Biotribology of a mobile bearing posterior stabilised knee design - Effect of motion restraint on wear,tibio-femoral kinematics and particles

The objective of our study was to evaluate the impact of a biphaseal anterior–posterior (AP) and internal–external (IE) motion restraint system on the wear behaviour, tibio-femoral kinematics and particle release of a mobile bearing posterior stabilised knee design in comparison to the widely used linear restraint.     

Patterns of flowering and sex-ratio variation in the Mediterranean shrub Phillyrea angustifolia (Oleaceae): implications for the maintenance of males with hermaphrodites

The Mediterranean shrub Phillyrea angustifolia is one of the few plants that display androdioecy, a rare breeding system in which males co-occur with hermaphrodites. However, it has been difficult to account for male frequencies previously documented for this species, which have frequently been higher than 0.5. Here we present sex-ratio data from 13 sites in Spain and Portugal that throw further light on the maintenance of androdioecy in P. angustifolia . The inferred proportion of males in these populations was around 0.3, substantially lower that 0.5 and concurring with theoretical predictions for androdioecy. Differences in the proportion of hermaphrodites in flower between "stressed" and "nonstressed" sites suggest the existence of an important life-history trade-off between fruit production and the rate at which plants recover from recurrent disturbances such as fire. The reduced frequency of flowering by hermaphrodites relative to males may help to explain the maintenance of androdioecy in this long-lived, woody species.     

The parmodulin NRD-21 is an allosteric inhibitor of PAR1 Gq signaling with improved anti-inflammatory activity and stability

Novel analogs of the allosteric, biased PAR1 ligand ML161 (parmodulin 2, PM2) were prepared in order to identify potential anti-thrombotic and anti-inflammatory compounds of the parmodulin class with improved properties. Investigations of structure-activity relationships of the western portion of the 1,3-diaminobenzene scaffold were performed using an intracellular calcium mobilization assay with endothelial cells, and several heterocycles were identified that inhibited PAR1 at sub-micromolar concentrations. The oxazole NRD-21 was profiled in additional detail, and it was confirmed to act as a selective, reversible, negative allosteric modulator of PAR1. In addition to inhibiting human platelet aggregation, it showed superior anti-inflammatory activity to ML161 in a qPCR assay measuring the expression of tissue factor in response to the cytokine TNF-alpha in endothelial cells. Additionally, NRD-21 is much more plasma stable than ML161, and is a promising lead compound for the parmodulin class for anti-thrombotic and anti-inflammatory indications.     

An anthrone-based Kv7.2/7.3 channel blocker with improved properties for the investigation of psychiatric and neurodegenerative disorders

A set of novel Kv7.2/7.3 (KCNQ2/3) channel blockers was synthesized to address several liabilities of the known compounds XE991 (metabolic instability and CYP inhibition) and the clinical compound DMP 543 (acid instability, insolubility, and lipophilicity). Using the anthrone scaffold of the prior channel blockers, alternative heteroarylmethyl substituents were installed via enolate alkylation reactions. Incorporation of a pyridazine and a fluorinated pyridine gave an analog (compound 18, JDP-107) with a promising combination of potency (IC₅₀ = 0.16 μM in a Kv7.2 thallium flux assay), efficacy in a Kv7.2/7.3 patch clamp assay, and drug-like properties.