University of Alberta

About: University of Alberta is a education organization based out in Edmonton, Alberta, Canada. It is known for research contribution in the topics: Population & Health care. The organization has 65403 authors who have published 154847 publications receiving 5358338 citations. The organization is also known as: Ualberta & UAlberta.

Identification of a mast-cell-specific receptor crucial for pseudo-allergic drug reactions

Abstract: Mast cells are primary effectors in allergic reactions, and may have important roles in disease by secreting histamine and various inflammatory and immunomodulatory substances. Although they are classically activated by immunoglobulin (Ig)E antibodies, a unique property of mast cells is their antibody-independent responsiveness to a range of cationic substances, collectively called basic secretagogues, including inflammatory peptides and drugs associated with allergic-type reactions. The pathogenic roles of these substances have prompted a decades-long search for their receptor(s). Here we report that basic secretagogues activate mouse mast cells in vitro and in vivo through a single receptor, Mrgprb2, the orthologue of the human G-protein-coupled receptor MRGPRX2. Secretagogue-induced histamine release, inflammation and airway contraction are abolished in Mrgprb2-null mutant mice. Furthermore, we show that most classes of US Food and Drug Administration (FDA)-approved peptidergic drugs associated with allergic-type injection-site reactions also activate Mrgprb2 and MRGPRX2, and that injection-site inflammation is absent in mutant mice. Finally, we determine that Mrgprb2 and MRGPRX2 are targets of many small-molecule drugs associated with systemic pseudo-allergic, or anaphylactoid, reactions; we show that drug-induced symptoms of anaphylactoid responses are significantly reduced in knockout mice; and we identify a common chemical motif in several of these molecules that may help predict side effects of other compounds. These discoveries introduce a mouse model to study mast cell activation by basic secretagogues and identify MRGPRX2 as a potential therapeutic target to reduce a subset of drug-induced adverse effects.

Shiga-like toxins are neutralized by tailored multivalent carbohydrate ligands

Abstract: The diseases caused by Shiga and cholera toxins account for the loss of millions of lives each year. Both belong to the clinically significant subset of bacterial AB5 toxins consisting of an enzymatically active A subunit that gains entry to susceptible mammalian cells after oligosaccharide recognition by the B5 homopentamer. Therapies might target the obligatory oligosaccharide-toxin recognition event, but the low intrinsic affinity of carbohydrate-protein interactions hampers the development of low-molecular-weight inhibitors. The toxins circumvent low affinity by binding simultaneously to five or more cell-surface carbohydrates. Here we demonstrate the use of the crystal structure of the B5 subunit of Escherichia coli O157:H7 Shiga-like toxin I (SLT-I) in complex with an analogue of its carbohydrate receptor to design an oligovalent, water-soluble carbohydrate ligand (named STARFISH), with subnanomolar inhibitory activity. The in vitro inhibitory activity is 1-10-million-fold higher than that of univalent ligands and is by far the highest molar activity of any inhibitor yet reported for Shiga-like toxins I and II. Crystallography of the STARFISH/Shiga-like toxin I complex explains this activity. Two trisaccharide receptors at the tips of each of five spacer arms simultaneously engage all five B subunits of two toxin molecules.

Understanding strategic change: The contribution of archetypes

Abstract: We examined the concept of archetype, implicit in a number of contemporary approaches to the study of organizational design and change. Despite an emerging interest in archetypes, the concept has r...

Systematic review of sedentary behaviour and health indicators in school-aged children and youth: an update.

Abstract: Accumulating evidence suggests that, independent of physical activity levels, sedentary behaviours are associated with increased risk of cardio-metabolic disease, all-cause mortality, and a variety of physiological and psychological problems. Therefore, the purpose of this systematic review is to determine the relationship between sedentary behaviour and health indicators in school-aged children and youth aged 5-17 years. Online databases (MEDLINE, EMBASE and PsycINFO), personal libraries and government documents were searched for relevant studies examining time spent engaging in sedentary behaviours and six specific health indicators (body composition, fitness, metabolic syndrome and cardiovascular disease, self-esteem, pro-social behaviour and academic achievement). 232 studies including 983,840 participants met inclusion criteria and were included in the review. Television (TV) watching was the most common measure of sedentary behaviour and body composition was the most common outcome measure. Qualitative analysis of all studies revealed a dose-response relation between increased sedentary behaviour and unfavourable health outcomes. Watching TV for more than 2 hours per day was associated with unfavourable body composition, decreased fitness, lowered scores for self-esteem and pro-social behaviour and decreased academic achievement. Meta-analysis was completed for randomized controlled studies that aimed to reduce sedentary time and reported change in body mass index (BMI) as their primary outcome. In this regard, a metaanalysis revealed an overall significant effect of -0.81 (95% CI of -1.44 to -0.17, p = 0.01) indicating an overall decrease in mean BMI associated with the interventions. There is a large body of evidence from all study designs which suggests that decreasing any type of sedentary time is associated with lower health risk in youth aged 5-17 years. In particular, the evidence suggests that daily TV viewing in excess of 2 hours is associated with reduced physical and psychosocial health, and that lowering sedentary time leads to reductions in BMI.