Bisubstrate inhibitors of catechol O-methyltransferase (COMT): the crucial role of the ribose structural unit for inhibitor binding affinity

Inhibition of the enzyme catechol O-methyltransferase offers a therapeutic handle to regulate the catabolism of catecholamine neurotransmitters, providing valuable assistance in the treatment of CNS disorders such as Parkinson's disease. A series of ribose-modified bisubstrate inhibitors of COMT featuring 2'-deoxy-, 3'-deoxy-, 2'-aminodeoxy-3'-deoxy-, and 2'-deoxy-3'-aminodeoxyribose-derived central moieties and analogues containing the carbocyclic skeleton of the natural product aristeromycin were synthesized and evaluated to investigate the molecular recognition properties of the ribose binding site in the enzyme. Key synthetic intermediates in the ribose-derived series were obtained by deoxygenative [1,2]-hydride shift rearrangement of adenosine derivatives; highlights in the synthesis of carbocyclic aristeromycin analogues include a diastereoselective cyclopropanation step and nucleobase introduction with a modified Mitsunobu protocol. In vitro biological evaluation and kinetic studies revealed dramatic effects of the ribose modification on binding affinity: 3'-deoxygenation of the ribose gave potent inhibitors (IC50 values in the nanomolar range), which stands in sharp contrast to the remarkable decrease in potency observed for 2'-deoxy derivatives (IC50 values in the micromolar range). Aminodeoxy analogues were only weakly active, whereas the change of the tetrahydrofuran skeleton to a carbocycle unexpectedly led to a complete loss of biological activity. These results confirm that the ribose structural unit of the bisubstrate inhibitors of COMT is a key element of molecular recognition and that modifications thereof are delicate and may lead to surprises.     

基于PLC的流量比值控制系统设计

本文主要介绍了一种用于化工领域的流量比值控制系统。以三菱PLC为控制中心,结合传感器、流量计等设备,组成流量比值控制系统,以氯化钾和硫酸制造硫酸钾工艺为例介绍此控制系统在化工领域的应用。控制系统根据氯化钾流量控制硫酸的流量,满足了工艺要求,实际应用表明该系统具有较高的控制精度和稳定性。     

Time-resolved fluorescence polarization dynamics and optical imaging of Cytate: a prostate cancer receptor-targeted contrast agent

Cypate-octreote peptide analogue conjugate (Cytate) was investigated as a prostate cancer receptor-targeted contrast agent. The absorption and fluorescence spectra of Cytate were ranged in the near-infrared "tissue optical window." Time-resolved investigation of polarization-dependent fluorescence emitted from Cytate in solution as well as in cancerous and normal prostate tissues was conducted. Polarization preservation characteristics of Cytate in solution and tissues were studied. Fluorescence intensity emitted from the Cytate-stained cancerous prostate tissue was found to be much stronger than that from the Cytate-stained normal prostate tissue, indicating more Cytate uptake in the former tissue type. The polarization anisotropy of Cytate contained in cancerous prostate tissue was found to be larger than that in the normal prostate tissue, indicating a larger degree of polarization preservation in Cytate-stained cancerous tissue. The temporal profiles of fluorescence from Cytate solution and from Cytate-stained prostate tissue were fitted using a time-dependent fluorescence depolarization model. The photoluminescence imaging of Cytate-stained cancerous and normal prostate tissues was accomplished, showing the potential of Cytate as a fluorescence marker for prostate cancer detection.     

Multi-functional chitosan nanoparticles encapsulating quantum dots and Gd-DTPA as imaging probes for bio-applications

Chitosan was used to encapsulate both CdSe/ZnS quantum dots (QDs) and the magnetic resonance imaging (MRI) contrast agent gadolinium-diethylenetriaminepentaacetate (Gd-DTPA), forming multi-functional nanoparticles that can be used in a wide range of in vitro or in vivo studies as fluorescent biological labels as well as MRI contrast agents, respectively. Multi-color QDs at pre-determined molar ratios were encapsulated into chitosan nanoparticles to produce bar-coding fluorescent labels. The encapsulated QDs and Gd-DTPA still maintained their desirable optical properties and relatively high relaxivity, respectively. The chitosan nanoparticles also showed good aqueous stability and enhanced biocompatibility on myoblast cells.     

Laser interference pattern ablation of a carbon fiber microelectrode: biosensor signal enhancement after enzyme attachment

Fluorescence microscopy was used to visualize the accumulated fluorescent product of the enzyme alkaline phosphatase to indicate where active covalently bound enzyme remained on the surface after application of a Nd: YAG laser interference pattern to a surface that was first globally derivatized with the covalently bound enzyme. The electrochemical kinetics of the same carbon fiber surface were examined through the electrogenerated chemiluminescence of Ru(bpy)(3)2+ to determine that electron-transfer sites were indeed segregated from the enzyme-binding sites. The enzyme-derivatized areas are determined to be separate and distinct from the areas of enhanced electron transfer. Two other enzymes, glucose oxidase and malic dehydrogenase, were then covalently bound to carbon fiber microelectrode surfaces in order to verify the change in detection limit of their respective cofactors, NADH or H2O2, under a variety of surface conditions. The S/N of an enzyme-modified electrode after laser interference pattern photoablation and electrocatalytic treatment is improved by more than 1 order of magnitude over that observed at an electrode that is globally enzyme modified.     

Collection of fluorescence from single molecules in microspheres: effects of illumination geometry

The collection of fluorescence from a molecule inside a sphere illuminated with single or counterpropagating plane waves is modeled. The results are applicable to microdroplet-based single molecule detection techniques and to some microparticle characterization techniques using inelastic emission. The large position-dependent variations in the fluorescence collection rate are primarily attributable to variations in the excitation intensity. With plane-wave illumination the collection from shadow regions is low because the incident energy is refracted by the droplet surface away from these regions. The average collection rate from molecules in shadow regions can be increased by illuminating with counterpropagating beams.     

Preparation of self-assembled zinc oxide nanoparticles multilayer films under ultrasonic irradiation

Zinc oxide nanoparticles were synthesized and self-assembled on the reactive surface of a glass slide functionalized with (3-mercaptopropyl)-trimethoxysilane under ultrasonic irradiation. The structure, morphology, and optical property of the zinc oxide nanoparticles were investigated by TEM, XRD, and UV-vis spectroscopy. The functionalized glass slide was soaked in an aqueous solution which dispersed zinc oxide nanoparticles under ultrasonic irradiation. Zinc oxide multilayer films grew up to several layers (up to 5 layers) depending on the immersion time. The self-assembled zinc oxide nanoparticles multilayer films were characterized using UV-vis spectroscopy and SEM. Ultrasonic irradiation was an efficient method to make multilayer films on the functionalized glass slide with zinc oxide nanoparticles.     

Automatic target recognition employing signal compression

Quadratic correlation filters (QCFs) have been used successfully to detect and recognize targets embedded in background clutter. Recently, a QCF called the Rayleigh quotient quadratic correlation filter (RQQCF) was formulated for automatic target recognition (ATR) in IR imagery. Using training images from target and clutter classes, the RQQCF explicitly maximized a class separation metric. What we believe to be a novel approach is presented for ATR that synthesizes the RQQCF using compressed images. The proposed approach considerably reduces the computational complexity and storage requirements while retaining the high recognition accuracy of the original RQQCF technique. The advantages of the proposed scheme are illustrated using sample results obtained from experiments on IR imagery.