An eicosanoid-centric view of atherothrombotic risk factors

Cardiovascular disease is the foremost cause of morbidity and mortality in the Western world. Atherosclerosis followed by thrombosis (atherothrombosis) is the pathological process underlying most myocardial, cerebral, and peripheral vascular events. Atherothrombosis is a complex and heterogeneous inflammatory process that involves interactions between many cell types (including vascular smooth muscle cells, endothelial cells, macrophages, and platelets) and processes (including migration, proliferation, and activation). Despite a wealth of knowledge from many recent studies using knockout mouse and human genetic studies (GWAS and candidate approach) identifying genes and proteins directly involved in these processes, traditional cardiovascular risk factors (hyperlipidemia, hypertension, smoking, diabetes mellitus, sex, and age) remain the most useful predictor of disease. Eicosanoids (20 carbon polyunsaturated fatty acid derivatives of arachidonic acid and other essential fatty acids) are emerging as important regulators of cardiovascular disease processes. Drugs indirectly modulating these signals, including COX-1/COX-2 inhibitors, have proven to play major roles in the atherothrombotic process. However, the complexity of their roles and regulation by opposing eicosanoid signaling, have contributed to the lack of therapies directed at the eicosanoid receptors themselves. This is likely to change, as our understanding of the structure, signaling, and function of the eicosanoid receptors improves. Indeed, a major advance is emerging from the characterization of dysfunctional naturally occurring mutations of the eicosanoid receptors. In light of the proven and continuing importance of risk factors, we have elected to focus on the relationship between eicosanoids and cardiovascular risk factors.     

Comparison of the epiproct structure of two closely related species, Sweltsa fidelis (Banks) and S. revelstoka (Jewett) (Plecoptera: Chloroperlidae)

The male epiprocts of 2 closely related western Nearctic species, Sweltsa fidelis (Banks) and S. revelstoka (Jewett), were examined using SEM. The males of these 2 species have been historically distinguished by epiproct measurements. The ratio of the length of the base to greatest width versus total epiproct length ranges from 0.49 μm to 0.67 μm (￣ x = 0.56) in S. fidelis and 0.55 μm to 0.69 μm (￣ x = 0.60) in S. revelstoka . Similarities in measurement suggest that the location of the greatest epiproct width is not a reliable and consistent character for distinguishing males of these 2 species.     

Genome-wide association and linkage identify modifier loci of lung disease severity in cystic fibrosis at 11p13 and 20q13.2

A combined genome-wide association and linkage study was used to identify loci causing variation in cystic fibrosis lung disease severity. We identified a significant association (P = 3.34 × 10(-8)) near EHF and APIP (chr11p13) in p.Phe508del homozygotes (n = 1,978). The association replicated in p.Phe508del homozygotes (P = 0.006) from a separate family based study (n = 557), with P = 1.49 × 10(-9) for the three-study joint meta-analysis. Linkage analysis of 486 sibling pairs from the family based study identified a significant quantitative trait locus on chromosome 20q13.2 (log(10) odds = 5.03). Our findings provide insight into the causes of variation in lung disease severity in cystic fibrosis and suggest new therapeutic targets for this life-limiting disorder.     

SLC2A9 influences uric acid concentrations with pronounced sex-specific effects

Serum uric acid concentrations are correlated with gout and clinical entities such as cardiovascular disease and diabetes. In the genome-wide association study KORA (Kooperative Gesundheitsforschung in der Region Augsburg) F3 500K (n = 1,644), the most significant SNPs associated with uric acid concentrations mapped within introns 4 and 6 of SLC2A9, a gene encoding a putative hexose transporter (effects: -0.23 to -0.36 mg/dl per copy of the minor allele). We replicated these findings in three independent samples from Germany (KORA S4 and SHIP (Study of Health in Pomerania)) and Austria (SAPHIR; Salzburg Atherosclerosis Prevention Program in Subjects at High Individual Risk), with P values ranging from 1.2 x 10(-8) to 1.0 x 10(-32). Analysis of whole blood RNA expression profiles from a KORA F3 500K subgroup (n = 117) showed a significant association between the SLC2A9 isoform 2 and urate concentrations. The SLC2A9 genotypes also showed significant association with self-reported gout. The proportion of the variance of serum uric acid concentrations explained by genotypes was about 1.2% in men and 6% in women, and the percentage accounted for by expression levels was 3.5% in men and 15% in women.     

Positive selection of CD4+ T cells mediated by MHC class II-bearing stromal cell in the thymic cortex

T lymphocytes differentiate in the thymus, where functionally immature, CD4+CD8+ (double positive) thymocytes develop into functionally mature CD4+ helper cells and CD8+ cytotoxic (single positive) T cells. The thymus is the site where self-reactive T cells are negatively selected (clonally deleted) and where T cells with the capacity to recognize foreign antigens in association with self-proteins encoded by the major histocompatibility complex (MHC) are positively selected. The net result of these developmental pathways is a T-cell repertoire that is both self-tolerant and self-restricted. One unresolved issue is the identity of the thymic stromal cells that mediate the negative and positive selection of the T-cell repertoire. Previous work has pointed to a bone-marrow-derived macrophage or dendritic cell as the inducer of tolerance, whereas a radiation-resistant, deoxyguanosine-resistant thymic cell seems to mediate the positive selection of self-MHC restricted T cells. Thymic stromal cells in the cortex interact with the T-cell antigen receptor on thymocytes. Using several strains of transgenic mice that express the class II MHC molecule I-E in specific regions of the thymus, we show directly that the positive selection of T cells is mediated by an I-E-bearing cell in the thymic cortex.     

Metric inference for social networks

Using a natural metric on the space of networks, we define a probability measure for network-valued random variables. This measure is indexed by two parameters, which are interpretable as a location parameter and a dispersion parameter. From this structure, one can develop maximum likelihood estimates, hypothesis tests and confidence regions, all in the context of independent and identically distributed networks. The value of this perspective is illustrated through application to portions of the friedship cognitive social structure data gathered by Krackhardt (1987).We thank Ove Frank, David Krackhardt, the editor and the referees for their constructive comments and suggestions.     

A markup model for forecasting inflation for the euro area

We develop a small model for forecasting inflation for the euro area using quarterly data over the period June 1973 to March 1999. The model is used to provide inflation forecasts from June 1999 to March 2002. We compare the forecasts from our model with those derived from six competing forecasting models, including autoregressions, vector autoregressions and Phillips‐curve based models. A considerable gain in forecasting performance is demonstrated using a relative root mean squared error criterion and the Diebold–Mariano test to make forecast comparisons. Copyright © 2006 John Wiley & Sons, Ltd.     

Heterozygous deletion of the linked genes ZIC1 and ZIC4 is involved in Dandy-Walker malformation

Dandy-Walker malformation (DWM; OMIM #220200) is a common but poorly understood congenital cerebellar malformation in humans. Through physical mapping of 3q2 interstitial deletions in several individuals with DWM, we defined the first critical region associated with DWM, encompassing two adjacent Zinc finger in cerebellum genes, ZIC1 and ZIC4. Mice with a heterozygous deletion of these two linked genes have a phenotype that closely resembles DWM, providing a mouse model for this malformation.