Chemogenomic Analysis of G-Protein Coupled Receptors and Their Ligands Deciphers Locks and Keys Governing Diverse Aspects of Signalling

Understanding the molecular mechanism of signalling in the important super-family of G-protein-coupled receptors (GPCRs) is causally related to questions of how and where these receptors can be activated or inhibited. In this context, it is of great interest to unravel the common molecular features of GPCRs as well as those related to an active or inactive state or to subtype specific G-protein coupling. In our underlying chemogenomics study, we analyse for the first time the statistical link between the properties of G-protein-coupled receptors and GPCR ligands. The technique of mutual information (MI) is able to reveal statistical inter-dependence between variations in amino acid residues on the one hand and variations in ligand molecular descriptors on the other. Although this MI analysis uses novel information that differs from the results of known site-directed mutagenesis studies or published GPCR crystal structures, the method is capable of identifying the well-known common ligand binding region of GPCRs between the upper part of the seven transmembrane helices and the second extracellular loop. The analysis shows amino acid positions that are sensitive to either stimulating (agonistic) or inhibitory (antagonistic) ligand effects or both. It appears that amino acid positions for antagonistic and agonistic effects are both concentrated around the extracellular region, but selective agonistic effects are cumulated between transmembrane helices (TMHs) 2, 3, and ECL2, while selective residues for antagonistic effects are located at the top of helices 5 and 6. Above all, the MI analysis provides detailed indications about amino acids located in the transmembrane region of these receptors that determine G-protein signalling pathway preferences

Quantitative modeling of the physiology of ascites in portal hypertension

Although the factors involved in cirrhotic ascites have been studied for a century, a number of observations are not understood, including the action of diuretics in the treatment of ascites and the ability of the plasma-ascitic albumin gradient to diagnose portal hypertension. This communication presents an explanation of ascites based solely on pathophysiological alterations within the peritoneal cavity. A quantitative model is described based on experimental vascular and intraperitoneal pressures, lymph flow, and peritoneal space compliance. The model's predictions accurately mimic clinical observations in ascites, including the magnitude and time course of changes observed following paracentesis or diuretic therapy

Control of Mycobacterium fortuitum and Mycobacterium intracellulare infections with respect to distinct granuloma formations in livers of BALB/c mice

Mycobacterium fortuitum is a rapidly growing nontuberculous Mycobacterium that can cause a range of diseases in humans. Complications from M. fortuitum infection have been associated with numerous surgical procedures. A protective immune response against pathogenic mycobacterial infections is dependent on the granuloma formation. Within the granuloma, the macrophage effector response can inhibit bacterial replication and mediate the intracellular killing of bacteria. The granulomatous responses of BALB/c mice to rapidly and slowly growing mycobacteria were assessed in vivo and the bacterial loads in spleens and livers from M. fortuitum and Mycobacterium intracellulare-infected mice, as well as the number and size of granulomas in liver sections, were quantified. Bacterial loads were found to be approximately two times lower in M. fortuitum-infected mice than in M. intracellulare-infected mice and M. fortuitum-infected mice presented fewer granulomas compared to M. intracellulare-infected mice. These granulomas were characterized by the presence of Mac-1+ and CD4+ cells. Additionally, IFN-γmRNA expression was higher in the livers of M. fortuitum-infected mice than in those of M. intracellulare-infected mice. These data clearly show that mice are more capable of controlling an infection with M. fortuitum than M. intracellulare. This capacity is likely related to distinct granuloma formations in mice infected with M. fortuitum but not with M. intracellulare

Apnea and Bronchiolitis Due to Respiratory Syncytial Virus

A study was made of 146 children admitted to hospital with bronchiolitis due to respiratory syncytial virus. Fifteen subjects (10%) had apnoea. Six of the 16 infants (38%) less than two months of age had apnoea, compared with nine of 130 children (6.9%) over two months old (

Serum C-Reactive Protein in Children with Liver Disease and Ascites

Background: The diagnosis of peritonitis as a complication of cirrhosis is an important clinical problem. Objectives: The aim of this study was to evaluate serum C-reactive protein levels as a diagnostic factor for spontaneous bacterial peritonitis (SBP) in child patients with liver disease. Methods: In this study, 150 children diagnosed with liver disease and ascites upon admission to Nemazee Teaching Hospital (Shiraz, Iran) were examined. Patients were divided into spontaneous bacterial peritonitis and sterile ascetic fluid groups according to the PMN count >= 250/mm(3) in the ascetic fluids. Routine laboratory tests were conducted and quantitative C-reactive protein (CRP) levels were measured for all of the patients. Accuracy, sensitivity, and specificity of CRP was evaluated for diagnosis of SBP. Results: Of 150 cirrhotic patients, 109 patients presented without SBP (52.29 male, mean age: 5.02 +/- 4.49 years) and 41 patients presented with SBP (51.21 male, mean age: 4.71 years). Cell counts, protein levels, albumin levels, and lactate dehydrogenize (LDH) levels of the ascetic fluid and serum samples in the SBP group were higher than the rates for those without SBP (P = 250/mm(3), and cultured ascites were 69.23, 90.25, 88.43, and 84.32, respectively. The areas under the curve of CRP for SBP based on the PMN count >= 250/mm(3) and cultured ascites was 0.94 (CI 95: 0.90 to 0.96) and 0.85 (CI 95: 0.84 to 0.92), respectively (P < 0.001). Conclusions: Our study showed that CRP is a marker with high sensitivity and specificity for the diagnosis of SBP in cirrhotic children