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.     

Invariant polarimetric contrast parameters of light with Gaussian fluctuations in three dimensions

We propose a rigorous definition of the minimal set of parameters that characterize the difference between two partially polarized states of light whose electric fields vary in three dimensions with Gaussian fluctuations. Although two such states are a priori defined by eighteen parameters, we demonstrate that the performance of processing tasks such as detection, localization, or segmentation of spatial or temporal polarization variations is uniquely determined by three scalar functions of these parameters. These functions define a "polarimetric contrast" that simplifies the analysis and the specification of processing techniques on polarimetric signals and images. This result can also be used to analyze the definition of the degree of polarization of a three-dimensional state of light with Gaussian fluctuations in comparison, with respect to its polarimetric contrast parameters, with a totally depolarized light. We show that these contrast parameters are a simple function of the degrees of polarization previously proposed by Barakat [Opt. Acta 30, 1171 (1983)] and Set?l? et al. [Phys. Rev. Lett. 88, 123902 (2002)]. Finally, we analyze the dimension of the set of contrast parameters in different particular situations.     

Bimodal spatial distribution of macular pigment: evidence of a gender relationship

The spatial distribution of the optical density of the human macular pigment measured by two-wavelength autofluorescence imaging exhibits in over half of the subjects an annulus of higher density superimposed on a central exponential-like distribution. This annulus is located at about 0.7 degrees from the fovea. Women have broader distributions than men, and they are more likely to exhibit this bimodal distribution. Maxwell's spot reported by subjects matches the measured distribution of their pigment. Evidence that the shape of the foveal depression may be gender related leads us to hypothesize that differences in macular pigment distribution are related to anatomical differences in the shape of the foveal depression.     

Characterization of bacteriocins from two Lactococcus lactis subsp. lactis isolates

In this study, bacteriocins from two Lactococcus lactis subsp. lactis isolates from raw milk samples in Turkey designated OC1 and OC2, respectively, were characterized and identified. The activity spectra of the bacteriocins were determined by using different indicator bacteria including Listeria, Bacillus and Staphylococcus spp. Bacteriocins were tested for their sensitivity to different enzymes, heat treatments and pH values. Loss of bacteriocin activities after alpha-amylase treatment suggested that they form aggregates with carbohydrates. Molecular masses of the purified bacteriocins were determined by SDS-PAGE. PCR amplification was carried out with specific primers for the detection of their structural genes. As a result of these studies, the two bacteriocins were characterized as nisin and lacticin 481, respectively. Examination of plasmid contents of the isolates and the results of plasmid curing and conjugation experiments showed that in L. lactis subsp. lactis OC1 strain the 39.7-kb plasmid is responsible for nisin production, lactose fermentation and proteolytic activity, whereas the 16.0-kb plasmid is responsible for lacticin 481 production and lactose fermentation in L. lactis subsp. lactis OC2 strain.     

Combining Fourier transform-ion cyclotron resonance/mass spectrometry analysis and Kendrick plots for silicon speciation and molecular characterization in petroleum products at trace levels

A new method combining FT-ICR/MS analysis and Kendrick plots for the characterization of silicon species at trace levels in light petroleum products is presented. The method provides efficient instrumental detection limits ranging from 80 ng/kg to 5 μg/kg and reliable mass accuracy lower than 0.50 ppm for model silicon molecules in spiked gasoline. More than 3000 peaks could be detected in the m/z 50-500 range depending on the nature of the gasoline sample analyzed. An in-house software program was used to calculate Kendrick plots. Then, an algorithm searched, selected, and represented silicon species classes (O(2)Si, O(3)Si, and O(4)Si classes) in Kendrick plots by incorporating model molecules' information (i.e., exact mass and intensity). This procedure allowed the complete characterization of more than 50 new silicon species with different degrees of unsaturation in petroleum products.     

Fully tunable active polarization imager for contrast enhancement and partial polarimetry

We present the design and the practical implementation of a polarimetric imaging system based on liquid-crystal modulators that allows generation and analysis of any polarization state on the Poincaré sphere. This system is more versatile than standard Mueller imagers that are based on optimized, but limited, sets of illumination and analysis states. Examples of benefits brought by these extra degrees of freedom are illustrated on two different applications: contrast enhancement and extraction of partial polarimetric properties of a scene.     

