G-protein-coupled receptors (GPCRs) participate in a broad range of physiological functions. A priority for fundamental and clinical research, therefore, is to decipher the function of over 140 remaining orphan GPCRs. The suprachiasmatic nucleus (SCN), the brain's circadian pacemaker, governs daily rhythms in behaviour and physiology. Here we launch the SCN orphan GPCR project to (i) search for murine orphan GPCRs with enriched expression in the SCN, (ii) generate mutant animals deficient in candidate GPCRs, and (iii) analyse the impact on circadian rhythms. We thereby identify Gpr176 as an SCN-enriched orphan GPCR that sets the pace of circadian behaviour. Gpr176 is expressed in a circadian manner by SCN neurons, and molecular characterization reveals that it represses cAMP signalling in an agonist-independent manner. Gpr176 acts independently of, and in parallel to, the Vipr2 GPCR, not through the canonical Gi, but via the unique G-protein subclass Gz.

AIMTo verify the validity of the endoscopy guidelines for patients taking warfarin or direct oral anticoagulants (DOAC).METHODSWe collected data from 218 patients receiving oral anticoagulants (73 DOAC users, 145 warfarin users) and 218 patients not receiving any antithrombotics (age- and sex-matched controls) who underwent polypectomy. (1) We evaluated post-polypectomy bleeding (PPB) risk in patients receiving warfarin or DOAC compared with controls; (2) we assessed the risks of PPB and thromboembolism between three AC management methods: Discontinuing AC with heparin bridge (HPB) (endoscopy guideline recommendation), continuing AC, and discontinuing AC without HPB.RESULTSPPB rate was significantly higher in warfarin users and DOAC users compared with controls (13.7% and 13.7% vs 0.9%, P < 0.001), but was not significantly different between rivaroxaban (13.2%), dabigatran (11.1%), and apixaban (13.3%) users. Two thromboembolic events occurred in warfarin users, but none in DOAC users. Compared with the continuing anticoagulant group, the discontinuing anticoagulant with HPB group (guideline recommendation) had a higher PPB rate (10.8% vs 19.6%, P = 0.087). These findings were significantly evident in warfarin but not DOAC users. One thrombotic event occurred in the discontinuing anticoagulant with HPB group and the discontinuing anticoagulant without HPB group; none occurred in the continuing anticoagulant group.CONCLUSIONPPB risk was similar between patients taking warfarin and DOAC. Thromboembolism was observed in warfarin users only. The guideline recommendations for HPB should be re-considered.

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Cefpirome was highly stable to hydrolysis by various P-lactamases, although it was hydrolyzed to some extent by R plasmid-mediated penicillinase of Richmond-Sykes type Va/b and by chromosomal cephalosporinases from Bacteroides species. The compound had a very low affinity for cephalosporinases from Enterobacter cloacae, Citrobacterfreundii, Serratia marcescens, and Proteus vulgaris. Cefpirome showed strong antimicrobial activity against eight I-lactamase (cephalosporinase)-producing strains which have become resistant to broad-spectrum cephalosporins; especially against E. cloacae and C. freundii, it had the highest activity among the cephalosporins used. Its activity against ampicillin-resistant R plasmid-containing transconjugant isolates of Escherichia coli was as high as that against the recipient strain E. coli X1037. The inducer activity of cefpirome in S. marcescens and P. vulgaris increased dose dependently, whereas cephamycin derivatives showed high inducer activity at low concentrations. A relatively low affinity of cefpirome for 13-lactamases is considered to be one of the reasons for its high antimicrobial activity against such enzyme-producing strains. In addition, other factors such as good penetration through the outer membrane and affinity for the target sites may also be involved in the high activity of cefpirome.