The tumor suppressor PDCD4 is a proinflammatory protein that promotes activation of the transcription factor NF-kappaB and suppresses interleukin 10 (IL-10). Here we found that mice deficient in PDCD4 were protected from lipopolysaccharide (LPS)-induced death. The induction of NF-kappaB and IL-6 by LPS required PDCD4, whereas LPS enhanced IL-10 induction in cells lacking PDCD4. Treatment of human peripheral blood mononuclear cells with LPS resulted in lower PDCD4 expression, which was due to induction of the microRNA miR-21 via the adaptor MyD88 and NF-kappaB. Transfection of cells with a miR-21 precursor blocked NF-kappaB activity and promoted IL-10 production in response to LPS, whereas transfection with antisense oligonucleotides to miR-21 or targeted protection of the miR-21 site in Pdcd4 mRNA had the opposite effect. Thus, miR-21 regulates PDCD4 expression after LPS stimulation.

Building trust through collaboration, institutional development, and social learning enhances efforts to foster ecosystem management and resolve multi‐scale society–environment dilemmas. One emerging approach aimed at addressing these dilemmas is adaptive co‐management. This method draws explicit attention to the learning (experiential and experimental) and collaboration (vertical and horizontal) functions necessary to improve our understanding of, and ability to respond to, complex social–ecological systems. Here, we identify and outline the core features of adaptive co‐management, which include innovative institutional arrangements and incentives across spatiotemporal scales and levels, learning through complexity and change, monitoring and assessment of interventions, the role of power, and opportunities to link science with policy.

No abstract

. 2012. The interplay of well-being and resilience in applying a social-ecological perspective. ABSTRACT. Innovative combinations of social and ecological theory are required to deal with complexity and change in humanecological systems. We examined the interplay and complementarities that emerge by linking resilience and social well-being approaches. First, we reflected on the limitations of applying ecological resilience concepts to social systems from the perspective of social theory, and particularly, the concept of well-being. Second, we examined the interplay of resilience and well-being concepts in fostering a social-ecological perspective that promises more appropriate management and policy actions. We examined five key points of interplay: (1) the limits of optimization thinking (e.g., maximum sustainable yield), (2) the role of human agency and values, (3) understandings of scale, (4) insights on "controlling variables," and (5) perspectives on thresholds and boundaries. Based on this synthesis, we offer insights to move incrementally towards interdisciplinary research and governance for complex social-ecological systems.

Despite longstanding recognition that small-scale fisheries make multiple contributions to economies, societies and cultures, assessing these contributions and incorporating them into policy and decision-making has suffered from a lack of a comprehensive integrating ‘lens’. This paper focuses on the concept of ‘wellbeing’ as a means to accomplish this integration, thereby unravelling and better assessing complex social and economic issues within the context of fisheries governance. We emphasize the relevance of the three key components of wellbeing – the material, relational and subjective dimensions, each of which is relevant to wellbeing at scales ranging from individual, household, community, fishery to human-ecological systems as a whole. We review nine major approaches influential in shaping current thinking and practice on wellbeing: the economics of happiness, poverty, capabilities, gender, human rights, sustainable livelihoods, vulnerability, social capital, and social wellbeing. The concept of identity is a thread that runs through the relational and subjective components of social wellbeing, as well as several other approaches and thus emerges as a critical element of small-scale fisheries that requires explicit recognition in governance analysis. A social wellbeing lens is applied to critically review a global body of literature discussing the social, economic and political dimensions of small-scale fishing communities, seeking to understand the relevance and value addition of applying wellbeing concepts in small-scale fisheries

Death of pancreatic β cells is a pathological hallmark of type 1 diabetes (T1D). However, the molecular mechanisms of β cell death and its regulation are poorly understood. Here we describe a unique regulatory pathway of β cell death that comprises microRNA-21, its target tumor suppressor PDCD4, and its upstream transcriptional activator nuclear factor-κB (NF-κB). In pancreatic β cells, c-Rel and p65 of the NF-κB family activated the mir21 gene promoter and increased miR-21 RNA levels; miR-21 in turn decreased the level of PDCD4, which is able to induce cell death through the Bax family of apoptotic proteins. Consequently, PDCD4 deficiency in pancreatic β cells renders them resistant to death, and PDCD4 deficiency in NOD or C57BL/6 mice conferred resistance to spontaneous diabetes and diabetes induced by autoimmune T cells or the β cell toxin streptozotocin (STZ). Thus, the NF-κB−microRNA-21−PDCD4 axis plays a crucial role in T1D and represents a unique therapeutic target for treating the disease.

Summary The connection between cancer and inflammation is widely recognized; yet the underlying molecular mechanisms are poorly understood. We report here that TIPE2 provides a molecular bridge from inflammation to cancer by targeting the Ras signaling pathway. TIPE2 binds the Ras-interacting domain of the RalGDS family of proteins, which are essential effectors of activated Ras. This binding prevented Ras from forming an active complex, thereby inhibiting the activation of the downstream signaling molecules Ral and AKT. Consequently, TIPE2 deficiency led to heightened activation of Ral and AKT, resistance to cell death, increased migration, and dysregulation of exocyst complex formation. Conversely, TIPE2 overexpression induced cell death and significantly inhibited Ras-induced tumorigenesis in mice. Importantly, TIPE2 expression was either completely lost or significantly down-regulated in human hepatic cancer. Thus, TIPE2 is an inhibitor of both inflammation and cancer, and potential drug target for inflammatory and neoplastic diseases.

Phagocytosis and oxidative burst are two major effector arms of innate immunity. Although it is known that both are activated by Toll-like receptors (TLRs) and Rac GTPases, how their strengths are controlled in quiescent and TLR-activated cells is not clear. We report here that TIPE2 (TNFAIP8L2) serves as a negative regulator of innate immunity by linking TLRs to Rac. TLRs control the expression levels of TIPE2, which in turn dictates the strengths of phagocytosis and oxidative burst by binding to and blocking Rac GTPases. Consequently, TIPE2 knockout cells have enhanced phagocytic and bactericidal activities and TIPE2 knockout mice are resistant to bacterial infection. Thus, TIPE2 sets the strengths of phagocytosis and oxidative burst and may be targeted to effectively control infections.