Cryo-EM structure of an activated VIP1 receptor-G protein complex revealed by a NanoBiT tethering strategy.

Vasoactive intestinal polypeptide receptor (VIP1R) is a widely expressed class B G protein-coupled receptor and a drug target for the treatment of neuronal, metabolic, and inflammatory diseases. However, our understanding of its mechanism of action and the potential of drug discovery targeting this receptor is limited by the lack of structural information of VIP1R. Here we report a cryo-electron microscopy structure of human VIP1R bound to PACAP27 and Gs heterotrimer, whose complex assembly is stabilized by a NanoBiT tethering strategy. Comparison with other class B GPCR structures reveals that PACAP27 engages VIP1R with its N-terminus inserting into the ligand binding pocket at the transmembrane bundle of the receptor, which subsequently couples to the G protein in a receptor-specific manner. This structure has provided insights into the molecular basis of PACAP27 binding and VIP receptor activation. The methodology of the NanoBiT tethering may help to provide structural information of unstable complexes.

Diagnostic values of red cell distribution width, platelet distribution width and neutrophil-lymphocyte count ratio for sepsis.

The aim of this study was to evaluate the diagnostic efficiency of red blood cell distribution width (RDW), platelet distribution width (PDW), the neutrophil-lymphocyte count ratio (NLCR), procalcitonin (PCT) and C-reactive protein (CRP) for the prediction of sepsis. A total of 120 consecutive patients who underwent blood culture testing were included. The PCT and CRP levels, and RDW, PDW and NLCR percentages were determined and compared between patients with positive blood cultures and those without. The PCT, CRP, RDW, PDW and NLCR values were significantly higher in patients with positive blood culture compared with those without. PCT and NLCR each had a high diagnostic performance for the prediction of sepsis, with an area under the curve (AUC) for sepsis of 0.829 and 0.718, respectively. A combination of RDW, PDW and NLCR also exhibited a good diagnostic performance for sepsis (AUC, 0.704). NLCR is easily obtained by automated hematological analysis. Moreover, NLCR was found to have a high diagnostic efficiency for the prediction of sepsis, with greater sensitivity and accuracy than CRP. In conclusion, PCT exhibited the optimal diagnostic performance among the tested markers. The combination of the three parameters of RDW, PDW and NLCR, demonstrated a high diagnostic performance similar to that of PCT.

Diagnostic value of carcinoembryonic antigen and carcinoma antigen 19-9 for colorectal carcinoma.

OBJECTIVE: The purpose of this study was to evaluate the diagnostic efficiency of colorectal carcinoma (CRC) with the tumor markers Carcinoembryonic Antigen (CEA) and Carbohydrate Antigen 19-9 (CA 19-9), in addition to investigating whether CA 19-9 can be used to screen the disease process in patients with CRC who had no elevation of CEA levels. METHODS: Serum levels of CEA and CA 19-9 were measured in: 138 patients with CRC; 111 patients with benign colorectal diseases. The diagnostic value was performed using the logistic regression equation and receiver operating characteristic curves (ROC). RESULTS: The serum levels of CEA and CA 19-9 in the patients with CRC were significantly higher than those in the patients with benign colorectal diseases (P < 0.001). Receiver operating characteristic curves (ROC) in the patients with CRC versus those with benign colorectal disease yielded the optimal cut-off value of 3.36 ng/ml for CEA and 23.9 U/ml for CA 19-9, respectively. The area under ROC curve (AUC) was 0.789 for CEA, 0.690 for CA 19-9 and 0.900 for the combination of the two tumor markers. The combination resulted in a higher Youden index and a sensitivity of 85.3%. CONCLUSION: The combined detection of serum CEA and CA 19-9 could play a pivotal role in the diagnosis of CRC, and could drastically improve the sensitivity for the diagnosis of CRC. CA 19-9 might be a tumor biomarker in addition to CEA for CRC.

Effect of 1-[4- [2-(4-bromobenzenesulfonamino) ethyl] phenylsulfonyl]-3-(trans-4-methylcyclohexyl)urea (I4), a new synthetic sulfonylurea compound, on glucose metabolism in vivo and in vitro.

BACKGROUND: 1-[4-[2-(4-Bromobenzenesulfonamino)ethyl]phenylsulfonyl]-3-(trans-4-methylcyclohexyl)urea (I4, CAS 865483-06-3), a totally synthetic new sulfonylurea compound, incorporating part of the hypoglycemic structure of glimepiride (CAS 93479-97-1) and having anti-TXA2 receptor properties, was designed and synthesized. Its hypoglycemic property had not been reported yet. AIM: To study the hypoglycemic effects of I4 and its primary mechanisms of action. METHODS: A rat model of type 2 diabetes was established by intraperitoneal injection of small doses of streptozotocin combined with high calorie feeding. Normal fasted mice and type 2 diabetic rats were used to assay the hypoglycemic actions of I4. Blood glucose and immunoreactive insulin concentrations were measured and the effects of I4 on insulin release from rat isolated pancreatic islets were examined. A liver cell line, Hep G2, was used to examine effects on glucose consumption, glycogen synthesis and glucokinase activity. RESULTS: Oral administration of I4 (1-10 mg/kg) produced a marked, dose-dependent reduction in blood glucose in normal mice and type 2 diabetic rats and improved oral glucose tolerance. Plasma insulin concentrations were increased, and 14 increased insulin release from rat isolated pancreatic islets and from the isolated perfused rat pancreas. I4 (1-100 micromol x L(-1)) also produced an insulin-independent increase in glucose consumption by Hep G2 cells, increased glycogen synthesis and glucokinase activity of these cells. Glimepiride produced similar effects on glucose consumption and glycogen synthesis but did not facilitate glucokinase activity of Hep G2 cells. CONCLUSION: I4 markedly improved glucose metabolism in normal animals and type 2 diabetic rats, probably by increasing insulin secretion and stimulating hepatic glucose uptake and glycogen synthesis.