17 research outputs found

    Prevention and Mitigation of Acute Radiation Syndrome in Mice by Synthetic Lipopeptide Agonists of Toll-Like Receptor 2 (TLR2)

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    Bacterial lipoproteins (BLP) induce innate immune responses in mammals by activating heterodimeric receptor complexes containing Toll-like receptor 2 (TLR2). TLR2 signaling results in nuclear factor-kappaB (NF-ÎșB)-dependent upregulation of anti-apoptotic factors, anti-oxidants and cytokines, all of which have been implicated in radiation protection. Here we demonstrate that synthetic lipopeptides (sLP) that mimic the structure of naturally occurring mycoplasmal BLP significantly increase mouse survival following lethal total body irradiation (TBI) when administered between 48 hours before and 24 hours after irradiation. The TBI dose ranges against which sLP are effective indicate that sLP primarily impact the hematopoietic (HP) component of acute radiation syndrome. Indeed, sLP treatment accelerated recovery of bone marrow (BM) and spleen cellularity and ameliorated thrombocytopenia of irradiated mice. sLP did not improve survival of irradiated TLR2-knockout mice, confirming that sLP-mediated radioprotection requires TLR2. However, sLP was radioprotective in chimeric mice containing TLR2-null BM on a wild type background, indicating that radioprotection of the HP system by sLP is, at least in part, indirect and initiated in non-BM cells. sLP injection resulted in strong transient induction of multiple cytokines with known roles in hematopoiesis, including granulocyte colony-stimulating factor (G-CSF), keratinocyte chemoattractant (KC) and interleukin-6 (IL-6). sLP-induced cytokines, particularly G-CSF, are likely mediators of the radioprotective/mitigative activity of sLP. This study illustrates the strong potential of LP-based TLR2 agonists for anti-radiation prophylaxis and therapy in defense and medical scenarios

    Between Commerce and Empire: David Hume, Colonial Slavery, and Commercial Incivility

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    Eighteenth-century Enlightenment thought has recently been reclaimed as a robust, albeit short-lived, cosmopolitan critique of European imperialism. This essay complicates this interpretation through a study of David Hume’s reflections on commerce, empire and slavery. I argue that while Hume condemned the colonial system of monopoly, war and conquest, his strictures against empire did not extend to colonial slavery in the Atlantic. This was because colonial slavery represented a manifestly uncivil institution when judged by enlightened metropolitan sensibilities, yet also a decisively commercial institution pivotal to the eighteenth-century global economy. Confronted by the paradoxical ‘commercial incivility’ of modern slavery, Hume opted for disavowing the link between slavery and commerce, and confined his criticism of slavery to its ancient, feudal and Asiatic incarnations. I contend that Hume’s disavowal of the commercial barbarism of the Atlantic economy is part of a broader ideological effort to separate the idea of commerce from its imperial origins and posit it as the liberal antithesis of empire. The implications of analysis, I conclude, go beyond the eighteenth-century debates over commerce and empire, and more generally pertain to the contradictory entwinement of liberalism and capitalism

    Motivation crowding and the federal civil servant: Evidence from the U.S. internal revenue service

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    Pay-for-performance reforms create “high-powered” incentives for civil servants to meet or exceed specified performance objectives as measured by such things as customer satisfaction. Economists and social psychologists have advanced the claim that high-powered incentives for performance may empirically lessen the effect of civil servants' intrinsic motivation toward achieving agency goals (motivation can be “crowded out”). Nonetheless, well-designed pay-for-performance incentives may “crowd in” intrinsic motivation. A number of federal agencies and subagencies have undergone personnel management reforms that raise the specter of this pattern of “motivation crowding.” Does it happen? Is intrinsic motivation crowded in or crowded out? This paper employs item response theory to create measurement models for the estimation a latent trait of intrinsic motivation for employees of the Internal Revenue Service (IRS) and Office of the Comptroller of the Currency (OCC) using data from the 2002 Federal Human Capital Survey. The IRS, but not the OCC, implemented a paybanding system that imposed high-powered performance incentives on supervisors, but not on non-supervisory personnel. Results suggest that the IRS reward structure crowded in intrinsic motivation at the lowest levels, but that at the highest levels of motivation intrinsic motivation is crowded out, a pattern not seen in the OCC data
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