Genetic determinants of 5-lipoxygenase pathway in a Spanish population and their relationship with cardiovascular risk

ObjectiveLeukotrienes (LT) play a role in inflammation, cardiovascular diseases, and cancer. Although some studies suggest that there are genes that determine variability of some LT-related phenotypes, the genetic influence on these phenotypes has not been evaluated.MethodsThe relative contributions of genetic and environmental influences to the 5-lipoxygenase pathway-related phenotypes (5-Lipoxygenase, five lipoxygenase activating protein (FLAP), LTA₄-hydrolase and LTC₄-synthase expression, and LTB₄-plasma concentration and LTB₄ production by stimulated whole blood) were assessed in a sample of 934 individuals in 35 extended families. Our design is based on extended families recruited through a probands with idiopathic thrombophilia. This strategy allows us the analysis of the effects of measured covariates (such as sex, age and smoking), genes, and environmental variables shared by members of a household.ResultsAll of these phenotypes showed significant genetic contributions, with heritabilities ranging from 0.33 to 0.51 for enzyme expression and from 0.25 to 0.50 for LTB₄ production of the residual phenotypic variance. Significant phenotypic and genetic correlation among the LT-related traits was found. More importantly, FLAP and LTA₄-hydrolase expression exhibit significant genetic correlations with arterial thrombosis, indicating that some of the genes that influence quantitative variation in these phenotypes also influence the risk of thrombosis.ConclusionThis is the first study that quantifies the genetic component of 5-Lipoxygenase pathway phenotypes. The high heritability of these traits and the significant genetic correlations between arterial thrombosis and some of these phenotypes suggest that the exploitation of correlated quantitative phenotypes will aid the search for susceptibility genes.     

Regulatory element copy number differences shape primate expression profiles

Gene expression differences are shaped by selective pressures and contribute to phenotypic differences between species. We identified 964 copy number differences (CNDs) of conserved sequences across three primate species and examined their potential effects on gene expression profiles. Samples with copy number different genes had significantly different expression than samples with neutral copy number. Genes encoding regulatory molecules differed in copy number and were associated with significant expression differences. Additionally, we identified 127 CNDs that were processed pseudogenes and some of which were expressed. Furthermore, there were copy number-different regulatory regions such as ultraconserved elements and long intergenic noncoding RNAs with the potential to affect expression. We postulate that CNDs of these conserved sequences fine-tune developmental pathways by altering the levels of RNA.     

Identification of human neutralizing antibodies that bind to complex epitopes on dengue virions

Dengue is a mosquito-borne flavivirus that is spreading at an unprecedented rate and has developed into a major health and economic burden in over 50 countries. Even though infected individuals develop potent and long-lasting serotype-specific neutralizing antibodies (Abs), the epitopes engaged by human neutralizing Abs have not been identified. Here, we demonstrate that the dengue virus (DENV)-specific serum Ab response in humans consists of a large fraction of cross-reactive, poorly neutralizing Abs and a small fraction of serotype-specific, potently inhibitory Abs. Although many mouse-generated, strongly neutralizing monoclonal antibodies (mAbs) recognize epitopes that are present on recombinant DENV envelope (E) proteins, unexpectedly, the majority of neutralizing Abs in human immune sera bound to intact virions but not to the ectodomain of purified soluble E proteins. These conclusions with polyclonal Abs were confirmed with newly generated human mAbs derived from DENV-immune individuals. Two of three strongly neutralizing human mAbs bound to E protein epitopes that were preserved on the virion but not on recombinant E (rE) protein. We propose that humans produce Abs that neutralize DENV infection by binding a complex, quaternary structure epitope that is expressed only when E proteins are assembled on a virus particle. Mapping studies indicate that this epitope has a footprint that spans adjacent E protein dimers and includes residues at the hinge between domains I and II of E protein. These results have significant implications for the DENV Ab and vaccine field.     

Extra-large letter spacing improves reading in dyslexia

Although the causes of dyslexia are still debated, all researchers agree that the main challenge is to find ways that allow a child with dyslexia to read more words in less time, because reading more is undisputedly the most efficient intervention for dyslexia. Sophisticated training programs exist, but they typically target the component skills of reading, such as phonological awareness. After the component skills have improved, the main challenge remains (that is, reading deficits must be treated by reading more--a vicious circle for a dyslexic child). Here, we show that a simple manipulation of letter spacing substantially improved text reading performance on the fly (without any training) in a large, unselected sample of Italian and French dyslexic children. Extra-large letter spacing helps reading, because dyslexics are abnormally affected by crowding, a perceptual phenomenon with detrimental effects on letter recognition that is modulated by the spacing between letters. Extra-large letter spacing may help to break the vicious circle by rendering the reading material more easily accessible.     

Withania somnifera reverses Alzheimer's disease pathology by enhancing low-density lipoprotein receptor-related protein in liver

A 30-d course of oral administration of a semipurified extract of the root of Withania somnifera consisting predominantly of withanolides and withanosides reversed behavioral deficits, plaque pathology, accumulation of β-amyloid peptides (Aβ) and oligomers in the brains of middle-aged and old APP/PS1 Alzheimer's disease transgenic mice. It was similarly effective in reversing behavioral deficits and plaque load in APPSwInd mice (line J20). The temporal sequence involved an increase in plasma Aβ and a decrease in brain Aβ monomer after 7 d, indicating increased transport of Aβ from the brain to the periphery. Enhanced expression of low-density lipoprotein receptor-related protein (LRP) in brain microvessels and the Aβ-degrading protease neprilysin (NEP) occurred 14-21 d after a substantial decrease in brain Aβ levels. However, significant increase in liver LRP and NEP occurred much earlier, at 7 d, and were accompanied by a rise in plasma sLRP, a peripheral sink for brain Aβ. In WT mice, the extract induced liver, but not brain, LRP and NEP and decreased plasma and brain Aβ, indicating that increase in liver LRP and sLRP occurring independent of Aβ concentration could result in clearance of Aβ. Selective down-regulation of liver LRP, but not NEP, abrogated the therapeutic effects of the extract. The remarkable therapeutic effect of W. somnifera mediated through up-regulation of liver LRP indicates that targeting the periphery offers a unique mechanism for Aβ clearance and reverses the behavioral deficits and pathology seen in Alzheimer's disease models.