Discovery of GPR183 Agonists Based on an Antagonist Scaffold

The G protein-coupled receptor GPR183/EBI2, which is activated by oxysterols, is a therapeutic target for inflammatory and metabolic diseases where both antagonists and agonists are of potential interest. Using the piperazine diamide core of the known GPR183 antagonist (E)-3-(4-bromophenyl)-1-(4-(4-methoxybenzoyl)piperazin-1-yl)prop-2-en-1-one (NIBR189) as starting point, we identified and sourced 79 structurally related compounds that were commercially available. In vitro screening of this compound collection using a Ca²⁺ mobilization assay resulted in the identification of 10 compounds with agonist properties. To enable establishment of initial structure-activity relationship trends, these were supplemented with five in-house compounds, two of which were also shown to be GPR183 agonists. Taken together, our findings suggest that the agonist activity of this compound series is dictated by the substitution pattern of one of the two distal phenyl rings, which functions as a molecular efficacy-switch.     

Cardiac risk in surgery. A review and guidelines for risk evaluation and reduction of cardiac risk in general surgery

We report herein the phenotypic and functional analysis of human bone marrow and thymus derived early T cells. Commitment to T cell lineage is acquired during CD7 antigen expression by CD34+ precursors in human bone marrow and before thymus colonization. Early thymocytes show similar phenotypic characteristics as bone marrow T cells. They rapidly acquire CD4 before the dual expression of CD4 and CD8. Their expansion and differentiation is regulated by two major factors: thymic stroma and cytokines produced by these stroma cells or by thymocytes themselves. Among cytokines, IL1 and sCD23 produced by thymic epithelial cells support in vitro early T cell development.     

Improving convergence of Iterative Feedback Tuning

Iterative Feedback Tuning constitutes an attractive control loop tuning method for processes in the absence of an accurate process model. It is a purely data driven approach aiming at optimizing the closed loop performance. The standard formulation ensures an unbiased estimate of the loop performance cost function gradient with respect to the control parameters. This gradient is important in a search algorithm. The extension presented in this paper further ensures informative data to improve the convergence properties of the method and hence reduce the total number of required plant experiments especially when tuning for disturbance rejection. Informative data is achieved through application of an external probing signal in the tuning algorithm. The probing signal is designed based on a constrained optimization which utilizes an approximate black box model of the process. This model estimate is further used to guarantee nominal stability and to improve the parameter update using a line search algorithm for determining the iteration step size. The proposed algorithm is compared to the classical formulation in a simulation study of a disturbance rejection problem. This type of problem is notoriously difficult for Iterative Feedback Tuning due to the lack of excitation from the reference.     

Stabilization of pluronic gels in the presence of different polysaccharides

Several different polysaccharides have been added to pluronic F127 (poloxamer 407) gels to test their ability to stabilize the gels against dissolution in aqueous media over time. The studied polysaccharides include κ‐carrageenan, chitosan, hyaluronic acid, pectin, alginate, hydroxyethylcellulose, and ethyl(hydroxyethyl)cellulose. Although all the considered polysaccharides slowed down the dissolution time of the pluronic gels, unmodified polysaccharides only had a modest stabilization effect. However, hydrophobic modification of polysaccharides with a sufficiently long hydrocarbon chain (C₁₆) was found to partly prevent the gels from dissolving for more than 6 months. Shorter hydrocarbon chains did not have the same effect, even at high degrees of hydrophobicity. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40465.     

Microparticles based on hydrophobically modified chitosan as drug carriers

In this work, a hydrophobically modified (HM) chitosan derivative was prepared by covalent linkage of C₁₂ groups to the chitosan backbone. HM‐chitosan microparticles were prepared according to an emulsification‐solvent evaporation method and naltrexone (NTX) was used as a model drug. For comparison, unmodified chitosan and poly lactic‐co‐glycolic acid (PLGA) microparticles were also tested as carriers for NTX. HM‐chitosan formed viscous semi‐dilute solutions, suggesting a high level of chain entanglements and hydrophobic associations. HM‐chitosan microparticles generally showed higher production yield and encapsulation efficiency, as compared with chitosan and PLGA. The burst release shown by chitosan microparticles was significantly reduced when using the HM‐chitosan derivative. An enhanced control of drug release was observed over at least 50 days. PLGA particles demonstrated inferior controlled release properties as compared to HM‐chitosan subsequent to the initial release stage. These results revealed the potential of hydrophobic modification of chitosan as a means to improve the stability and sustained delivery properties of the polymer. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40055.     

