The apoptosome is a multiprotein complex comprising Apaf-1, cytochrome c, and caspase-9 that functions to activate caspase-3 downstream of mitochondria in response to apoptotic signals. Binding of cytochrome c and dATP to Apaf-1 in the cytosol leads to the assembly of a heptameric complex in which each Apaf-1 subunit is bound noncovalently to a procaspase-9 subunit via their respective CARD domains. Assembly of the apoptosome results in the proteolytic cleavage of procaspase-9 at the cleavage site PEPD 315 to yield the large (p35) and small (p12) caspase-9 subunits. In addition to the PEPD site, caspase-9 contains a caspase-3 cleavage site (DQLD 330 ), which when cleaved, produces a smaller p10 subunit in which the NH 2 -terminal 15 amino acids of p12, including the XIAP BIR3 binding motif, are removed. Using purified proteins in a reconstituted reaction in vitro, we have assessed the relative impact of Asp 315 and Asp 330cleavage on caspase-9 activity within the apoptosome. In addition, we characterized the effect of caspase-3 feedback cleavage of caspase-9 on the rate of caspase-3 activation, and the potential ramifications of Asp 330 cleavage on XIAP-mediated inhibition of the apoptosome. We have found that cleavage of procaspase-9 at Asp 330 to generate p35, p10 or p37, p10 forms resulted in a significant increase (up to 8-fold) in apoptosome activity compared with p35/p12. The significance of this increase was demonstrated by the near complete loss of apoptosome-mediated caspase-3 activity when a point mutant (D330A) of procaspase-9 was substituted for wild-type procaspase-9 in the apoptosome. In addition, cleavage at Asp 330 exposed a novel p10 NH 2 -terminal peptide motif (AISS) that retained the ability to mediate XIAP inhibition of caspase-9. Thus, whereas feedback cleavage of caspase-9 by caspase-3 significantly increases the activity of the apoptosome, it does little to attenuate its sensitivity to inhibition by XIAP.

Elite philanthropy—voluntary giving at scale by wealthy individuals, couples and families—is intimately bound up with the exercise of power by elites. This theoretically oriented review examines how big philanthropy in the United States and United Kingdom serves to extend elite control from the domain of the economic to the domains of the social and political, and with what results. Elite philanthropy, we argue, is not simply a benign force for good, born of altruism, but is heavily implicated in what we call the new age of inequalities, certainly as consequence and potentially as cause. Philanthropy at scale pays dividends to donors as much as it brings sustenance to beneficiaries. The research contribution we make is fourfold. First, we demonstrate that the true nature and effects of elite philanthropy can only be understood in the context of what Bourdieu calls the field of power, which maintains the economic, social and political hegemony of the super‐rich, nationally and globally. Second, we demonstrate how elite philanthropy systemically concentrates power in the hands of mega foundations and the most prestigious endowed charitable organizations. Third, we explicate the similarities and differences between the four main types of elite philanthropy—institutionally supportive, market‐oriented, developmental and transformational—revealing how and why different sections within the elite express themselves through philanthropy. Fourth, we show how elite philanthropy functions to lock in and perpetuate inequalities rather than remedying them. We conclude by outlining proposals for future research, recognizing that under‐specification of constructs has hitherto limited the integration of philanthropy within the mainstream of management and organizational research.

Genome-wide association studies have shown that Krüppel-like factor 14 (KLF14) is associated with both Type 2 diabetes mellitus and lipid metabolism. However, its role in chronic inflammatory responses and the pathogenesis of atherosclerosis remains unknown. The present study was designed to investigate both in vivo and in vitro the impact of KLF14 on chronic inflammatory responses and atherosclerosis. ApoE KO mice, a well-established animal model of atherosclerosis, had higher expressions of KLF14 in aorta tissues than that in C57BL/6 J mice when fed the high-fat diet (HFD) or standard chow diet. Adenovirus-mediated KLF14 knockdown markedly reduced the circulating levels of proinflammatory cytokines and the formation of atherosclerotic lesions in HFD-fed ApoE KO mice. In the in vitro study, KLF14 overexpression in the RAW264.7 macrophages significantly increased the expressions of inflammatory cytokines, total cholesterol (TC), cholesteryl ester (CE), and the ratio of CE to TC in the cells treated with acetylated low-density lipoproteins (AcLDL). Conversely, KLF14 knockdown remarkably attenuated AcLDL-induced increase in TC, CE, and the ratio of CE to TC as well as the expressions of inflammatory cytokines. Furthermore, up-regulation or down-regulation of KLF14 markedly elevated or inhibited the phosphorylation levels of p38 MAPK and ERK1/2 in AcLDL-stimulated RAW264.7 macrophages, respectively. Importantly, treatment with p38 MAPK or ERK1/2 inhibitor nullified the effects of KLF14 on inflammatory cytokine expressions in the cells. These data demonstrate an important role for KLF14 expression in atherosclerotic lesion formation.

No abstract

We examine the role of mediators in locally embedding the community foundation model of philanthropy to enable its global diffusion. We hold that mediators, as trusted agents within elite networks, promote and legitimate institutional innovation by tailoring the model to satisfy local requirements. They thereby limit resistance while creating future potentialities. Our novel addition to the community foundation literature stems from research on the transatlantic diffusion of the community foundation template from the United States to the United Kingdom focused on an in-depth case study of one of Europe’s largest community foundation, that serving Tyne & Wear and Northumberland in North East England. Our findings suggest that success in embedding the community foundation model depends on rendering it fit-for-context and fit-for-purpose. Mediators operating at both the macro and micro level matter because they have the cultural, social, and symbolic capital needed to win acceptance for initially alien philanthropic principles, practices, and structures.