Effect of nitrogen on the antibacterial behavior of oxynitride glasses

The main drawback of bioglasses is their restricted use in load bearing applications and the consequent need to develop stronger glassy materials. This has led to the consideration of oxynitride glasses for numerous biomedical applications. This paper investigated two different types of glasses at a constant cationic ratio, with and without nitrogen (a N containing and a N-free glass composition) to better understand the effect of N on the biological properties of glasses. The results revealed that the addition of N increased the glass transition temperature, isoelectric point (IEP) and slightly increased wettability. Moreover, compared to N including glass, N-free glass exhibited better anti-bacterial activity against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus), two key bacteria that infect implants. In summary, these in vitro results indicated that amine functional groups existing in N containing glasses which are missing in N-free glasses, caused a slight difference in wetting behavior and a more obvious change in isoelectric point and in bacterial response. N-free glasses exhibited better inhibitory results both against E. coli and S. aureus compared to N including glass suggesting that oxygen rich glasses should be further studied for their novel antibacterial properties.     

In Vivo Albumin-Binding of a C-Functionalized Cyclam Platform for 64Cu-PET/CT Imaging in Breast Cancer Model

An improved glucose-chelator-albumin bioconjugate (GluCAB) derivative, GluCAB-2^Mal, has been synthesized and studied for in vivo ⁶⁴Cu-PET/CT imaging in breast cancer mice models together with its first-generation analogue GluCAB-1^Mal. The radioligand works on the principle of tumor targeting through the enhanced permeability and retention (EPR) effect with a supportive role played by glucose metabolism. [⁶⁴Cu]Cu-GluCAB-2^Mal (99 % RCP) exhibited high serum stability with immediate binding to serum proteins. In vivo experiments for comparison between tumor targeting of [⁶⁴Cu]Cu-GluCAB-2^Mal and previous-generation [⁶⁴Cu]Cu-GluCAB-1^Mal encompassed microPET/CT imaging and biodistribution analysis in an allograft E0771 breast cancer mouse model. Tumor uptake of [⁶⁴Cu]Cu-GluCAB-2^Mal was clearly evident with twice as much accumulation as compared to its predecessor and a tumor/muscle ratio of up to 5 after 24 h. Further comparison indicated a decrease in liver accumulation for [⁶⁴Cu]Cu-Glu-CAB-2^Mal.     

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.     

Ratiometric Detection of Glutathione Based on Disulfide Linkage Rupture between a FRET Coumarin Donor and a Rhodamine Acceptor

Abnormal levels of glutathione, a cellular antioxidant, can lead to a variety of diseases. We have constructed a near-infrared ratiometric fluorescent probe to detect glutathione concentrations in biological samples. The probe consists of a coumarin donor, which is connected through a disulfide-tethered linker to a rhodamine acceptor. Under the excitation of the coumarin donor at 405 nm, the probe shows weak visible fluorescence of the coumarin donor at 470 nm and strong near-infrared fluorescence of the rhodamine acceptor at 652 nm due to efficient Forster resonance energy transfer (FRET) from the donor to the acceptor. Glutathione breaks the disulfide bond through reduction, which results in a dramatic increase in coumarin fluorescence and a corresponding decrease in rhodamine fluorescence. The probe possesses excellent cell permeability, biocompatibility, and good ratiometric fluorescence responses to glutathione and cysteine with a self-calibration capability. The probe was utilized to ratiometrically visualize glutathione concentration alterations in HeLa cells and Drosophila melanogaster larvae.     

An integrated dimensionality reduction and surrogate optimization approach for plant-wide chemical process operation

With liquefied natural gas becoming increasingly prevalent as a flexible source of energy, the design and optimization of industrial refrigeration cycles becomes even more important. In this article, we propose an integrated surrogate modeling and optimization framework to model and optimize the complex CryoMan Cascade refrigeration cycle. Dimensionality reduction techniques are used to reduce the large number of process decision variables which are subsequently supplied to an array of Gaussian processes, modeling both the process objective as well as feasibility constraints. Through iterative resampling of the rigorous model, this data-driven surrogate is continually refined and subsequently optimized. This approach was not only able to improve on the results of directly optimizing the process flow sheet but also located the set of optimal operating conditions in only 2 h as opposed to the original 3 weeks, facilitating its use in the operational optimization and enhanced process design of large-scale industrial chemical systems.     

