Mutational analysis of human CEACAM1: the potential of receptor polymorphism in increasing host susceptibility to bacterial infection

A common overlapping site on the N-terminal IgV-like domain of human carcinoembryonic antigen (CEA)-related cell adhesion molecules (CEACAMs) is targeted by several important human respiratory pathogens. These include Neisseria meningitidis (Nm) and Haemophilus influenzae (Hi) that can cause disseminated or persistent localized infections. To define the precise structural features that determine the binding of distinct pathogens with CEACAMs, we have undertaken molecular modelling and mutation of the receptor molecules at previously implicated key target residues required for bacterial binding. These include Ser-32, Tyr-34, Val-39, Gln-44 and Gln-89, in addition to Ile-91, the primary docking site for the pathogens. Most, but not all, of these residues located adjacent to each other in a previous N-domain model of human CEACAM1, which was based on REI, CD2 and CD4. In the current studies, we have refined this model based on the mouse CEACAM1 crystal structure, and observe that all of the above residues form an exposed continuous binding region on the N-domain. Examination of the model also suggested that substitution of two of these residues 34 and 89 could affect the accessibility of Ile-91 for ligand binding. By introducing selected mutations at the positions 91, 34 and 89, we confirmed the primary importance of Ile-91 in all bacterial binding to CEACAM1 despite the inter- and intraspecies structural differences between the bacterial CEACAM-binding ligands. The studies further indicated that the efficiency of binding was significantly enhanced for specific strains by mutations such as Y34F and Q89N, which also altered the hierarchy of Nm versus Hi strain binding. These studies imply that distinct polymorphisms in human epithelial CEACAMs have the potential to decrease or increase the risk of infection by the receptor-targeting pathogens

Phase Behavior of Aqueous Na-K-Mg-Ca-CI-NO3 Mixtures: Isopiestic Measurements and Thermodynamic Modeling

A comprehensive model has been established for calculating thermodynamic properties of multicomponent aqueous systems containing the Na{sup +}, K{sup +}, Mg{sup 2+}, Ca{sup 2+}, Cl{sup -}, and NO{sub 3}{sup -} ions. The thermodynamic framework is based on a previously developed model for mixed-solvent electrolyte solutions. The framework has been designed to reproduce the properties of salt solutions at temperatures ranging from the freezing point to 300 C and concentrations ranging from infinite dilution to the fused salt limit. The model has been parameterized using a combination of an extensive literature database and new isopiestic measurements for thirteen salt mixtures at 140 C. The measurements have been performed using Oak Ridge National Laboratory's (ORNL) previously designed gravimetric isopiestic apparatus, which makes it possible to detect solid phase precipitation. Water activities are reported for mixtures with a fixed ratio of salts as a function of the total apparent salt mole fraction. The isopiestic measurements reported here simultaneously reflect two fundamental properties of the system, i.e., the activity of water as a function of solution concentration and the occurrence of solid-liquid transitions. The thermodynamic model accurately reproduces the new isopiestic data as well as literature data for binary, ternary and higher-order subsystems. Because of its high accuracy in calculating vapor-liquid and solid-liquid equilibria, the model is suitable for studying deliquescence behavior of multicomponent salt systems

Deregulation and the New Zealand Agricultural Sector: A Review

Since July 1984 the New Zealand Government has been following a policy of disengagement and deregulation throughout the New Zealand economy. The impacts of the new policy have been felt at both the macro and the micro level. For the agricultural sector, a closer relationship to international prices and costs has been sought, with less industry assistance and direct support from the Government. With the removal of special privileges formerly enjoyed, the agricultural sector has also become more closely aligned with and vulnerable to changes in major macro parameters in the economy such as exchange rates, interest rates, inflation control and budget economies. The alignment of the agricultural economy with international prices and costs is likely to bring about a smaller and more competitive sector than was previously the case

Deregulation and the New Zealand Agricultural Sector: A Review

Since July 1984 the New Zealand Government has been following a policy of disengagement and deregulation throughout the New Zealand economy. The impacts of the new policy have been felt at both the macro and the micro level. For the agricultural sector, a closer relationship to international prices and costs has been sought, with less industry assistance and direct support from the Government. With the removal of special privileges formerly enjoyed, the agricultural sector has also become more closely aligned with and vulnerable to changes in major macro parameters in the economy such as exchange rates, interest rates, inflation control and budget economies. The alignment of the agricultural economy with international prices and costs is likely to bring about a smaller and more competitive sector than was previously the case.Agricultural and Food Policy,

Association of TLR2 gene Arg753Gln polymorphism with urinary tract infection in children

WOS: 000250940400001PubMed ID: 18001294The aim of this study is to investigate Arg753Gln allele polymorphisms of toll-like receptor-2 (TLR2) gene distribution, allele frequency in urinary tract infection (UTI) and genotype-phenotype association of TLR2 gene in children with UTI. The polymorphism was investigated in 124 children with UTI (22 boys and 102 girls; mean age 5.81 +/- 3.47 years) with direct DNA sequencing-based method. TLR2 gene Arg753Gln allele frequency was higher in the patient group when compared with control group (OR 3.14, 95%CI 1.53-6.44, P < 0.001). The frequency of the Arg753Gln allele was significantly higher in gram-positive group than in gram-negative group (OR 7.64, 95%CI 2.80-20.81, P < 0.001). The frequency of UTI was found significantly higher in the Arg753Gln allele carriers of TLR2 gene than the non-carriers (OR 4.94, 95%CI 1.09-22.33, P < 0.05). Similarly, the incidence of asymptomatic UTI was also found significantly higher in the group carrying Arg753Gln allele (OR 3.73, 95%Cl 1.54-9.04, P < 0.05). As a result, we suggest that TLR2 gene could be the predisposing factor for urinary tract infection. Additionally, we observed that subjects carrying the TLR2 Arg753Gln allele had higher risk of urinary tract infection with gram-positive pathogens, history of more than two attacks of UTI and asymptomatic UTI