Nicholas Lynch

Targeting of mannan-binding lectin-associated serine protease-2 confers protection from myocardial and gastrointestinal ischemia/reperfusion injury

Complement research experienced a renaissance with the discovery of a third activation route, the lectin pathway. We developed a unique model of total lectin pathway deficiency, a mouse strain lacking mannan-binding lectin-associated serine protease-2 (MASP-2), and analyzed the role of MASP-2 in two models of postischemic reperfusion injury (IRI). In a model of transient myocardial IRI, MASP-2–deficient mice had significantly smaller infarct volumes than their wild-type littermates. Mice deficient in the downstream complement component C4 were not protected, suggesting the existence of a previously undescribed lectin pathway-dependent C4-bypass. Lectin pathway-mediated activation of C3 in the absence of C4 was demonstrated in vitro and shown to require MASP-2, C2, and MASP-1/3. MASP-2 deficiency also protects mice from gastrointestinal IRI, as do mAb-based inhibitors of MASP-2. The therapeutic effects of MASP-2 inhibition in this experimental model suggest the utility of anti–MASP-2 antibody therapy in reperfusion injury and other lectin pathway-mediated disorders.

MICROFIBRIL-ASSOCIATED PROTEIN 4 IS PRESENT IN LUNG WASHINGS AND BINDS TO THE COLLAGEN REGION OF LUNG SURFACTANT PROTEIN D

We have purified a glycoprotein from bovine lung washings using affinity chromatography on a maltose-affinity column. On SDS-polyacrylamide gel electrophoresis the protein showed a molecular mass of 36 kDa in the reduced state and 66 kDa in the unreduced state. On gel permeation chromatography the apparent molecular mass was 250 kDa. N-terminal sequencing showed homology to the human matrix protein microfibril-associated protein (hMFAP4), and the glycoprotein was designated bovine MFAP4 (bMFAP4). Lung surfactant protein D (SP-D) was also purified from lung washings, and calcium-dependent binding was demonstrated between bMFAP4 and SP-D. hMFAP4 was cloned, and recombinant hMFAP4 showed the same binding pattern to SP-D as bMFAP4. No binding was seen to recombinant SP-D composed of the neck region and carbohydrate recognition domain of SP-D, indicating that the interaction between MFAP4 and SP-D is mediated via the collagen region of SP-D. MFAP4 also showed calcium-dependent binding to mannan, which was partially inhibited by maltose. Our findings indicate that MFAP4 has two binding specificities, one for collagen and one for carbohydrate, and we suggest that MFAP4 may fix the collectins in the extracellular compartment during inflammation.

Requirement of neuronal ribosome synthesis for growth and maintenance of the dendritic tree

The nucleolus serves as a principal site of ribosome biogenesis but is also implicated in various non-ribosomal functions, including negative regulation of the pro-apoptotic transcription factor p53. Although disruption of the nucleolus may trigger the p53-dependent neuronal death, neurotoxic consequences of a selective impairment of ribosome production are unclear. Here, we report that in rat forebrain neuronal maturation is associated with a remarkable expansion of ribosomes despite postnatal down-regulation of ribosomal biogenesis. In cultured rat hippocampal neurons, inhibition of the latter process by knockdowns of ribosomal proteins S6, S14, or L4 reduced ribosome content without disrupting nucleolar integrity, cell survival, and signaling responses to the neurotrophin brain-derived neurotrophic factor. Moreover, reduced general protein synthesis and/or formation of RNA stress granules suggested diminished ribosome recruitment to at least some mRNAs. Such a translational insufficiency was accompanied by impairment of brain-derived neurotrophic factor-mediated dendritic growth. Finally, RNA stress granules and smaller dendritic trees were also observed when ribosomal proteins were depleted from neurons with established dendrites. Thus, a robust ribosomal apparatus is required to carry out protein synthesis that supports dendritic growth and maintenance. Consequently, deficits of ribosomal biogenesis may disturb neurodevelopment by reducing neuronal connectivity. Finally, as stress granule formation and dendritic loss occur early in neurodegenerative diseases, disrupted homeostasis of ribosomes may initiate and/or amplify neurodegeneration-associated disconnection of neuronal circuitries.

Ecological modernization, techno-politics and social life cycle assessment: a view from human geography

PurposeAlthough Social Life Cycle Assessment (SLCA) is a growing field of inquiry and intervention, to date, there has been a dearth of engagement between this field and critical social scientists interested in questions of the societal impacts of goods and services. In response, this paper is written from the perspectives of two human geographers, new to the field of SLCA. Our aim is to offer an ‘outsiders’ perspective of, and commentary on, the growing field of SLCA, which we frame as a form of political intervention that seeks to have real-world impacts on the lives and futures of diverse peoples and places.MethodsTo address these questions, we explore SLCA’s underpinning assumptions by critically reviewing the worldviews that inform its methods, including debates in the literature about sustainable development and corporate social responsibility.Results and discussionSLCA’s normative and practical applications resonate strongly with an ecological modernization framework. This framework forwards social change via incremental and institutional interventions that promotes continued development, and privileges objectivity, impartiality and the search for a totalizing knowledge of the impacts of good and services.ConclusionsExploring SLCA’s epistemological foundations illuminates, and in turn, can help to address some of the key challenges SLCA currently faces. Drawing attention to SLCA’s inheren raison d’etre encourages more debate about the overall intentions and limits of the field, and represents not a weakness but rather its inherent quality of exploring the complex world of social impacts.

Divine Living: Marketing and Selling Churches as Lofts in Toronto, Canada

Abstract In recent years, a growing number of churches no longer used by religious groups have been converted to loft housing. Church lofts offer consumers heritage architecture and unique aesthetics, elements that distinguish these spaces in the housing market. In order to sell converted churches as viable homes, however, developers and their marketing teams deploy a variety of marketing strategies. Through an analysis of advertising media in Toronto, Ontario, in this paper, I show how former churches are repackaged and promoted with a heritage identity that fits a normative ideal of upscale loft living. In particular, I analyse three central marketing themes: the reinvention of a church to a house and home, the production of identity through place names and the representation of church lofts in the urban landscape. Woven together, these themes rewrite a building’s religious past and legitimize an emerging housing market that makes use of built religious heritage.

Domesticating the church: the reuse of urban churches as loft living in the post-secular city

Abstract In recent years, numerous mainline Christian denominations throughout Canada have sold their places of worship in the real estate market in response to declines in religious membership and participation. At the same time, a growing demand for creative residential spaces by a group of the new middle class encourages the redevelopment of churches into upscale lofts, a practice connected to but divergent from the post-industrial loft living made popular in cities like New York. In this paper, I explore how the production and consumption of churches as lofts represents a novel terrain of private urban redevelopment. Church lofts are an emergent form of housing and the latest frontier in the remaking of material, cultural and religious landscapes in the post-secular city – a context where novel forms of secularity take shape alongside new expressions of religion. With an empirical focus on Toronto, I investigate how ‘redundant’ worship spaces are appropriated and transformed into private domestic spaces of commodified religion and heritage. Rebuilt as unique but exclusive places to live, church lofts are part of a secular upscaling of the central city, a process that increasingly remakes the city as a place of capital reinvestment, middle-class colonization and socio-secular upgrading.