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.     

Effects of feed composition,protein denaturation and storage of milk serum protein/lactose powders on lactosylation

During whey powder production, the feed is subjected to several heat treatments which can cause lactosylation of proteins. In this study, lactosylation of whey proteins was evaluated in spray-dried powders before and after storage by varying the native protein fraction as well as the serum protein/lactose ratio in the powders. The lactosylation of native α-lactalbumin and β-lactoglobulin in the powders before storage was not affected to a large extent by the protein denaturation or if the feed had been heat treated in a high or low lactose environment. After storage (relative humidity of 23.5%, 30 °C, 25 days), the kinetic of lactosylation tended to increase with increasing native protein fraction and bulk protein content in the powders. An explanation could be that proteins dissolved in the lactose glassy structure might have a lower reactivity, while proteins present in the protein glassy structure with dissolved lactose may display higher lactosylation reactivity.     

A numerical model to predict the powder–binder separation during micro-powder injection molding

The micro-powder injection molding (micro-PIM) process has the potential to bridge the gap between the design and manufacturing of micro-components that are often used in small and handy devices. Numerical modeling helps to analyze and overcome various difficulties of micro-PIM. In the present work, a numerical model is developed to predict the powder–binder separation (a common defect in PIM and especially severe in micro-PIM) during the injection of an alumina feedstock. A powder–binder separation criterion is proposed dealing with applied injection pressure and friction force between the powder and binder. An indirect comparison of feedstock travel time between two locations is used to validate the model. The predicted segregation from the simulated result is supported by a qualitative experimental measurement. The developed model can be used to optimize injection parameters to get a defect-free product.     

In situ observation of synthesized nanoparticles in ultra-dilute aerosols via X-ray scattering

In-air epitaxy of nanostructures (Aerotaxy) has recently emerged as a viable route for fast, large-scale production. In this study, we use small-angle X-ray scattering to perform direct in-flight characterizations of the first step of this process, i.e., the engineered formation of Au and Pt aerosol nanoparticles by spark generation in a flow of N₂ gas. This represents a particular challenge for characterization because the particle density can be extremely low in controlled production. The particles produced are examined during production at operational pressures close to atmospheric conditions and exhibit a lognormal size distribution ranging from 5–100 nm. The Au and Pt particle production and detection are compared. We observe and characterize the nanoparticles at different stages of synthesis and extract the corresponding dominant physical properties, including the average particle diameter and sphericity, as influenced by particle sintering and the presence of aggregates. We observe highly sorted and sintered spherical Au nanoparticles at ultra-dilute concentrations (< 5 × 10⁵ particles/cm³) corresponding to a volume fraction below 3 × 10^–10, which is orders of magnitude below that of previously measured aerosols. We independently confirm an average particle radius of 25 nm via Guinier and Kratky plot analysis. Our study indicates that with high-intensity synchrotron beams and careful consideration of background removal, size and shape information can be obtained for extremely low particle concentrations with industrially relevant narrow size distributions.

     

Influence of temperature cycling and pore fluid on tensile strength of chalk

Calcite has a highly anisotropic thermal expansion coefficient, and repeated heating and cooling cycles can potentially destabilize chalks by breaking cement bonds between neighboring particles. Based on tensile strength measurements, we investigated how temperature cycles induce weakening of chalk. Tensile strength tests were performed on chalk specimens sampled from Kansas (USA) and Mons (Belgium), each with differing amounts of contact cement. Samples of the two chalk types were tested in dry and water-saturated states, and then exposed to 0, 15, and 30 temperature cycles in order to find out under what circumstances thermally induced tensile strength reduction occurs. The testing results show that the dry samples were not influenced by temperature cycling in either of the chalk types. However, in the water-saturated state, tensile strength is increasingly reduced with progressive numbers of temperature cycles for both chalk samples, especially for the more cemented Kansas chalk. The Kansas chalk demonstrated higher initial tensile strength compared to the less cemented Mons chalk, but the strength of both chalks was reduced by the same relative proportion when undergoing thermal cycles in the water-saturated state.     

