The effect of -difluorination on the conformation and properties of a model macrocyclic system.

Conformational control of drug candidates to engineer improved potency and ADME properties is an ongoing area of research. Macrocyclic rings tend to offer a greater degree of rigidity than non-cyclised small molecules, and, as a result they are perfect platforms to instil conformational controls. In this study, the difluoroalkoxyphenyl moiety is examined as a tool to alter the conformation of macrocycles.

Timing of Surgery for Proximal Humeral Fracture Treated with Shoulder Hemiarthroplasty, Best Results with Surgery Within 2 Weeks.

Background: Preoperative delay may affect the outcome of proximal humerus fractures treated with shoulder hemiarthroplasty. There is currently no consensus for the recommended preoperative time interval. The aim was to examine how the time to surgery with shoulder hemiarthroplasty after a proximal humerus fracture affected the patient-reported outcome.

Fundamental units of numerosity estimation.

Humans can approximately enumerate a large number of objects at a single glance. While several mechanisms have been proposed to account for this ability, the fundamental units over which they operate remain unclear. Previous studies have argued that estimation mechanisms act only on topologically distinct units or on units formed by spatial grouping cues such as proximity and connectivity, but not on units grouped by similarity.

Cattle Cleanliness from the View of Swedish Farmers and Official Animal Welfare Inspectors.

Dirty cattle have been commonly recorded in official animal welfare inspections in Sweden for years. The relevant authorities have initiated work to better understand the causes of dirty cattle, in order to improve compliance and standardize the grounds for categorizing a farm as non-compliant with welfare legislation when dirty animals are present. This study investigated the occurrence of dirty cattle in official animal welfare controls, on Swedish cattle farms, and examined farmers' views on the reasons for non-compliance and on key factors in keeping animals clean.

Protease-activated receptor-2 ligands reveal orthosteric and allosteric mechanisms of receptor inhibition.

Protease-activated receptor-2 (PAR2) has been implicated in multiple pathophysiologies but drug discovery is challenging due to low small molecule tractability and a complex activation mechanism. Here we report the pharmacological profiling of a potent new agonist, suggested by molecular modelling to bind in the putative orthosteric site, and two novel PAR2 antagonists with distinctly different mechanisms of inhibition. We identify coupling between different PAR2 binding sites.