This paper argues that the 'competitive liberalisation' of national governments of the past several decades has created a 'market' for regional economic integration agreements (EIAs). Evidence shows that countries that have selected into EIAs - such as free trade agreements - have 'chosen well' in the sense that the same economic characteristics that explain and predict bilateral EIAs also explain and predict bilateral trade flows. We show that previous ex post empirical evaluations of the effects of EIAs on trade have tended to underestimate the effects due to ignoring the (endogenous) self-selection bias of country pairs into EIAs. Accounting for this bias, we find that European economic integration had a much larger impact on trade over the period 1960-2000 than previously found, and other more recent EIAs have had economically and statistically significant effects on members' trade. The results shed further light on understanding the causes and consequences of the growth of regionalism. Copyright 2008 The Authors.

We introduce RegData, formerly known as the Industry-specific Regulatory Constraint Database. RegData annually quantifies federal regulations by industry and regulatory agency for all federal regulations from 1997-2012. The quantification of regulations at the industry level for all industries is without precedent. RegData measures regulation for industries at the two, three, and four-digit levels of the North American Industry Classification System. We created this database using text analysis to count binding constraints in the wording of regulations, as codified in the Code of Federal Regulations, and to measure the applicability of regulatory text to different industries. We validate our measures of regulation by examining known episodes of regulatory growth and deregulation, as well as by comparing our measures to an existing, cross-sectional measure of regulation. Researchers can use this database to study the determinants of industry regulations and to study regulations' effects on a massive array of dependent variables, both across industries and time.JEL codes: K2, L5, N4, Y1

The presence of tumor-infiltrating T cells is associated with favorable patient outcomes, yet most pancreatic cancers are immunologically silent and resistant to currently available immunotherapies. Here we show using a syngeneic orthotopic implantation model of pancreatic cancer that Pik3ca regulates tumor immunogenicity. Genetic silencing of Pik3ca in Kras G12D /Trp53 R172H -driven pancreatic tumors resulted in infiltration of T cells, complete tumor regression, and 100% survival of immunocompetent host mice. By contrast, Pik3ca -null tumors implanted in T cell–deficient mice progressed and killed all of the animals. Adoptive transfer of tumor antigen–experienced T cells eliminated Pik3ca -null tumors in immunodeficient mice. Loss of PIK3CA or inhibition of its effector AKT increased the expression of MHC class I and CD80 on tumor cells. These changes contributed to the increased susceptibility of Pik3ca -null tumors to T cell surveillance. Our results indicate that tumor cell PIK3CA-AKT signaling limits T cell recognition and clearance of pancreatic cancer cells. Strategies that target this pathway may yield an effective immunotherapy for this cancer.

Although the pathogenesis of Parkinson's disease (PD) remains unknown, it appears that microglial activation is associated with enhanced neurodegeneration in animal models of PD as well as in PD patients. Experimentally, C57BL/6 and SWR/J mice demonstrate striking differences in the extent of dopaminergic (DAergic) neurodegeneration induced by a parkinsonian toxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The purpose of this study was to determine whether differences in microglial activation between these two strains of mice could provide insight into the variability seen in toxicant induced neuronal death, and subsequently to use a high-throughput proteomic method, combining stable isotope labeling with amino acids in cell culture (SILAC) with liquid chromatography and tandem mass spectrometry, to compare the microglial proteomes of C57BL/6 and SWR/J mice after stimulation with a classical microglial activator, lipopolysaccharide (LPS). We found that DAergic neurotoxicity induced by LPS in a primary neuron-microglia coculture was twofold greater with microglia isolated from the brains of C57BL/6 mice compared with that of SWR/J mice. Upon proteomic analysis we found that, out of over 1,000 proteins identified and quantified, 400 displayed a significant difference in their relative abundance between these two murine strains. Several proteins, which had relatively higher levels in C57BL/6 mice, have previously been implicated in LPS-mediated microglial activation, including those involved in the COX-2 pathway and in prostaglandin E-2 (PGE(2)) production. To validate our proteomic results we confirmed the increased expression level of iNOS in C57BL/6 vs. SWR/J microglia with semiquantitative Western blot. Further analysis of our proteomic discovery data will likely reveal numerous novel proteins involved in inflammation-mediated neurotoxicity in PD.

Interleukin-22 (IL-22) signaling in the intestines is critical for promoting tissue-protective functions. However, since a diverse array of cell types (absorptive and secretory epithelium as well as stem cells) express IL-22Ra1, a receptor for IL-22, it has been difficult to determine what cell type(s) specifically respond to IL-22 to mediate intestinal mucosal host defense. Here, we report that IL-22 signaling in the small intestine is positively correlated with Paneth cell differentiation programs. Our Il22Ra1fl/fl;Lgr5-EGFP-creERT2-specific knockout mice and, independently, our lineage-tracing findings rule out the involvement of Lgr5+ intestinal stem cell (ISC)-dependent IL-22Ra1 signaling in regulating the lineage commitment of epithelial cells, including Paneth cells. Using novel Paneth cell-specific IL-22Ra1 knockout mice (Il22Ra1fl/fl;Defa6-cre), we show that IL-22 signaling in Paneth cells is required for small intestinal host defense. We show that Paneth cell maturation, antimicrobial effector function, expression of specific WNTs, and organoid morphogenesis are dependent on cell-intrinsic IL-22Ra1 signaling. Furthermore, IL-22 signaling in Paneth cells regulates the intestinal commensal bacteria and microbiota-dependent IL-17A immune responses. Finally, we show ISC and, independently, Paneth cell-specific IL-22Ra1 signaling are critical for providing immunity against Salmonella enterica serovar Typhimurium. Collectively, our findings illustrate a previously unknown role of IL-22 in Paneth cell-mediated small intestinal host defense.