Cyclooxygenase-2 Inhibition Enhances Activation of T Helper Type 1 Responses During Salmonella Infection

Production of IL-12 and IFN-γ secretion are important components of the protective host response against the intracellular bacterial pathogen, Salmonella typhimurium. While infection with Salmonella does elicit this T helper type 1 response, its magnitude does not appear to be sufficient to prevent infection or limit pathogenesis. Therefore we have investigated factors which might limit a T helper type 1 response following infection. Previously we found that infection of antigen presenting cells with Salmonella dramatically increases cyclooxygenase-2 (COX-2) activity, resulting in high levels of prostaglandin E2 (PGE2). Since PGE2 production can have profound effects on initiation of T helper type 1 responses, we questioned whether this mediator might limit antigen-specific T cell activation. Here we show that blockage of COX-2 activity with the selective inhibitor celecoxib leads to enhancement of the T helper type 1 components stimulated by Salmonella infection. In vitro studies demonstrate the induction of IL-12 and IFN-γ upon Salmonella exposure, which are further increased following COX-2 inhibition. Taken together these in vitro studies suggest that COX-2 activity can limit a salmonella-initiated T helper type 1 response

Modeling and Analyzing Periodic Distributed Computations

Abstract. The earlier work on predicate detection has assumed that the given computation is finite. Detecting violation of a liveness predicate requires that the predicate be evaluated on an infinite computation. In this work, we develop the theory and associated algorithms for predicate detection in infinite runs. In practice, an infinite run can be determined in finite time only if it consists of a recurrent behavior with some finite prefix. Therefore, our study is restricted to such runs. We introduce the concept of d-diagram, which is a finite representation of infinite directed graphs. Given a d-diagram that represents an infinite distributed computation, we solve the problem of determining if a global predicate ever became true in the computation. The crucial aspect of this problem is the stopping rule that tells us when to conclude that the predicate can never become true in future. We also provide an algorithm to provide vector timestamps to events in the computation for determining the dependency relationship between any two events in the infinite run.

Distribution and Evolution of von Willebrand/Integrin A Domains: Widely Dispersed Domains with Roles in Cell Adhesion and Elsewhere

The von Willebrand A (VWA) domain is a well-studied domain involved in cell adhesion, in extracellular matrix proteins, and in integrin receptors. A number of human diseases arise from mutations in VWA domains. We have analyzed the phylogenetic distribution of this domain and the relationships among ∼500 proteins containing this domain. Although the majority of VWA-containing proteins are extracellular, the most ancient ones, present in all eukaryotes, are all intracellular proteins involved in functions such as transcription, DNA repair, ribosomal and membrane transport, and the proteasome. A common feature seems to be involvement in multiprotein complexes. Subsequent evolution involved deployment of VWA domains by Metazoa in extracellular proteins involved in cell adhesion such as integrin β subunits (all Metazoa). Nematodes and chordates separately expanded their complements of extracellular matrix proteins containing VWA domains, whereas plants expanded their intracellular complement. Chordates developed VWA-containing integrin α subunits, collagens, and other extracellular matrix proteins (e.g., matrilins, cochlin/vitrin, and von Willebrand factor). Consideration of the known properties of VWA domains in integrins and extracellular matrix proteins allows insights into their involvement in protein–protein interactions and the roles of bound divalent cations and conformational changes. These allow inferences about similar functions in novel situations such as protease regulators (e.g., complement factors and trypsin inhibitors) and intracellular proteins (e.g., helicases, chelatases, and copines)