The rice SUB1A-1 gene, which encodes a group VII ethylene response factor (ERFVII), plays a pivotal role in rice survival under flooding stress, as well as other abiotic stresses. In Arabidopsis, five ERFVII factors play roles in regulating hypoxic responses. A characteristic feature of Arabidopsis ERFVIIs is a destabilizing N terminus, which functions as an N-degron that targets them for degradation via the oxygen-dependent N-end rule pathway of proteolysis, but permits their stabilization during hypoxia for hypoxia-responsive signaling. Despite having the canonical N-degron sequence, SUB1A-1 is not under N-end rule regulation, suggesting a distinct hypoxia signaling pathway in rice during submergence. Herein we show that two other rice ERFVIIs gene, ERF66 and ERF67, are directly transcriptionally up-regulated by SUB1A-1 under submergence. In contrast to SUB1A-1, ERF66 and ERF67 are substrates of the N-end rule pathway that are stabilized under hypoxia and may be responsible for triggering a stronger transcriptional response to promote submergence survival. In support of this, overexpression of ERF66 or ERF67 leads to activation of anaerobic survival genes and enhanced submergence tolerance. Furthermore, by using structural and protein-interaction analyses, we show that the C terminus of SUB1A-1 prevents its degradation via the N-end rule and directly interacts with the SUB1A-1 N terminus, which may explain the enhanced stability of SUB1A-1 despite bearing an N-degron sequence. In summary, our results suggest that SUB1A-1, ERF66, and ERF67 form a regulatory cascade involving transcriptional and N-end rule control, which allows rice to distinguish flooding from other SUB1A-1–regulated stresses.

The apical sodium-dependent bile acid transporter (ASBT) transports bile salts from the lumen of the gastrointestinal (GI) tract to the liver via the portal vein. Multiple pharmaceutical companies have exploited the physiological link between ASBT and hepatic cholesterol metabolism, which led to the clinical investigation of ASBT inhibitors as lipid-lowering agents. While modest lipid effects were demonstrated, the potential utility of ASBT inhibitors for treatment of type 2 diabetes has been relatively unexplored. We initiated a lead optimization effort that focused on the identification of a potent, nonabsorbable ASBT inhibitor starting from the first-generation inhibitor 264W94 (1). Extensive SAR studies culminated in the discovery of GSK2330672 (56) as a highly potent, nonabsorbable ASBT inhibitor which lowers glucose in an animal model of type 2 diabetes and shows excellent developability properties for evaluating the potential therapeutic utility of a nonabsorbable ASBT inhibitor for treatment of patients with type 2 diabetes.

PURPOSE: We systematically reviewed the literature in order to determine whether evidence indicated that preoperative stoma site marking reduces the occurrence of postoperative stoma and peristomal complications. DESIGN: Systematic review with meta-analysis of pooled findings. SUBJECTS/SETTING: We systematically reviewed 6 electronic databases including PubMed, MEDLINE, CINAHL, Cochrane Library for English language articles, along with the Airiti Library and Wanfang Data for Chinese articles for evidence related to the effects of stoma site marking on stoma and peristomal complications. We sought articles published from their inception to January 31, 2018. METHODS: Ten studies that included 2109 participants, each comparing 2 groups of patients who did and did not undergo preoperative stoma site marking, were retrieved and analyzed. RESULTS: In patients who underwent stoma site marking, the marking was associated with reduced stoma and peristomal complications in all stoma types (odds ratio [OR] = 0.52; 95% CI, 0.42-0.64; P < .001). Patients who underwent stoma and had fecal ostomies experienced fewer complications (OR = 0.34; 95% CI, 0.25-0.47; P < .001) than patients with unmarked stomas. In contrast, patients with urostomies did not experience fewer complications when compared to those with unmarked ostomies (OR = 0.531; 95% CI, 0.23-1.21; P = .132). Persons with fecal ostomies also had fewer hernias and peristomal skin complications (ORs = 0.25 and 0.30; 95% CIs, 0.09-0.71 and 0.20-0.44, respectively; both Ps < .001). The results revealed that stoma site marking was associated with reduced early and late stoma and peristomal complications (ORs = 0.76 and 0.38; 95% CIs, 0.61-0.94 and 0.32-0.46; P = .010 and P < .001, respectively). CONCLUSIONS: Preoperative stoma site marking is associated with a reduced occurrence of stoma and peristomal complications and should be considered as a standard of preoperative care.