The effect of newt toxin on an invasive snail

Hydrobiologia - Invasive species are well documented to impact native species where they are introduced. In the Santa Monica Mountains, a native species of amphibian, the California newt (Taricha...     

Erythrocyte membrane alterations in Huntington disease: Effects of γ-aminobutyric acid

The interaction of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) with erythrocyte membranes from patients with Huntington disease and normal controls has been studied by electron spin resonance. GABA affects the physical state of erythrocyte membrane proteins in control and Huntington disease differently. In addition, after exposure of spin-labeled Huntington disease erythrocyte membranes to 0.1 mM GABA, the relevant electron spin resonance parameters reflecting the physical state of membrane proteins are indistinguishable from those of untreated control membranes. These findings support the concept that this disease is associated with a generalized membrane defect.     

Affinity maturation increases the stability and plasticity of the Fv domain of anti-protein antibodies

The somatic mutations accumulated in variable and framework regions of antibodies produce structural changes that increase the affinity towards the antigen. This implies conformational and non covalent bonding changes at the paratope, as well as possible quaternary structure changes and rearrangements at the V_H-V_L interface. The consequences of the affinity maturation on the stability of the Fv domain were studied in a system composed of two closely related antibodies, F10.6.6 and D44.1, which recognize the same hen egg-white lysozyme (HEL) epitope. The mAb F10.6.6 has an affinity constant 700 times higher than D44.1, due to a higher surface complementarity to HEL. The structure of the free form of the Fab F10.6.6 presented here allows a comparative study of the conformational changes produced upon binding to antigen. By means of structural comparison, kinetics and thermodynamics of binding and stability studies on Fab and Fv fragments of both antibodies, we have determined that the affinity maturation process of anti-protein antibodies affects the shape of the combining site and the secondary structure content of the variable domain, stabilizes the V_H-V_L interaction, and consequently produces an increase of the Fv domain stability, improving the binding to antigen.     

Association between proximity to the attending nephrologist and mortality among patients receiving hemodialysis

Background

Many Canadian patients who receive hemodialysis live far from their attending nephrologist, which may affect clinical outcomes. We investigated whether patients receiving hemodialysis who live farther from their attending nephrologist are more likely to die than those who live closer.

Methods

We studied a random sample of 18 722 patients who began hemodialysis between 1990 and 2000 in Canada. We calculated the distance between each patient''s residence location at the start of dialysis and the practice location of their attending nephrologist. We used Cox proportional hazards models to examine the adjusted relation between distance and clinical outcomes (death from all causes, infectious causes and cardiovascular causes) over a follow-up period of up to 14 years.

Results

During the follow-up period (median 2.5 yr, interquartile range 1.0–4.7 yr), 11 582 (62%) patients died. Compared with patients who lived within 50 km of their nephrologist, the adjusted hazard ratio of death among those who lived 50.1–150 km away was 1.06 (95% confidence interval [CI] 1.01–1.12), 1.13 (95% CI 1.04–1.22) for those who lived 150.1–300 km away and 1.13 (95% CI 1.03–1.24) for those who lived more than 300 km from their nephrologist (p for trend < 0.001). The risk of death from infectious causes increased with greater distance from the attending nephrologist (p for trend < 0.001). The risk of death from cardiovascular causes did not increase with distance from the attending nephrologist (p for trend = 0.21). Compared with patients who lived within 50 km of their nephrologist, the adjusted hazard ratio of death among those who lived more than 300 km away was 1.75 (95% CI 1.32–2.32) for infectious causes and 0.93 (95% CI 0.79–1.09) for cardiovascular causes.

Conclusions

Mortality associated with hemodialysis was greater among patients who lived farther from their attending nephrologist, as compared with those who lived closer. This was especially evident for death from infectious causes.In Canada, no one is denied renal replacement therapy because of their residence location; however, a substantial proportion of patients receiving dialysis live more than 300 km from the closest nephrologist.¹ Since this geographic barrier may make it more difficult to provide high-quality renal care, it is plausible that disparities in access to appropriate care may result in differences in health outcomes. Despite the potential implications for health policy, this issue has not been formally studied.We sought to examine this issue using data collected prospectively from patients who began hemodialysis in Canada between 1990 and 2000. We hypothesized that patients who lived farther away from their attending nephrologist would be more likely than patients who lived closer to die after starting dialysis.     

Functional genomics complements quantitative genetics in identifying disease-gene associations

An ultimate goal of genetic research is to understand the connection between genotype and phenotype in order to improve the diagnosis and treatment of diseases. The quantitative genetics field has developed a suite of statistical methods to associate genetic loci with diseases and phenotypes, including quantitative trait loci (QTL) linkage mapping and genome-wide association studies (GWAS). However, each of these approaches have technical and biological shortcomings. For example, the amount of heritable variation explained by GWAS is often surprisingly small and the resolution of many QTL linkage mapping studies is poor. The predictive power and interpretation of QTL and GWAS results are consequently limited. In this study, we propose a complementary approach to quantitative genetics by interrogating the vast amount of high-throughput genomic data in model organisms to functionally associate genes with phenotypes and diseases. Our algorithm combines the genome-wide functional relationship network for the laboratory mouse and a state-of-the-art machine learning method. We demonstrate the superior accuracy of this algorithm through predicting genes associated with each of 1157 diverse phenotype ontology terms. Comparison between our prediction results and a meta-analysis of quantitative genetic studies reveals both overlapping candidates and distinct, accurate predictions uniquely identified by our approach. Focusing on bone mineral density (BMD), a phenotype related to osteoporotic fracture, we experimentally validated two of our novel predictions (not observed in any previous GWAS/QTL studies) and found significant bone density defects for both Timp2 and Abcg8 deficient mice. Our results suggest that the integration of functional genomics data into networks, which itself is informative of protein function and interactions, can successfully be utilized as a complementary approach to quantitative genetics to predict disease risks. All supplementary material is available at http://cbfg.jax.org/phenotype.