The effect of microencapsulated phase change materials on the rheology of geopolymer and Portland cement mortars

The effect of microencapsulated phase-change materials (MPCM) on the rheological properties of pre-set geopolymer and Portland cement mortars was examined. Microcapsules with hydrophilic and hydrophobic shells were compared. The shear rate dependency of the viscosities fitted well to a double Carreau model. The zero shear viscosities are higher for geopolymer mortar, illustrating poorer workability. The time evolution of the viscosities was explored at shear rates of 1 and 10 s⁻¹. New empirical equations were developed to quantify the time-dependent viscosity changes. The highest shear rate disrupted the buildup of the mortar structures much more than the lower shear rate. Microcapsules with a hydrophobic shell affect the rheological properties much less than the microcapsules with a hydrophilic shell, due to the higher water adsorption onto the hydrophilic microcapsules. Shear forces was found to break down the initial structures within geopolymer mortars more easily than for Portland cement mortars, while the geopolymer reaction products are able to withstand shear forces better than Portland cement hydration products. Initially, the viscosity of geopolymer mortars increases relatively slowly during due to formation of geopolymer precursors; at longer times, there is a steeper viscosity rise caused by the development of a 3D-geopolymer network. Disruption of agglomerates causes the viscosities of portland cement mortars to decrease during the first few minutes, after which the hydration process (increasing viscosities) competes with shear-induced disruption of the structures (decreasing viscosities), resulting in a complex viscosity behavior.     

Coffee and cancer risk,epidemiological evidence,and molecular mechanisms

Although early studies suggested that coffee consumption might increase risk of some cancers, more comprehensive epidemiological and experimental data now generally indicate either neutral or beneficial effects. In this review, we summarize the current evidence for associations between breast, prostate, colorectal, and liver cancers and the consumption of coffee, and discuss the experimental evidence for potential chemopreventive mechanisms of coffee and coffee constituents. The epidemiological evidence consistently indicates that coffee protects against liver cancer, and also point toward protective effects for risk of colorectal cancers (with relative risks of 0.50 (95% CI: 0.42–0.59) and 0.83 (95% CI: 0.75–0.92), respectively, in the most recent meta‐analyses). There seems to be no association between the overall risk of breast and prostate cancer and coffee intake. However, for subgroups such as postmenopausal breast cancers, advanced prostate cancers, and breast and prostate cancer survivors, an inverse association with coffee intake is indicated. Potential mechanisms for chemopreventive effects of coffee phytochemicals includes inhibition of oxidative stress and oxidative damage, regulation of DNA repair, phase II enzymatic activity, apoptosis, inflammation, as well as having antiproliferative, antiangiogenetic effects and antimetastatic effects. The experimental evidence for effects of coffee and coffee constituents on each of these processes is discussed.     

Phenolic antioxidants in wood smoke

Ten prominent dimethoxyphenols were determined in birchwood smoke from choked and open laboratory burning and in chimney smoke from a tiled stove. The structures of the methoxyphenols are similar to those of the well-known tocopherol and ubiquinol antioxidants. The 2,6-dimethoxyphenols characterising hardwood smoke are stronger antioxidants than the corresponding 2-methoxyphenols present mainly in softwood smoke. The antioxidant activity is highest for the 2,6-dimethoxyphenols with 4-alkenyl and 4-alkyl groups, which constitute 60-70% of the total amount of dimethoxyphenols. Phenolic antioxidants are scavengers of oxygen radicals and should be considered when health hazards of small-scale incomplete biomass burning are estimated.     

Effect of surfactant concentration, pH, and shear rate on the rheological properties of aqueous systems of a hydrophobically modifed chitosan and its unmodified analogue

Oscillatory shear, shear relaxation and viscosity experiments have been carried out on semidilute solutions of chitosan and on a hydrophobically modified analogue (HM-chitosan) in 1% acetic acid. This was done in the presence of various amounts of cetyltrimethylammonium bromide (CTAB) and at different pH values. All the rheological measurements on the HM-chitosan solutions revealed significant polymer-surfactant interaction and pH effects. The observed rheological effects were least pronounced at pH ≈ 4, while a strong viscoelastic response was found at pH values of 1 and 5 in HM-chitosan solutions of low surfactant concentration. At these conditions, significant shear-thinning effects were observed. In semidilute solutions of unmodified chitosan, the influence of pH, surfactant concentration and shear rate on the rheological properties was moderate or insignificant. Received: 25 September 1996/Revised version: 30 October 1996/Accepted: 4 November 1996     

Real-time medical video processing, enabled by hardware accelerated correlations

Image processing involving correlation based filter algorithms have proved extremely useful for image enhancement, feature extraction and recognition, in a wide range of medical applications, but is almost exclusively used with still images due to the amount of computations required by the correlations. In this paper, we present two different practical methods for applying correlation-based algorithms to real-time video images, using hardware accelerated correlation, as well as our results in applying the method to optical venography. The first method employs a GPU accelerated personal computer, while the second method employs an embedded FPGA. We will discuss major difference between the two approaches, and their suitability for clinical use. The system presented detects blood vessels in human forearms in images from NIR camera setup for the use in a clinical environment.