A Potent Mimetic of the Siglec-8 Ligand 6’-Sulfo-Sialyl Lewisx

Siglecs are members of the immunoglobulin gene family containing sialic acid binding N-terminal domains. Among them, Siglec-8 is expressed on various cell types of the immune system such as eosinophils, mast cells and weakly on basophils. Cross-linking of Siglec-8 with monoclonal antibodies triggers apoptosis in eosinophils and inhibits degranulation of mast cells, making Siglec-8 a promising target for the treatment of eosinophil- and mast cell-associated diseases such as asthma. The tetrasaccharide 6’-sulfo-sialyl Lewis^x has been identified as a specific Siglec-8 ligand in glycan array screening. Here, we describe an extended study enlightening the pharmacophores of 6’-sulfo-sialyl Lewis^x and the successful development of a high-affinity mimetic. Retaining the neuraminic acid core, the introduction of a carbocyclic mimetic of the Gal moiety and a sulfonamide substituent in the 9-position gave a 20-fold improved binding affinity. Finally, the residence time, which usually is the Achilles tendon of carbohydrate/lectin interactions, could be improved.     

环保法规对船舶涂料企业的冲击及应对措施的探讨

随着我国环境保护法规《大气污染防治法》的修订和《涂料征收消费税通知》的公布,探讨了其对船舶涂料企业的冲击及其应对措施。     

Multichromic polymers based on pyrene clicked thienylpyrrole

In this study, the effect of pendant pyrene on the optical and electronic properties of poly(2,5‐dithienylpyrrole)s was studied. For this purpose a new pyrene coupled 2,5‐dithienylpyrrole derivative (SNS‐pyrene) was synthesized through click reaction. SNS‐pyrene was electrochemically polymerized and its electrochemical and optical properties were investigated by electrochemical and optical techniques. The polymer had a band gap of 3.36 eV and displayed light green to blue color variation upon oxidation in less than 2.48 s. Additionally, electrochemical copolymerization of SNS‐pyrene with 3,4‐ethylenedioxythiophene was achieved whilst a detailed investigation was performed on the effect of electrochemical polymerization conditions on the optoelectronic properties of the copolymers. Studies revealed that the copolymers exhibit multichromic reversible redox behavior with lower band gaps and shorter switching times than their parent polymer, P(SNS‐pyrene) © 2014 Society of Chemical Industry.     

Discovery of Affinity-Based Probes for Btk Occupancy Assays

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.     

Application of Vis–NIR hyperspectral imaging in classification between fresh and frozen-thawed pork Longissimus Dorsi muscles

Fresh and frozen-thawed (F-T) pork meats were classified by Vis–NIR hyperspectral imaging. Eight optimal wavelengths (624, 673, 460, 588, 583, 448, 552 and 609 nm) were selected by successive projections algorithm (SPA). The first three principal components (PCs) obtained by principal component analysis (PCA) accounted for over 99.98% of variance. Gray-level-gradient co-occurrence matrix (GLGCM) was applied to extract 45 textural features from the PC images. The correct classification rate (CCR) was employed to evaluate the performance of the partial least squares-discriminate analysis (PLS-DA) models, by using (A) the reflected spectra at full wavelengths and (B) those at the optimal wavelengths, (C) the extracted textures based on the PC images, and (D) the fused variables combining spectra at the optimal wavelengths and textures. The results showed that the best CCR of 97.73% was achieved by applying (D), confirming the high potential of textures for fresh and F-T meat discrimination.     

An iterative method for suboptimal control of linear time-delayed systems

This article presents a new approach for solving the Optimal Control Problem (OCP) of linear time-delay systems with a quadratic cost functional. The proposed method can also be used for designing optimal control time-delay systems with disturbance. In this study, the Variational Iteration Method (VIM) is employed to convert the original Time-Delay Optimal Control Problem (TDOCP) into a sequence of nonhomogeneous linear two-point boundary value problems (TPBVPs). The optimal control law obtained consists of an accurate linear feedback term and a nonlinear compensation term which is the limit of an adjoint vector sequence. The feedback term is determined by solving Riccati matrix differential equation. By using the finite-step iteration of a nonlinear compensation sequence, we can obtain a suboptimal control law. Finally, Illustrative examples are included to demonstrate the validity and applicability of the technique.     

Does decision quality (always) increase with the size of information samples? Some vicissitudes in applying the law of large numbers.

Adaptive decision making requires that contingencies between decision options and their relative assets be assessed accurately and quickly. The present research addresses the challenging notion that contingencies may be more visible from small than from large samples of observations. An algorithmic account for such a seemingly paradoxical effect is offered within a satisficing-choice framework. Accordingly, a choice is only made when the sample contingency describing the relative evaluation of the 2 options exceeds a critical threshold. Small samples, because of the high dispersion of their sampling distribution, facilitate above-threshold contingencies. Across a broad range of parameters, the resulting small-sample advantage in terms of hits is stronger than their disadvantage in false alarms. Computer simulations and experiments support the model predictions. The relative advantage of small samples is most apparent when information loss is low, when the threshold is high relative to the ecological contingency, and when the sampling process is self-truncated. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

重力坝模型的尺寸效应

利用两个不同比尺预制缝重力坝模型的试验成果，以有限元富集技术进行非线性断裂分析，建立了极限承载力和长度比尺的确定性尺寸效应公式。混凝土重力坝的断裂尺寸效应满足指数衰减关系，用三次指数衰减公式可以准确地预测原型的极限承载力。断裂过程区的相对长度是引起模型试验尺寸效应的主要原因。数值计算结果表明，断裂过程区相对长度不仅是与材料有关的参数，能否充分发展还取决于结构尺寸和几何形状；断裂过程区相对长度的尺寸效应不同于统计尺寸效应和断裂参数尺寸效应，具有尺寸范围效应。断裂过程区相对长度在小试件、大试件和相对无穷大试件的发展程度不同。