Cyclic AMP induces integrin-mediated cell adhesion through Epac and Rap1 upon stimulation of the β2-adrenergic receptor

cAMP controls many cellular processes mainly through the activation of protein kinase A (PKA). However, more recently PKA-independent pathways have been established through the exchange protein directly activated by cAMP (Epac), a guanine nucleotide exchange factor for the small GTPases Rap1 and Rap2. In this report, we show that cAMP can induce integrin-mediated cell adhesion through Epac and Rap1. Indeed, when Ovcar3 cells were treated with cAMP, cells adhered more rapidly to fibronectin. This cAMP effect was insensitive to the PKA inhibitor H-89. A similar increase was observed when the cells were transfected with Epac. Both the cAMP effect and the Epac effect on cell adhesion were abolished by the expression of Rap1–GTPase-activating protein, indicating the involvement of Rap1 in the signaling pathway. Importantly, a recently characterized cAMP analogue, 8-(4-chloro-phenylthio)-2′-O-methyladenosine-3′,5′-cyclic monophosphate, which specifically activates Epac but not PKA, induced Rap-dependent cell adhesion. Finally, we demonstrate that external stimuli of cAMP signaling, i.e., isoproterenol, which activates the Gαs-coupled β2-adrenergic receptor can induce integrin-mediated cell adhesion through the Epac-Rap1 pathway. From these results we conclude that cAMP mediates receptor-induced integrin-mediated cell adhesion to fibronectin through the Epac-Rap1 signaling pathway

Th1 Lymphokine Production Profiles of Nickel-Specific CD4+ T-Lymphocyte Clones from Nickel Contact Allergic and Non-Allergic Individuals

Panels of nickel-specific T-lymphocyte clones (TLC) were prepared from nickel-allergic and non-allergic donors. TLC from both panels showed similar levels of expression of TCRα/β, CD4, CD2, CD25, and CD29 and recognized nickel in association with class II HLA molecules with restriction determinants in HLA-DR, HLA-DP, and HLA-DQ. The lymphokine secretion was analyzed in TLC from both panels upon antigen-specific or non-specific stimulation and was compared with the secretion profiles of representants of pre-established human atopen-specific Th1 and Th2 cells. Nickel-specific TLC from both panels showed a lymphokine secretion pattern similar to the atopen-specific Th1 cells, although there was some variation from clone to clone. Most TLC secreted substantial amounts of IFN-γ, IL-2, TNF-α and GM-CSF, but little or no IL-4 and IL-5. The variation observed mainly concerned IL-2 secretion that could be low or absent in some of the TLC. The general secretion pattern did not change upon different modes of stimulation, including activation via CD3, CD2, or CD28. Because nickel-specific TLC from allergic and non-allergic individuals show a similar Th1 secretion pattern, the present results give no evidence that aberrant lymphokine secretion by CD4+ T cells determines the contact allergic state, as was found for atopic allergy in a previous study

Щодо утворення сімейств атомарних радіальних базисних функцій

Наведено схему побудови сімейств атомарних радіальних базисних функцій, які є нескінченно диференційовними фінітними розв'язками функціонально-диференціальних рівнянь, породжених операторами Лапласа та Гельмгольца.The scheme of building a family of atomic radial basis functions which are infinitely differentiable finite solutions of the functional-differential equations containing the Laplace and Helmholtz operators is introduced

The M3 muscarinic receptor Is required for optimal adaptive immunity to Helminth and bacterial infection

Innate immunity is regulated by cholinergic signalling through nicotinic acetylcholine receptors. We show here that signalling through the M3 muscarinic acetylcholine receptor (M3R) plays an important role in adaptive immunity to both Nippostrongylus brasiliensis and Salmonella enterica serovar Typhimurium, as M3R-/- mice were impaired in their ability to resolve infection with either pathogen. CD4 T cell activation and cytokine production were reduced in M3R-/- mice. Immunity to secondary infection with N. brasiliensis was severely impaired, with reduced cytokine responses in M3R-/- mice accompanied by lower numbers of mucus-producing goblet cells and alternatively activated macrophages in the lungs. Ex vivo lymphocyte stimulation of cells from intact BALB/c mice infected with N. brasiliensis and S. typhimurium with muscarinic agonists resulted in enhanced production of IL-13 and IFN-γ respectively, which was blocked by an M3R-selective antagonist. Our data therefore indicate that cholinergic signalling via the M3R is essential for optimal Th1 and Th2 adaptive immunity to infection

Adjusted prognostic association of post-myocardial infarction depression withmortality and cardiovascular events: an individual patient data meta-analysis

Background: The association between depression after myocardial infarction (post-MI) and increased risk of mortality and cardiac morbidity may be due to cardiac disease severity. Aims: To combine original data from studies on the association between post-MI depression and prognosis into one database. To investigate to what extent post-MI depression predicts prognosis independently of disease severity. Method: Individual patient data meta-analysis of studies, using multilevel, multivariable Cox regression analyses. Results:Sixteen studies participated, creating a database of 10,175 post-MI patients. HRs for post-MI depression were 1.32 (95%CI 1.26-1.38, p Conclusions: The association between post-MI depression and prognosis is attenuated after adjustment for cardiac disease severity. Still, depression remains independently associated with prognosis, with a 22% increased risk of all-cause mortality and a 13% increased risk of cardiovascular events per standard deviation in depression z-score. Declaration of interest: None

Collusion through Joint R&D: An Empirical Assessment

This paper tests whether upstream R&D cooperation leads to downstream collusion. We consider an oligopolistic setting where firms enter in research joint ventures (RJVs) to lower production costs or coordinate on collusion in the product market. We show that a sufficient condition for identifying collusive behavior is a decline in the market share of RJV-participating firms, which is also necessary and sufficient for a decrease in consumer welfare. Using information from the US National Cooperation Research Act, we estimate a market share equation correcting for the endogeneity of RJV participation and R&D expenditures. We find robust evidence that large networks between direct competitors – created through firms being members in several RJVs at the same time – are conducive to collusive outcomes in the product market which reduce consumer welfare. By contrast, RJVs among non-competitors are efficiency enhancing