Activated protein C (APC) reduces mortality of severe sepsis patients but increases the risk of serious bleeding. APC exerts anticoagulant activity by proteolysis of factors Va/VIIIa. APC also exerts antiinflammatory and antiapoptotic effects and stabilizes endothelial barrier function by APC-initiated cell signaling that requires two receptors, endothelial cell protein C receptor (EPCR) and protease-activated receptor 1 (PAR1). The relative importance of APC's various activities for efficacy in sepsis is unknown. We used protein engineering of mouse APC and genetically altered mice to clarify mechanisms for the efficacy of APC in mouse sepsis models. Mortality reduction in LPS-induced endotoxemia required the enzymatic active site of APC, EPCR, and PAR-1, highlighting a key role for APC's cytoprotective actions. A recombinant APC variant with normal signaling but <10% anticoagulant activity (5A-APC) was as effective as wild-type APC in reducing mortality after LPS challenge, and enhanced the survival of mice subjected to peritonitis induced by gram-positive or -negative bacteria or to polymicrobial peritoneal sepsis triggered by colon ascendens stent implantation. Thus, APC's efficacy in severe sepsis is predominantly based on EPCR- and PAR1-dependent cell signaling, and APC variants with normal cell signaling but reduced anticoagulant activities retain efficacy while reducing the risk of bleeding.

The current understanding of boundary-layer receptivity to external acoustic and vortical disturbances is reviewed. Recent advances in theoretical modeling, numerical simulations, and experiments are discussed. It is shown that aspects of the theory have been validated and that the mechanisms by which freestream disturbances provide the initial conditions for unstable waves are better understood. Challenges remain, however, particularly with respect to freestream turbulence.

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A theoretical model is developed for the sound generated when a convected vortical or entropic gust encounters an airfoil at non-zero angle of attack. The theory is based on a linearization of the Euler equations about the steady subsonic flow past the airfoil. High-frequency gusts, whose wavelengths are short compared to the airfoil chord, but long compared to the displacement of the mean-flow stagnation point from the leading edge, are considered. The analysis utilizes singular-perturbation techniques and involves four asymptotic regions. Local regions, which scale on the gust wavelength, are present at the airfoil leading and trailing edges. Behind the airfoil a ‘transition’ region, which is similar to the transition zone between illuminated and shadow zones in optical problems, is present. In the outer region, far away from the airfoil edges and wake, the solution has a geometric-acoustics form. The primary sound generation is found to be concentrated in the local leading-edge region. The trailing edge plays a secondary role as a scatterer of the sound generated in the leading-edge region. Parametric calculations are presented which illustrate that moderate levels of airfoil steady loading can significantly affect the sound field produced by airfoil–gust interactions.

Activated protein C (aPC) therapy reduces mortality in adult patients with severe sepsis. In mouse endotoxemia and sepsis models, mortality reduction requires the cell signaling function of aPC, mediated through protease-activated receptor-1 (PAR1) and endothelial protein C receptor (EPCR; also known as Procr). Candidate cellular targets of aPC include vascular endothelial cells and leukocytes. Here, we show that expression of EPCR and PAR1 on hematopoietic cells is required in mice for an aPC variant that mediates full cell signaling activity but only minimal anticoagulant function (5A-aPC) to reduce the mortality of endotoxemia. Expression of EPCR in mature murine immune cells was limited to a subset

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