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IL-10 is an 18-kDa cytokine with a key role in homeostatic control of inflammatory and immune responses. We have investigated how transcription of the IL-10 gene is regulated, so as to be able to understand the circumstances of IL-10 expression in both health and disease. In the mouse, IL-10 gene expression is regulated by a TATA-type promoter with a critical cis-acting element containing GGA repeats located at −89 to −77. Its complementary sequence is similar to the cis-acting elements (TCC repeats) in the promoters of genes encoding epidermal growth factor receptor and CD58. All these elements comprise a common CCTCCT sequence with less conserved C + T-rich sequences. Eliminating this CCTCCT sequence results in a marked reduction in promoter activity, suggesting a necessary role in IL-10 gene expression. Despite its dissimilarity to the G + C-rich Sp1 consensus sequence (GC box), Sp1 and Sp3 transcription factors could be shown to bind to this motif. The requirement for Sp1 and Sp3 in transcription of IL-10 was confirmed using Drosophila SL2 cells, which lack endogenous Sp factors. These results suggest that the transcription of IL-10 is positively regulated by both Sp1 and Sp3.

A focus of contemporary cancer therapeutic development is the targeting of both the transformed cell and the supporting cellular microenvironment. Cell migration is a fundamental cellular behavior required for the complex interplay between multiple cell types necessary for tumor development. We therefore developed a novel retroviral-based screening technology in primary human endothelial cells to discover genes that control cell migration. We identified the receptor tyrosine kinase Axl as a novel regulator of endothelial cell haptotactic migration towards the matrix factor vitronectin. Using small interfering RNA-mediated silencing and overexpression of wild-type or mutated receptor proteins, we show that Axl is a key regulator of multiple angiogenic behaviors including endothelial cell migration, proliferation, and tube formation in vitro. Moreover, using sustained, retrovirally delivered short hairpin RNA (shRNA) Axl knockdown, we show that Axl is necessary for in vivo angiogenesis in a mouse model. Furthermore, we show that Axl is also required for human breast carcinoma cells to form a tumor in vivo. These findings indicate that Axl regulates processes vital for both neovascularization and tumorigenesis. Disruption of Axl signaling using a small-molecule inhibitor will hence simultaneously affect both the tumor and stromal cell compartments and thus represents a unique approach for cancer therapeutic development. (Cancer Res 2005; 65(20): 9294-303)

IL-10 is an 18-kDa immunoregulatory cytokine the transcription of which is controlled by the ubiquitously expressed transcription factors Sp1 and Sp3. Although many cell types express IL-10 mRNA, not all make detectable amounts of protein, and levels of protein expression vary enormously. We show here that much of this variation can be accounted for by posttranscriptional mechanisms. Multiple copies of potential mRNA destabilizing motifs AUUUA and related sequences can be found to the 3′-untranslated region (UTR) of IL-10 mRNA distributed through three potential regulatory regions. Evidence of RNA-destabilizing activities in all three regions was deduced from luciferase reporter assays. The half-life of RNA containing the 3′-UTR of IL-10 mRNA was quite short in both nonstimulated (t1/2 = 1 h), and PMA-stimulated EL-4 cell (t1/2 = 3 h). In contrast, the half-life of RNA lacking the 3′-UTR was much longer (t1/2 = >12 h) whether cells were stimulated or not. This suggests that many cells are poised to secrete IL-10 and will do so if they receive appropriate posttranscriptional signals.

It is commonly assumed that Social Enterprises (SEs) are able to meet social outcomes and also be financially viable, however, little research supports this claim. Using hybrid organizing as a lens to analyse case study interview data from ten SEs delivering adult day care services, we identify three factors which affect a SEs ability to simultaneously achieve social outcomes and financial sustainability and thus create value-spillovers for society. These are: diverse income streams to strengthen financial viability and reduce reliance on service-level agreements and grants; delivering social quality (quality of social impact) as well as service quality, and a hybrid workforce.

Short 'product lives' and disposable packaging result in premature disposal of valuable resources. Industrialisation, mass production and global supply chains have resulted in a disconnect between people, places, materials and design. Upcycling is reuse of discarded materials which results in an increase in 'value'. We discuss the potential for creative upcycling to reconnect people with materials and establish cultures and communities of making. The reaction of the public to creative reuse is explored by creating a café structure made entirely from recycled materials, and this provides the starting point to consider the contexts in which upcycling occurs, the motivations for (and barriers to) reuse and upcycling, the potential benefits of upcycling in the context of affluent Western 'consumer' societies, and the scope for designers to imbue objects with the potential for creative reuse. We argue that designing to enable creative upcycling allows the future lives of objects to be contingent on context and culture, rather than being prescribed by the designer, with potential for widespread social, economic and environmental benefits.

This paper argues for the need to go beyond appreciating co-production as a stand-alone process. Rather it offers a holistic model of value creation for public services, by integrating insights from both the public administration and management and the service management and marketing literatures. The components of this model are the loci, elements, and processes of value creation. Coproduction is located within this model but only as one process, not as the pre-eminent one. The implications of this new model for public management theory and practice are explored. | BEYOND CO-PRODUCTION…Since the groundbreaking work of Ostrom (1972), co-production has become an influential discourse in public administration and management (PAM), defined as "regular, long-term relationships between professionalized service pro-viders… and service users… where all parties make substantial resource contributions" (Bovaird, 2007 p. 847). The discourse arose because of concerns about "nefarious" public officials "thwarting the will" of citizens for greater influence on their public services (Vroom & Yetton, 1973). A significant body of PAM research on co-production has subsequently matured, with a variety of foci. Inter alia, these foci include resource leverage, facilitation of innovation, and as a driver of public service reform (e.g.,

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