Regulation of immune cell function and differentiation by the NKG2D receptor

NKG2D is one of the most intensively studied immune receptors of the past decade. Its unique binding and signaling properties, expression pattern, and functions have been attracting much interest within the field due to its potent antiviral and anti-tumor properties. As an activating receptor, NKG2D is expressed on cells of the innate and adaptive immune system. It recognizes stress-induced MHC class I-like ligands and acts as a molecular sensor for cells jeopardized by viral infections or DNA damage. Although the activating functions of NKG2D have been well documented, recent analysis of NKG2D-deficient mice suggests that this receptor may have a regulatory role during NK cell development. In this review, we will revisit known aspects of NKG2D functions and present new insights in the proposed influence of this molecule on hematopoietic differentiation

Boosting drug bioavailability in men but not women through the action of an excipient

Active pharmaceutical ingredients are routinely formulated with a range of excipients in the manufacture of drug products. Excipients are considered to be inert components of the formulations, although recent research has contested its inactive behaviour. This study investigated the effect of the excipient polyethylene glycol 400 (PEG 400) on the oral bioavailability and intestinal permeability of cimetidine in male and female human volunteers. Aqueous solutions of cimetidine with pharmaceutically relevant concentrations of PEG 400 at 0% w/v (control), 0.3% w/v, 0.5% w/v, 0.7% w/v and 1.0% w/v were orally administered to both sexes. Urine samples were then collected and assayed for the determination of cimetidine which reflected oral bioavailability. This human study showed that PEG 400 at 0.3% w/v, 0.5% w/v and 0.7% w/v concentrations significantly increased cimetidine bioavailability by 34%, 58% and 41% respectively, although this enhancement was only demonstrated in men and not women (p  0.05). We have shown that PEG 400 interacts with intestinal P-glycoprotein (P-gp) expression differently in males and females. The mechanistic action of PEG 400 at gut level was further investigated on human jejunal tissues following the pre-treatment of the P-gp inhibitor PSC 833 (valspodar) on the transport of cimetidine. When intestinal P-gp was inhibited, the sex- and dose-dependent modulatory effect of PEG 400 with cimetidine was completely eradicated, thus confirming that PEG 400 has a modulatory - rather than inhibitory - effect on P-gp. In sum, the widely used excipient PEG 400 is not inert at pharmaceutically relevant concentrations and its modulatory effect is demonstrated at a human clinical level. Such pharmacological effects, however, are sex- and dose-dependent via its modulation on intestinal P-gp, as evidenced by the boost in cimetidine bioavailability only in male human volunteers. As such, these findings should be carefully considered towards the co-formulation of PEG 400 with drugs that are P-gp substrates

Analytical study of silane-based and wax-based additives on the interfacial bonding characteristics between natural rubber modified binder and different aggregate types

The modification of asphalt binder with natural rubber latex (NR) significantly improves the rutting and fatigue resistance of asphalt mixtures. However, NR-modified binder is prone to low workability and wettability due to its high viscosity. Therefore, this research focuses on examining the influences of silane and wax-based additives on the wettability of natural rubber-modified binders and the binder-aggregates adhesion performances. In this study, experimental and analytical approaches were used. The contact angles of asphalt binder were measured using a goniometer through the sessile drop method with three solvents: deionised water, formamide, and glycerol. The C++ algorithm was adopted to compute the surface free energy (SFE) elements of the asphalt binder. Analytical methods were employed to analyse the results based on the Young-Dupre equation, followed by linear regression to establish a correlation between the compatibility ratio (CR) and the SFE components. The results inferred that modified asphalt binders with additives possessed improved moisture resistance, wherein dry work adhesion values were less than 210 ​mJ/m2 under granite interfaces, whereas the limestone interface exhibited higher dry adhesion values of 340 ​mJ/m2 and below. Similar performance results were observed under wet adhesion conditions; with granite wet adhesive values observed below 120 ​mJ/m2, while limestone wet adhesion values were ascertained below 180 ​mJ/m2 for all tested samples and conditions. According to the spread–ability coefficient results, the limestone interface has greater spread-ability than granite interfaces. Meanwhile, compatibility ratio values indicated better compatibility of 1.9 or higher for tested samples under granite interfaces, whereas compatibility values of 1.7 and below were observed under limestone interfaces. Among the SFE components studied for correlation with CR, the acidic SFE component demonstrated excellent correlations (with R2 values greater than 0.91) under all ageing conditions. An inclusion of micro-level additive enhanced binder adhesion properties, resulting in a more resilient asphalt pavement