Influence of Different Additives on the Interaction of Quinolone Antibiotic Drug with Surfactant: Conductivity and Cloud Point Measurement Study

Conductometric and cloud point (CP) measurement studies have been performed to investigate the interaction of tetradecyltrimethylammonium bromide (TTAB) and Triton® X-100 (TX-100) with ciprofloxacin hydrochloride (CFH) in different solvents over the temperature range of 295.15–315.15 K. CFH is used for the treatment of various bacterial infections. The observed critical micelle concentration (CMC) values of TTAB were found to be reduced in the presence of electrolytes (Na₂SO₄/Na₃PO₄), and this reduction proceeds with the elevation of salt concentration. The order of the CMC of TTAB follows the trend: > >. The observed CMC values of TTAB were found to increase with increasing temperature and decrease with increasing concentration of CFH in aqueous medium. The values of Gibbs free energy of micellization () for the TTAB/TTAB + CFH mixture were found to be negative, implying spontaneous micellization. The estimated CP of TX-100 decreases with increasing concentration of TX-100 in aqueous medium. The CP values first decrease with increasing concentration of CFH and then increase at higher concentration of CFH almost in all cases investigated. The values of free energy of clouding were found to be positive in all cases studied implying that phase separation of TX-100 was nonspontaneous. The other thermodynamic parameters associated with the micellization of TTAB and the phase separation of TX-100 were estimated and explained.     

Development and in vivo response of hydroxyapatite/whitlockite from chicken bones as bone substitute using a chitosan membrane for guided bone regeneration

Biomaterials that meet the requirements to stimulate bone tissue formation play a vital role in orthopedics and dentistry. In this work, chitosan and a biphasic, non-cytotoxic material hydroxyapatite/whitlockite were obtained from natural sources, which are available as organic waste. The osteogenic activity was assessed using a rabbit model animal with a chitosan barrier membrane in combination with a bone-filling graft substitute composed of hydroxyapatite/whitlockite. FT-IR results showed the typical absorption bands of the chitosan and hydroxyapatite. Moreover, the X-ray diffraction pattern revealed a typical hexagonal phase of hydroxyapatite and rhombohedral structures related to whitlockite. Masson's trichrome stain showed an early formation of extracellular matrix mineralized, in accord with the surface morphology of a cortical mature bond observed by Scanning Electron Microscopy. The immunocytochemistry results showed a significant increase of positive immunoreactive cells to osteonectin in the treated defects in comparison with the control defects 6 and 8 weeks postoperatively. Overall, the results confirm that the use of this low-cost and versatile biomaterial as a barrier membrane and a bone substitute graft are useful for bone tissue engineering.     

Minimization of the Theoretical Error of Input Parameters for a Vapor Permeation Apparatus

All input experimental errors for membrane flux determination were analyzed. The overall error in pressure did not largely influence the determination of membrane flux. The main contribution to errors was ascribed to flow meters and membrane thickness. The choice of an optimal operational range for input parameters led to elimination of at least 2/3 of the theoretical relative error for subsequent evaluation of the permeability of individual species. This is especially valuable for low‐permeable membranes, whereas a very low relative theoretical error can be obtained in the case of highly permeable materials.     

Phase Field Modelling Allotropic Transformation of Solid Solution

Based on multiphase field conception and integrated with the idea of vectorvalued phase field, a phase field model for typical allotropic transformation of solid solution is proposed. The model takes the non-uniform distribution of grain boundaries of parent phase and crystal orientation into account in proper way, as being illustrated by the simulation of austenite to ferrite transformation in low carbon steel. It is found that the misorientation dependent grain boundary mobility shows strong influence on the formation of ferrite morphology comparing with the weak effect exerted by misorientation dependent grain boundary energy. The evolution of various types of grain boundaries are quantitatively characterized in terms of its respective grain boundary energy dissipation. The simulated ferrite fraction agrees well with the expectation from phase diagram, which verifies this model.