Associations have been reported of the seven-repeat (7R) allele of the human dopamine receptor D4 (DRD4) gene with both attentiondeficit͞hyperactivity disorder and the personality trait of novelty seeking. This polymorphism occurs in a 48-bp tandem repeat in the coding region of DRD4, with the most common allele containing four repeats (4R) and rarer variants containing 2-11. Here we show by DNA resequencing͞haplotyping of 600 DRD4 alleles, representing a worldwide population sample, that the origin of 2R-6R alleles can be explained by simple one-step recombination͞mutation events. In contrast, the 7R allele is not simply related to the other common alleles, differing by greater than six recombinations͞mutations. Strong linkage disequilibrium was found between the 7R allele and surrounding DRD4 polymorphisms, suggesting that this allele is at least 5-10-fold ''younger'' than the common 4R allele. Based on an observed bias toward nonsynonymous amino acid changes, the unusual DNA sequence organization, and the strong linkage disequilibrium surrounding the DRD4 7R allele, we propose that this allele originated as a rare mutational event that nevertheless increased to high frequency in human populations by positive selection.

Neurofibrillary tangles comprised of highly phosphorylated tau proteins are a key component of Alzheimer's disease pathology. Mice lacking Reelin (Reln), double-knockouts lacking the VLDL receptor (VLDLR) and ApoE receptor2 (ApoER2), and mice lacking disabled-1 (Dab1) display increased levels of phosphorylated tau. Because Reln binds to recombinant ApoE receptors, assembly of a Reln/ApoE-receptor/Dab1 (RAD) complex may initiate a signal transduction cascade that controls tau phosphorylation. Conversely, disruption of this RAD complex may increase tau phosphorylation and lead to neurodegeneration. To substantiate this concept, we mated Reln-deficient mice to ApoE-deficient mice and found that in the absence of Reln, tau phosphorylation increased as the amount of ApoE decreased. Paralleling the change in tau phosphorylation levels, we found that GSK-3beta activity increased in Reln-deficient mice and further increased in mice lacking both Reln and ApoE. CDK-5 activity was similar in mice lacking Reln, ApoE, or both. GSK-3beta and CDK-5 activity increased in Dab1-deficient mice, independent of ApoE levels. Further supporting the idea that increased tau phosphorylation results primarily from increased kinase activity, the activity of two phosphatases was similar in all conditions tested. These data support a novel, ligand-mediated signal transduction cascade--initiated by the assembly of a RAD complex that suppresses kinase activity and controls tau phosphorylation.

Data is increasingly being bought and sold online, and Webbased marketplace services have emerged to facilitate these activities. However, current mechanisms for pricing data are very simple: buyers can choose only from a set of explicit views, each with a specific price. In this paper, we propose a framework for pricing data on the Internet that, given the price of a few views, allows the price of any query to be derived automatically. We call this capability "querybased pricing." We first identify two important properties that the pricing function must satisfy, called arbitragefree and discount-free. Then, we prove that there exists a unique function that satisfies these properties and extends the seller's explicit prices to all queries. When both the views and the query are Unions of Conjunctive Queries, the complexity of computing the price is high. To ensure tractability, we restrict the explicit prices to be defined only on selection views (which is the common practice today). We give an algorithm with polynomial time data complexity for computing the price of any chain query by reducing the problem to network flow. Furthermore, we completely characterize the class of Conjunctive Queries without selfjoins that have PTIME data complexity (this class is slightly larger than chain queries), and prove that pricing all other queries is NP-complete, thus establishing a dichotomy on the complexity of the pricing problem when all views are selection queries.

The levels of plasma HDL cholesterol and apoA-I in NFB p50 subunit-deficient mice were significantly higher than those in wild-type mice under regular and high fat diets, without any significant difference in the level of total cholesterol. To examine the role of NFB in lipid metabolism, we studied its effect on the regulation of apoA-I secretion from human hepatoma HepG2 cells. Lipopolysaccharide-induced activation of NFB reduced the expression of apoA-I mRNA and protein, whereas adenovirus-mediated expression of IB␣ superrepressor ameliorated the reduction. This IB␣-induced apoA-I increase was blocked by preincubation with MK886, a selective inhibitor of peroxisome proliferatoractivated receptor ␣ (PPAR␣), suggesting that NFB inactivation induces apoA-I through activation of PPAR␣. To further support this idea, the expression of IB␣ increased apoA-I promoter activity, and this increase was blocked by preincubation with MK886. Mutations in the putative PPAR␣-binding site in the apoA-I promoter or lack of the site abrogated these changes. Taking these results together, inhibition of NFB increases apoA-I and HDL cholesterol through activation of PPAR␣ in vivo and in vitro. Our data suggest a new aspect of lipid metabolism and may lead to a new paradigm for prevention and treatment of atherosclerotic disease.

We address the problem of efficiently constructing materialized XML views of relational databases. In our setting, the XML view is specified by a query in the declarative query language of a middle-ware system, called SilkRoute. The middle-ware system evaluates a query by sending one or more SQL queries to the target relational database, integrating the resulting tuple streams, and adding the XML tags. We focus on how to best choose the SQL queries, without having control over the target RDBMS.