Gremlin1 preferentially binds to Bone Morphogenetic Protein-2 (BMP-2) and BMP-4 over BMP-7

Gremlin (Grem1) is a member of the DAN family of secreted bone morphogenetic protein (BMP) antagonists. Bone morphogenetic protein-7 (BMP-7) mediates protective effects during renal fibrosis-associated with diabetes and other renal diseases. The pathogenic mechanism of Grem1 during DN has been suggested to be binding and inhibition of BMP-7. However, the precise interactions between Grem1, BMP-7 and other BMPs have not been accurately defined. Here we show the affinity of Grem1 for BMP-7 is lower than that of BMP-2 and BMP-4, using a combination of surface plasmon resonance and cell culture techniques. Using kidney proximal tubule cells and HEK-293 cell Smad1/5/8 phosphorylation and BMP-dependent gene expression as readout, Grem1 consistently demonstrated a higher affinity for BMP-2>4>7. Cell-associated Grem1 did not inhibit BMP-2 or BMP-4 mediated signalling, suggesting that Grem1-BMP-2 binding occurred in solution, preventing BMP receptor activation. These data suggest that Grem1 preferentially binds to BMP-2 and this may be the dominant complex in a disease situation where levels of Grem1 and BMPs are elevated.

Partitioning Heritability of Regulatory and Cell-Type-Specific Variants across 11 Common Diseases

Regulatory and coding variants are known to be enriched with associations identified by genome-wide association studies (GWASs) of complex disease, but their contributions to trait heritability are currently unknown. We applied variance-component methods to imputed genotype data for 11 common diseases to partition the heritability explained by genotyped SNPs () across functional categories (while accounting for shared variance due to linkage disequilibrium). Extensive simulations showed that in contrast to current estimates from GWAS summary statistics, the variance-component approach partitions heritability accurately under a wide range of complex-disease architectures. Across the 11 diseases DNaseI hypersensitivity sites (DHSs) from 217 cell types spanned 16% of imputed SNPs (and 24% of genotyped SNPs) but explained an average of 79% (SE = 8%) of  from imputed SNPs (5.1× enrichment; p = 3.7 × 10⁻¹⁷) and 38% (SE = 4%) of  from genotyped SNPs (1.6× enrichment, p = 1.0 × 10⁻⁴). Further enrichment was observed at enhancer DHSs and cell-type-specific DHSs. In contrast, coding variants, which span 1% of the genome, explained <10% of  despite having the highest enrichment. We replicated these findings but found no significant contribution from rare coding variants in independent schizophrenia cohorts genotyped on GWAS and exome chips. Our results highlight the value of analyzing components of heritability to unravel the functional architecture of common disease.

Swift and Conversational Culture

Swift often noted his aversion to coffee-house conversation and to tavern talk, to gossip and company, and to being buried in Dublin in the years of his Deanship. Yet the popular myth of a morose, unsociable Swift belies both his engagement with various literary and political clubs in his early career and his participation in collaborative and experimental poetic games in his Dublin circles. This essay considers Swift’s involvement with three clubs in London (the Saturday Club, the Brothers’ Club, and the Scriblerians) and his writings on a number of fictional clubs (the Athenian Society, the Calves-Head Club, and a putative Society for the correction of the English language). While Swift wrote very little of his experience of actual clubs, the latter three, in addition to the Scriblerian Club as an imagined, rather than actual clubs, resulted in a number of defining poems and works in his career. When Swift settled in Dublin, poetry written and exchanged in a number of sociable circles characterised much of his published verse and gave glimpses of the circles and informal clubs which he formed among friends there. Although these poems are often dismissed as ‘trifles’, the essay argues that the poems are crucial for our understandings of ‘conversational culture’ or sociability in Swift’s Dublin.

Death and Consumer Culture

Among the most veiled and emotionally charged of life’s experiences are those related to death. Given that poetry has long been recognized as an unparalleled means of expressing and understanding the most complex and emotional aspects of life (Sherry and Schouten, 2002), it is of little surprise that few poets regarded as the finest of all wordsmiths have not, since time immemorial, grappled with death.

Recently, within marketing and consumer research, poetry has slowly but progressively come to be recognized as a means by which to understand, express, celebrate, and/or confront that which defies scientific or other more “scholarly” explanation (Canniford, 2012; Wijland, 2011; Sherry and Schouten, 2002). This “poetic turn” has manifest itself most notably within the nascent realm of Consumer Culture Theory (CCT); mainly in poetry reading sessions held—with published chapbooks in hand—in concurrence with the annual CCT symposium. Death-related poetry penned by marketing and consumer researchers has there entered—albeit randomly—the CCT circuit (see, for example: Arnould, 2014; Steinfield, 2014; Gabel, 2013, 2010; Downey, 2011, 2010a, 2010b, 2010c).

