Missense mutations and the magnitude of functional deficit: the example of factor IX

Summary Some missense changes are compatible with normal protein function while others compromise essential aspects of protein maturation, specific activity, or stability. For those missense changes that alter function in the intact organism, how likely is it for the mutated protein to retain appreciable residual activity? By genetic analysis of patients with hemophilia B of known severity, this question can be addressed for missense mutations that reduce factor IX activity by fourfold or more below the average. We estimate that missense changes cause only 59% of moderate and severe disease, but these mutations are almost always (95%) of independent origin. In contrast, missense mutations are found in virtually all (97%) families with mild disease, but only a minority of these (41%) are of independent origin. From the aggregate data, we estimate that most (71%) of the independent deleterious missense mutations cause at least a 20-fold decrease in factor IX activity.     

Complex binding interactions between multicomponent mixtures and odorant receptors in the olfactory organ of the Caribbean spiny lobster Panulirus argus

Our study was designed to examine how components of complex mixtures can inhibit the binding of other components to receptor sites in the olfactory system of the spiny lobster Panulirus argus. Biochemical binding assays were used to study how two- to six-component mixtures inhibit binding of the radiolabeled odorants taurine, L-glutamate and adenosine-5'-monophosphate to a tissue fraction rich in dendritic membrane of olfactory receptor neurons. Our results indicate that binding inhibition by mixtures can be large and is dependent on the nature of the odorant ligand and on the concentration and composition of the mixture. The binding inhibition by mixtures of structurally related components was generally predicted using a competitive binding model and binding inhibition data for the individual components. This was not the case for binding inhibition by most mixtures of structurally unrelated odorants. The binding inhibition for these mixtures was generally smaller than that for one or more of their components, indicating that complex binding interactions between components can reduce their ability to inhibit binding. The magnitude of binding inhibition was influenced more by the mixture's precise composition than by the number of components in it, since mixtures with few components were sometimes more inhibitory than mixtures with more components. These findings raise the possibility that complex binding interactions between components of a mixture and their receptors may shape the output of olfactory receptor neurons to complex mixtures.      

Evaluating the forced oscillation technique in the detection of early smoking-induced respiratory changes

Background  

Early detection of the effects of smoking is of the utmost importance in the prevention of chronic obstructive pulmonary disease (COPD). The forced oscillation technique (FOT) is easy to perform since it requires only tidal breathing and offers a detailed approach to investigate the mechanical properties of the respiratory system. The FOT was recently suggested as an attractive alternative for diagnosing initial obstruction in COPD, which may be helpful in detecting COPD in its initial phases. Thus, the purpose of this study was twofold: (1) to evaluate the ability of FOT to detect early smoking-induced respiratory alterations; and (2) to compare the sensitivity of FOT with spirometry in a sample of low tobacco-dose subjects.     

Effects of quantitative trait loci and the myostatin locus on trace and macro elements (minerals) in bovine liver,muscle and kidney

A quantitative trait locus (QTL) study of the concentrations of 14 trace and macro elements (minerals) in tissues of beef cattle was conducted in New Zealand. Back‐cross calves with Jersey and Limousin ancestry (202 heifers and 211 steers) were generated using first‐cross sires. This paper reports on testing for effects of QTL on the concentrations of minerals in liver, kidney and muscle in cattle at slaughter, following a growth phase during which rearing and finishing stages were on pasture. Fifteen QTL were identified (P < 0.05) on a genome‐wide basis in combined‐sire and within‐sire analyses. In addition, the possible effect of the Limousin myostatin F94L allele was tested by fitting each calf's myostatin genotype, and 16 QTL were identified. Twelve were in common with those QTL identified previously, comprising six affecting the liver (copper and zinc, on two chromosomes each; plus iron and molybdenum), three affecting the kidney (calcium, copper and iron), and three affecting muscle (iron, strontium and zinc).