Callesen Morin (fuelthomas74)

Protein-protein interaction (PPI) networks are fundamental for cellular processes. Small-molecule PPI enhancers have been shown to be powerful tools to fundamentally study PPIs and as starting points for potential new therapeutics. Yet, systematic approaches for their discovery are not widely available, and the design prerequisites of "molecular glues" are poorly understood. Covalent fragment-based screening can identify chemical starting points for these enhancers at specific sites in PPI interfaces. We recently reported a mass spectrometry-based disulfide-trapping (tethering) approach for a cysteine residue in the hub protein 14-3-3, an important regulator of phosphorylated client proteins. Here, we invert the strategy and report the development of a functional read-out for systematic identification of PPI enhancers based on fluorescence anisotropy (FA-tethering) with the reactive handle now on a client-derived peptide. Using the DNA-binding domain of the nuclear receptor Estrogen Related Receptor gamma (ERRγ), we target a native cysteine positioned at the 14-3-3 PPI interface and identify several fragments that form a disulfide bond to ERRγ and stabilize the complex up to 5-fold. Crystallography indicates that fragments bind in a pocket comprised of 14-3-3 and the ERRγ phosphopeptide. FA-tethering presents a streamlined methodology to discover molecular glues for protein complexes.Silicone passive samplers were assessed for measuring personal exposure to 37 flame retardants at three Québec e-waste recycling facilities. Silicone brooches (n = 45), wristbands (n = 28), and armbands (n = 9) worn during a ∼8 h work shift accumulated detectable amounts of 95-100% of the target compounds. Brooch concentrations were significantly correlated with those from active air samplers from which we conclude that the brooches could be used to approximate inhalation exposure and other exposures related to air concentrations such as dermal exposure. The generic sampling rate of the brooch (19 ± 11 m3 day-1 dm-2) was 13 and 22 times greater than estimated for home and office environments, respectively, likely because of the dusty work environment and greater movement of e-waste workers. BDE-209 concentrations in brooches and wristbands were moderately and significantly (p less then 0.05) correlated with levels in blood plasma; organophosphorus esters in brooches and wristbands were weakly and insignificantly correlated with their metabolite biomarkers in post-shift spot urine samples. Silicone brooches and wristbands deployed over a single shift in a dusty occupational setting can be useful for indicating the internal exposure to compounds with relatively long biological half-lives, but their use for compounds with relatively short half-lives is not clear and may require either a longer deployment time or an integrated biomarker measure.Amino acids are very important for oolong tea brisk-smooth mouthfeel which is mainly associated with bruising and withering treatment (BWT). In this study, metabolome and transcriptome analyses were performed to comprehensively investigate the changes in abundance of amino acids and the expression pattern of relevant genes during BWT of oolong tea manufacturing. Levels of most amino acids increased during BWT in the leaves harvested from 4 cultivars, while expression of the relevant function genes responsible for synthesis and transformation of amino acids up-regulated accordingly. Upstream hub genes including receptor-like protein kinase IKU2, serine/threonine-protein kinase PBL11, MYB transcription factor MYB2, ethylene-responsive transcription factor ERF114, WRKY transcription factor WRKY71, aspartate aminotransferase AATC, UDP-glycosyltransferase U91D1, and 4-hydroxy-4-methyl-2-oxoglutarate aldolase 2 RRAA2, were predicted to be involved in regulation of the function genes expression and the amino acids metabolism through weighted gene coexpression network analysis. A modulation mechanism for accumulation