Improving through-thickness conductivity of carbon fiber reinforced polymer using carbon nanotube/polyethylenimine at the interlaminar region

The through-thickness conductivity of carbon fiber reinforced polymer (CFRP) composite was increased by incorporating multiwalled carbon nanotubes in the interlaminar region. Carbon nanotubes (CNTs) were dispersed in a polyethylenimine (PEI) binder, which was then coated onto the carbon fiber fabric. Standard vacuum-assisted resin infusion process was applied to fabricate the composite laminates. This modification technique aims to enhance the electrical conductivity in through-thickness direction for the purpose of nondestructive testing, damage detection, and electromagnetic interference shielding. CNT concentrations ranging from 0 to 0.75 wt% were used and compared to pristine CFRP samples (reference). The through-thickness conductivity of the CFRP exhibited an improvement of up to 781% by adopting this technique. However, the dispersion of CNT in PEI led to a viscosity increase and poor wetting properties which resulted in the formation of voids/defects, poor adhesion (as shown in scanning electron micrographs) and the deterioration of the mechanical properties as manifested by interlaminar shear strength and dynamic mechanical analysis measurements.     

Development of a difunctional oxirane and multifunctional acrylate interpenetrating polymer network composite system with antimicrobial properties

This research continued the development of a difunctional Oxirane and multifunctional Acrylate interpenetrating polymer network composite System (OASys) with antimicrobial properties. The effects of 4-Isopropyl-4′-methyldiphenyliodonium tetrakis (pentafluorophenyl) borate (Borate), hexamethylene diamine (HMDA) and N,N-dimethyl p-toluidine (DMPT) on OASys (Epalloy 5001:dipentaerythritol hexaacrylate) composite hardness, contact angle, monomer-to-polymer degree of conversion (DoC), mechanical properties, polymerization shrinkage, shrinkage stress, and antimicrobial properties were determined. Bis-GMA:TEGDMA composites were used as the control. OASys composites with 9 wt% Borate and 0.5 wt% DMPT or 1.5 wt% HMDA had comparable hardness, DoC's and polymerization shrinkages to controls, but had lower contact angles and mechanical properties. Additionally, OASys composites with 1.5 wt% HMDA had significantly less polymerization stress than controls and demonstrated significant antibacterial activity against Streptococcus mutans and Lactobacillus casei out to 3 months. With lower shrinkage stress and long-term antimicrobial activity, OASys composites look promising for increasing the clinical lifetime of dental composites, but improvements in mechanical properties are needed.     

Functional Coupling of Slack Channels and P2X3 Receptors Contributes to Neuropathic Pain Processing

The sodium-activated potassium channel Slack (K_Na1.1, Slo2.2, or Kcnt1) is highly expressed in populations of sensory neurons, where it mediates the sodium-activated potassium current (I_KNa) and modulates neuronal activity. Previous studies suggest that Slack is involved in the processing of neuropathic pain. However, mechanisms underlying the regulation of Slack activity in this context are poorly understood. Using whole-cell patch-clamp recordings we found that Slack-mediated I_KNa in sensory neurons of mice is reduced after peripheral nerve injury, thereby contributing to neuropathic pain hypersensitivity. Interestingly, Slack is closely associated with ATP-sensitive P2X3 receptors in a population of sensory neurons. In vitro experiments revealed that Slack-mediated I_KNa may be bidirectionally modulated in response to P2X3 activation. Moreover, mice lacking Slack show altered nocifensive responses to P2X3 stimulation. Our study identifies P2X3/Slack signaling as a mechanism contributing to hypersensitivity after peripheral nerve injury and proposes a potential novel strategy for treatment of neuropathic pain.