discrete bilayers within a continuous fiber scaffold. The polymerization‐initiating group is then used to graft an antifouling polymer bottlebrush based on poly(ethylene glycol) from the fiber surface using CRP exclusively within one bilayer of the scaffold. The ability to include additional multifunctionality during CRP is showcased by integrating a biotinylated monomer unit into the polymerization step allowing postmodification of the scaffold with streptavidin‐coupled moieties. These combined processing techniques result in an effective bilayered and dual‐functionality scaffold with a cell‐adhesive surface and an opposing antifouling non‐cell‐adhesive surface in zonally specific regions across the thickness of the scaffold, demonstrated through fluorescent labelling and cell adhesion studies. This modular and versatile approach combines strategies to produce scaffolds with tailorable properties for many applications in tissue engineering and regenerative medicine.  相似文献   
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