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Hypoxia signaling influences tumor development through both cell-intrinsic and -extrinsic pathways. Inhibiting hypoxia-inducible factor (HIF) function has recently been approved as a cancer treatment strategy. Hence, it is important to understand how regulators of HIF may affect tumor growth under physiological conditions. Here we report that in aging mice factor-inhibiting HIF (FIH), one of the most studied negative regulators of HIF, is a haploinsufficient suppressor of spontaneous B cell lymphomas, particular pulmonary B cell lymphomas. FIH deficiency alters immune composition in aged mice and creates a tumor-supportive immune environment demonstrated in syngeneic mouse tumor models. Mechanistically, FIH-defective myeloid cells acquire tumor-supportive properties in response to signals secreted by cancer cells or produced in the tumor microenvironment with enhanced arginase expression and cytokine-directed migration. Together, these data demonstrate that under physiological conditions, FIH plays a key role in maintaining immune homeostasis and can suppress tumorigenesis through a cell-extrinsic pathway.
\n \n\n \n \nRNA sequencing and genetic data support spleen tyrosine kinase (SYK) and high affinity immunoglobulin epsilon receptor subunit gamma (FCER1G) as putative targets to be modulated for Alzheimer's disease (AD) therapy. FCER1G is a component of Fc receptor complexes that contain an immunoreceptor tyrosine-based activation motif (ITAM). SYK interacts with the Fc receptor by binding to doubly phosphorylated ITAM (p-ITAM) via its two tandem SH2 domains (SYK-tSH2). Interaction of the FCER1G p-ITAM with SYK-tSH2 enables SYK activation via phosphorylation. Since SYK activation is reported to exacerbate AD pathology, we hypothesized that disruption of this interaction would be beneficial for AD patients. Herein, we developed biochemical and biophysical assays to enable the discovery of small molecules that perturb the interaction between the FCER1G p-ITAM and SYK-tSH2. We identified two distinct chemotypes using a high-throughput screen (HTS) and orthogonally assessed their binding. Both chemotypes covalently modify SYK-tSH2 and inhibit its interaction with FCER1G p-ITAM, however, these compounds lack selectivity and this limits their utility as chemical tools.
\n \n\n \n \nHere, we present a protocol for lentiviral delivery of CRISPR-Cas9 to human induced pluripotent stem cell (iPSC)-derived macrophages using co-incubation with VPX virus-like particles (VPX-VLPs). We describe steps for producing polybrene and puromycin kill curves, VPX viral production, and VPX-VLP titration by western blotting. We then detail procedures for iPSC macrophage precursor lentiviral transduction and lentiviral CRISPR-Cas9-based knockout in iPSC-derived macrophages. This protocol uses efficient genome-editing techniques to explore macrophage involvement in immune response, chronic inflammation, neurodegenerative disease, and cancer progression. For complete details on the use and execution of this protocol, please refer to Navarro-Guerrero et\u00a0al.1.
\n \n\n \n \nThis book makes a forthright case for a shift in policy focus from 'community cohesion' to the broader notion of social cohesion, and is distinctive and innovative in its focus on evaluation. It constitutes an extremely valuable source both for practitioners involved in social cohesion interventions and for researchers and students studying theory-based evaluation and the policy areas highlighted (housing, intergenerational issues, the recession, education, communications, community development).
\n \n\n \n \nThis paper explores the notion of 'ethnic group' focussing, in particular, on attempts to transform the concept into an empirical indicator in population censuses. The latter is seen to be riven with difficulties, not least the fact that such measures tend to be attempting to address two conflicting agendas - one requiring an ascriptive, the other a subjective, measure. Illustrating the core arguments with the decennial census in Britain, the paper explores the contested political terrain underpinning the introduction of such a question, and then demonstrates that the construction of an 'ethnic group' indicator takes the form of a complex dialectical process involving negotiation and re-negotiation on the part of a myriad of social actors and structural forces at macro-, meso- and micro-levels. Finally, it reflects on broader concerns arising from the reification of the measure, not least its material effects in the context of debates and policies on 'multiculturalism'. \u00a9 2013 Copyright Taylor and Francis Group, LLC.
\n \n\n \n \nThe British government has instituted a wide range of educational reforms to tackle ethnic inequality. This article argues that over the past half century most of these have been driven by immediate political considerations and have failed to incorporate a broader, historical perspective. This has invariably led to short-term, and short cut, solutions to long-term, deeply entrenched problems that, in reality, transcend the world of education. The article evaluates all the major reform programs, ranging from assimilationism to multicultural education to anti-racist education. It concludes with discussion of the merits/demerits of faith schools and the use of school reorganization as a means of tackling ethnic segregation. \u00a9 2010 Elsevier Ltd. All rights reserved.
\n \n\n \n \nThere is a wide swathe, and indeed long history, of UK literature featuring attempts to theorise differentials in housing position and shifting spatial settlement patterns in relation to ethnicity and 'race' (and also, more recently, faith group). Most of the earlier accounts were based on simplified versions of the structure-agency dualism or one or other variant of rational choice theory. Responding to criticisms that these relied too heavily on overly static notions of 'choice' and 'constraint', a few then turned to a form of theorisation that deployed a modified version of Giddens' structuration theory. This paper seeks to take the debate further by developing a model that retains much of the essence of structuration yet embodies a more dynamic and theoretically nuanced interpretation of both structure and agency. Structure, normally seen predominantly as a form of social regulation, will be seen as multi-layered and multi-dimensional and also, importantly, as subject to often unpredictable exogenous factors. The concept of social agency will also be subjected to a radical re-conceptualisation that reflects, amongst other things, recent shifts in social capital theory interpreted in the light of rapid demographic change (influenced by geo-political factors), ongoing social inequality, racism, and heightened inter- and intra-communal tensions in some areas. \u00a9 2009 Taylor & Francis.
\n \n\n \n \nThis paper interrogates a concept at the core of a social policy agenda that has dominated thinking in the UK over the past decade. It argues that the notion of 'community cohesion' is based on a fundamentally flawed interpretation of the sources of tension and conflict in Britain's towns and cities. It overly ethnicizes societal divisions and essentializes ethnicity. Examining the development of government policy since 2001 the paper shows that the result has been a predominantly culturalist agenda that obscures key sources of division, most notably those related to social class and material inequality. It is argued that the hegemonic status of this policy stream has also undermined the equalities agenda. The paper concludes with a reflection on the implications of the emergence of a Conservative-led coalition government in May 2010. \u00a9 The Author(s) 2012.
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