On the influence of noise statistics on polarimetric contrast optimization

In active scalar polarimetric imaging systems, the illumination and analysis polarization states are degrees of freedom that can be used to maximize the performance. These optimal states depend on the statistics of the noise that perturbs image acquisition. We investigate the problem of optimization of discrimination ability (contrast) of such imagers in the presence of three different types of noise statistics frequently encountered in optical images (Gaussian, Poisson, and Gamma). To compare these different situations within a common theoretical framework, we use the Bhattacharyya distance and the Fisher ratio as measures of contrast. We show that the optimal states depend on a trade-off between the target/background intensity difference and the average intensity in the acquired image, and that this trade-off depends on the noise statistics. On a few examples, we show that the gain in contrast obtained by implementing the states adapted to the noise statistics actually present in the image can be significant.     

Multiband sensor using thick holographic gratings for sulfur detection by laser-induced breakdown spectroscopy

Detection of sulfur by optical emission spectroscopy generally presents some difficulties because the strongest lines are in the vacuum UV below 185 nm and therefore are readily absorbed by oxygen molecules in air. A novel concept for a low-cost and efficient system to detect sulfur using near-IR bands by laser-induced breakdown spectroscopy is here proposed. This concept is based on customized thick holographic gratings as spectral filtering elements. The signal integration and the temporal synchronization are performed using built-in custom electronics that amplify and integrate or trigger photodiode output signals. In this work, we use the near-IR lines at 921.287 nm and a background reference at 900 nm. Preliminary results show a limit of detection comparable to that of a conventional high-end system.     

A two‐and‐a‐half‐dimensional displacement‐based PML for elastodynamic wave propagation

This paper presents a perfectly matched layer (PML) technique for the numerical simulation of three‐dimensional linear elastodynamic problems, where the geometry is invariant in the longitudinal direction. Examples include transportation infrastructure, dams, lifelines, and alluvial valleys. For longitudinally invariant geometries, a computationally efficient two‐and‐a‐half‐dimensional (2.5D) approach can be applied, where the Fourier transform from the longitudinal coordinate to the wavenumber domain allows for the representation of the three‐dimensional radiated wave field on a two‐dimensional mesh. In this 2.5D framework, the equilibrium equations of a PML continuum are formulated in a weak form for an isotropic elastodynamic medium and discretized using a Galerkin approach. The 2.5D PML methodology is validated by computing the Green's displacements of a homogeneous halfspace, demonstrating that the 2.5D PML absorbs all propagating waves for different angles of incidence. Furthermore, the dynamic stiffness of a rigid strip foundation and the efficiency of a vibration isolating screen are computed. The examples demonstrate that the PML methodology is computationally efficient, especially when only the response of the structure or the near field response is of interest.Copyright © 2011 John Wiley & Sons, Ltd.     

Poly(hydroxyethyl methacrylate) based magnetic nanoparticles for plasmid DNA purification from Escherichia coli lysate

The aim of this study is to prepare poly(hydroxyethyl methacrylate-N-methacryloyl-(L)-histidine) [PHEMAH] magnetic nanoparticles for plasmid DNA (pDNA) purification from Escherichia coli (E. coli) cell lysate. Magnetic nanoparticles were produced by surfactant free emulsion polymerization. mPHEMAH nanoparticles were characterized by elemental analysis, Fourier transform infrared spectroscopy (FTIR), atomic force microscopy (AFM), vibrating sample magnetometer (VSM), electron spin resonance (ESR), thermogravimetric analyses (TGA) and transmission electron microscopy (TEM). Surface area, average particle size and size distribution were also performed. Specific surface area of the mPHEMAH nanoparticles was found to be 1180 m²/g. Elemental analysis of MAH for nitrogen was estimated as 0.18 mmol/g polymer. The amount of pDNA adsorbed onto the mPHEMAH nanoparticles first increased and then reached a saturation value at around 1.0 mg/mL of pDNA concentration. Compared with the mPHEMA nanoparticles (50 μg/g polymer), the pDNA adsorption capacity of the mPHEMAH nanoparticles (154 mg/g polymer) was improved significantly due to the MAH incorporation into the polymeric matrix. The maximum pDNA adsorption was achieved at 25 °C. The overall recovery of pDNA was calculated as 92%. The mPHEMAH nanoparticles could be used six times without decreasing the pDNA adsorption capacity significantly. The results indicate that the PHEMAH nanoparticles promise high selectivity for pDNA.