This chapter represents the first formal, organized attempt to better understand death-related consumption experience and meaning via the creation and dissemination of original works of poetry. The chapter’s title reflects the broad, eclectic perspective of death and consumption herein pursued. We consider funerary and other—good, service, and ideological—product consumption activities and experiences transpiring in the context of death. We also embrace the notion that death often brutally consumes those dealing with it; a sort of “consumption of consumers by death.” In turn, as vividly expressed in several of the poems in this chapter, consumption acts or experiences and/or memories thereof may be instrumental in coping with “being consumed by death.”

The interplay between clathrin-coated vesicles and cell signalling

Internalization of cargo proteins and lipids at the cell surface occurs in both a constitutive and signal-regulated manner through clathrin-mediated and other endocytic pathways. Clathrin-coated vesicle formation is a principal uptake route in response to signalling events. Protein-lipid and protein-protein interactions control both the targeting of signalling molecules and their binding partners to membrane compartments and the assembly of clathrin coats. An emerging aspect of membrane trafficking research is now addressing how signalling cascades and vesicle coat assembly and subsequently disassembly are integrated.

Wnt signaling in age-related macular degeneration: human macular tissue and mouse model

BACKGROUND: The wingless-type MMTV integration site (Wnt) signaling is a group of signal transduction pathways. In canonical Wnt pathway, Wnt ligands bind to low-density lipoprotein receptor-related protein 5 or 6 (LRP5 or LRP6), resulting in phosphorylation and activation of the receptor. We hypothesize that canonical Wnt pathway plays a role in the retinal lesion of age-related macular degeneration (AMD), a leading cause of irreversible central visual loss in elderly.

METHODS: We examined LRP6 phosphorylation and Wnt signaling cascade in human retinal sections and plasma kallistatin, an endogenous inhibitor of the Wnt pathway in AMD patients and non-AMD subjects. We also used the Ccl2 (-/-) /Cx3cr1 (-/-) /rd8 and Ccl2 (-/-) /Cx3cr1 (gfp/gfp) mouse models with AMD-like retinal degeneration to further explore the involvement of Wnt signaling activation in the retinal lesions in those models and to preclinically evaluate the role of Wnt signaling suppression as a potential therapeutic option for AMD.

RESULTS: We found higher levels of LRP6 (a key Wnt signaling receptor) protein phosphorylation and transcripts of the Wnt pathway-targeted genes, as well as higher beta-catenin protein in AMD macula compared to controls. Kallistatin was decreased in the plasma of AMD patients. Retinal non-phosphorylated-β-catenin and phosphorylated-LRP6 were higher in Ccl2 (-/-) /Cx3cr1 (-/-) /rd8 mice than that in wild type. Intravitreal administration of an anti-LRP6 antibody slowed the progression of retinal lesions in Ccl2 (-/-) /Cx3cr1 (-/-) /rd8 and Ccl2 (-/-) /Cx3cr1 (gfp/gfp) mice. Electroretinography of treated eyes exhibited larger amplitudes compared to controls in both mouse models. A2E, a retinoid byproduct associated with AMD was lower in the treated eyes of Ccl2 (-/-) /Cx3cr1 (-/-) /rd8 mice. Anti-LRP6 also suppressed the expression of Tnf-α and Icam-1 in Ccl2 (-/-) /Cx3cr1 (-/-) /rd8 retinas.

CONCLUSIONS: Wnt signaling may be disturbed in AMD patients, which could contribute to the retinal inflammation and increased A2E levels found in AMD. Aberrant activation of canonical Wnt signaling might also contribute to the focal retinal degenerative lesions of mouse models with Ccl2 and Cx3cr1 deficiency, and intravitreal administration of anti-LRP6 antibody could be beneficial by deactivating the canonical Wnt pathway.

Gender and Material Culture in Britain since 1600

What does material culture tell us about gendered identities and how does gender reveal the meaning of spaces and things?

If we look at the objects that we own, covet and which surround us in our everyday culture, there is a clear connection between ideas about gender and the material world. This book explores the material culture of the past to shed light on historical experiences and identities. Some essays focus on specific objects, such as an eighteenth-century jug or a twentieth-century powder puff, others on broader material environments, such as the sixteenth-century guild or the interior of a twentieth-century pub, while still others focus on the paraphernalia associated with certain actions, such as letter-writing or maintaining eighteenth-century men's hair.

Written by scholars in a range of history-related disciplines, the essays in this book offer exposés of current research methods and interests. These demonstrate to students how a relationship between material culture and gender is being addressed, while also revealing a variety of intellectual approaches and topics.