Rationale: Sepsis and acute lung injury (ALI) have devastatingly high mortality rates. Both are associated with increased vascular leak, a process regulated by complex molecular mechanisms. Objectives: We hypothesized that integrin avb3 could be an important determinant of vascular leak and endothelial permeability in sepsis and ALI. Methods: b3 subunit knockout mice were tested for lung vascular leak after endotracheal LPS, and systemic vascular leak and mortality after intraperitoneal LPS and cecal ligation and puncture. Possible contributory effects of b3 deficiency in platelets and other hematopoietic cells were excluded by bone marrow reconstitution experiments. Endothelial cells treated with avb3 antibodies were evaluated for sphingosine-1 phosphate (S1P)-mediated alterations in barrier function, cytoskeletal arrangement, and integrin localization. Measurements and Main Results: b3 knockout mice had increased vascular leak and pulmonary edema formation after endotracheal LPS, and increased vascular leak and mortality after intraperitoneal LPS and cecal ligation and puncture. In endothelial cells, avb3 antibodies inhibited barrier-enhancing and cortical actin responses to S1P. Furthermore, S1P induced translocation of avb3 from discrete focal adhesions to cortically distributed sites through Gi-and Rac1-mediated pathways. Cortical avb3 localization after S1P was decreased by avb3 antibodies, suggesting that ligation of the avb3 with its extracellular matrix ligands is required to stabilize cortical avb3 focal adhesions. Conclusions: Our studies identify a novel mechanism by which avb3 mitigates increased vascular leak, a pathophysiologic function central to sepsis and ALI. These studies suggest that drugs designed to block avb3 may have the unexpected side effect of intensifying sepsis-and ALI-associated vascular endothelial leak.Keywords: vascular endothelium; sepsis; acute lung injury; integrin Sepsis and acute lung injury (ALI) are associated with high mortality rates and worldwide healthcare burden (1-4). Development of these syndromes requires complex host responses involving multiple cell types, inflammatory mediators, and coagulation factors. One pathophysiologic hallmark common to both sepsis and ALI is increased vascular leak. Increased vascular leak in sepsis leads to redistribution of intravascular fluid to extravascular compartments, hypovolemia, hemoconcentration, and stasis of blood flow. In ALI, alveolar spaces become flooded with pulmonary edema, resulting in impaired gas exchange, arterial hypoxemia, and respiratory failure (4-6).It is generally believed that increased paracellular passage of solutes through the vascular endothelium occurs during acute inflammatory states (7,8). Frequently cited models suggest that paracellular gaps form because of disrupted homeostasis between cytoskeletal, adhesive cell-cell, and cell-matrix forces (8-10). Integrins, a large family of heterodimeric glycoprotein receptors, are important mediators of these cellular functions and have been shown to participa...

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This paper uses staggered bank branching deregulation across states in the UnitedStates to examine the impact of the resulting increase in the supply of credit on college enrollment from the 70s to early 90s. A significant advantage of our research design is that it produces estimates that are not confounded by wealth effects. We find that lifting branching restrictions raises college enrollment by about 2 percentage points (4%). Our results rule out alternative interpretations to the credit constraints channel.First, the effects are largest for low and middle income families, while insignificant for upper income families as well as bankrupt families who would have been unaffected by the increased access to private credit. Second, the effect of lifting branching restrictions subsided immediately following periods of increased loan limit through government student loan programs. We also show that household educational borrowing increased as a result of lifting branching restrictions. Our results provide novel evidence that credit constraints play an important role in determining household college enrollment decisions in the United States.

We study the impact of corporate taxes on barcode-level product prices using linked survey and administrative data. Our empirical strategy exploits the dichotomy between the location of production and the location of sales, providing estimates free from confounding demand shocks. We find significant effects of corporate taxes on prices with a net-of-tax elasticity of 0.17. The effects are larger for lower-price items and products purchased by low-income households and weaker for high-leverage firms. Approximately 31% of corporate tax incidence falls on consumers, suggesting that models used by policymakers significantly underestimate the incidence of corporate taxes on consumers.

We study how management practices shape export performance using matched productiontrade-management data for Chinese and American firms and a randomized control trial in India. Better managed firms are more likely to export, sell more products to more destinations, and earn higher export revenues and profits. They export higher-quality products at higher prices and lower quality-adjusted prices. They import a wider range of inputs and inputs of higher quality and price, from more advanced countries. We rationalize these patterns with a heterogeneous-firm model in which effective management improves performance by raising production efficiency and quality capacity.