A Traditional English (Not British) Country Gentleman of the Radical Left’: Understanding the Making and Unmaking of Edward Thompson's English Idiom

This essay discusses E. P. Thompson's relationship with an English sense of tradition, exploring in particular his shifting characterisation of an English idiom in the three closely linked, polemical rejoinders he offered to the ideas advanced by major Marxist intellectual figures in the 1960s and 1970s. It draws particular attention to themes that have either been overlooked or relegated to the margins by previous commentary—specifically, his rhetorical style and sense of audience. And it charts a notable, yet largely unnoticed, shift in his thinking in this period—from an appeal to an English sense of tradition to an assertion of the merit of historical forms of understanding.This is an Accepted Manuscript of an article published by Taylor & Francis in Contemporary British History on 6th October 2014, available online: http://wwww.tandfonline.com/10.1080/13619462.2014.962915

The Return of Englishness in British Political Culture -- The End of the Unions?

This article approaches the interpretation of elite and popular attitudes towards the United Kingdom's membership of the European Union through analysis of some of the rival perspectives on the national identity of the English that have become increasingly salient during the last two decades. It highlights their role as sources of some of the most influential ideas about nationhood, governance and state now shaping public discourse on the UK's membership of the EU. These include radical-democratic, restorationist and Anglo-British forms of patriotic discourse, which have prompted and responded to the growing prevalence of England as ‘an imagined community’ – a trend which has rendered other circles of attachment to the UK and Europe more tenuous and distant. A central conclusion of the article is that these emerging perspectives have spawned webs of belief that connect new and old ideas of nationhood to the political judgements that different actors are making about the E

Answering the West Lothian Question: a Critical Assessment of 'English Votes for English Laws' in the UK Parliament

In 2015, the UK House of Commons adopted new procedures known as ‘English Votes for English Laws’ (EVEL). This article evaluates whether EVEL has succeeded in answering the West Lothian Question, a constitutional anomaly arising from the asymmetrical character of governance in the UK. After outlining the historical background against which EVEL emerged as a supposed solution to this iconic question, the paper explains how the 2015 reform works, and proceeds to assess its operation during the 2015-17 parliament. It concludes that these new procedures appear to have overcome the main practical and constitutional obstacles associated with this type of reform, but they have, so far, failed to provide meaningful English representation at Westminster – particularly in relation to supplying England, and its MPs, with an enhanced ‘voice’.This work was supported by the Economic and Social Research Council and the Centre on Constitutional Change [grant number ES/L003325/1]; and by a British Academy/Leverhulme Small Research Grant [grant number SG152634]

Lipoprotein-associated phospholipase A2 (Lp-PLA2) as a therapeutic target to prevent retinal vasopermeability during diabetes

Lipoprotein-associated phospholipase A2 (Lp-PLA2) hydrolyses oxidized low-density lipoproteins into proinflammatory products, which can have detrimental effects on vascular function. As a specific inhibitor of Lp-PLA2, darapladib has been shown to be protective against atherogenesis and vascular leakage in diabetic and hypercholesterolemic animal models. This study has investigated whether Lp-PLA2 and its major enzymatic product, lysophosphatidylcholine (LPC), are involved in blood-retinal barrier (BRB) damage during diabetic retinopathy. We assessed BRB protection in diabetic rats through use of species-specific analogs of darapladib. Systemic Lp-PLA2 inhibition using SB-435495 at 10 mg/kg (i.p.) effectively suppressed BRB breakdown in streptozotocin-diabetic Brown Norway rats. This inhibitory effect was comparable to intravitreal VEGF neutralization, and the protection against BRB dysfunction was additive when both targets were inhibited simultaneously. Mechanistic studies in primary brain and retinal microvascular endothelial cells, as well as occluded rat pial microvessels, showed that luminal but not abluminal LPC potently induced permeability, and that this required signaling by the VEGF receptor 2 (VEGFR2). Taken together, this study demonstrates that Lp-PLA2 inhibition can effectively prevent diabetes-mediated BRB dysfunction and that LPC impacts on the retinal vascular endothelium to induce vasopermeability via VEGFR2. Thus, Lp-PLA2 may be a useful therapeutic target for patients with diabetic macular edema (DME), perhaps in combination with currently administered anti-VEGF agents

The Enteropathogenic E. coli (EPEC) Tir Effector Inhibits NF-κB Activity by Targeting TNFα Receptor-Associated Factors

Enteropathogenic Escherichia coli (EPEC) disease depends on the transfer of effector proteins into epithelia lining the human small intestine. EPEC E2348/69 has at least 20 effector genes of which six are located with the effector-delivery system genes on the Locus of Enterocyte Effacement (LEE) Pathogenicity Island. Our previous work implied that non-LEE-encoded (Nle) effectors possess functions that inhibit epithelial anti-microbial and inflammation-inducing responses by blocking NF-κB transcription factor activity. Indeed, screens by us and others have identified novel inhibitory mechanisms for NleC and NleH, with key co-operative functions for NleB1 and NleE1. Here, we demonstrate that the LEE-encoded Translocated-intimin receptor (Tir) effector has a potent and specific ability to inhibit NF-κB activation. Indeed, biochemical, imaging and immunoprecipitation studies reveal a novel inhibitory mechanism whereby Tir interaction with cytoplasm-located TNFα receptor-associated factor (TRAF) adaptor proteins induces their proteasomal-independent degradation. Infection studies support this Tir-TRAF relationship but reveal that Tir, like NleC and NleH, has a non-essential contribution in EPEC's NF-κB inhibitory capacity linked to Tir's activity being suppressed by undefined EPEC factors. Infections in a disease-relevant intestinal model confirm key NF-κB inhibitory roles for the NleB1/NleE1 effectors, with other studies providing insights on host targets. The work not only reveals a second Intimin-independent property for Tir and a novel EPEC effector-mediated NF-κB inhibitory mechanism but also lends itself to speculations on the evolution of EPEC's capacity to inhibit NF-κB function

A Multitrait–Multimethod Analysis of the Construct Validity of Child Anxiety Disorders in a Clinical Sample

The present study examines the construct validity of separation anxiety disorder (SAD), social phobia (SoP), panic disorder (PD), and generalized anxiety disorder (GAD) in a clinical sample of children. Participants were 174 children, 6 to 17 years old (94 boys) who had undergone a diagnostic evaluation at a university hospital based clinic. Parent and child ratings of symptom severity were assessed using the Multidimensional Anxiety Scale for Children (MASC). Diagnostician ratings were obtained from the Anxiety Disorders Interview Schedule for Children and Parents (ADIS: C/P). Discriminant and convergent validity were assessed using confirmatory factor analytic techniques to test a multitrait–multimethod model. Confirmatory factor analyses supported the current classification of these child anxiety disorders. The disorders demonstrated statistical independence from each other (discriminant validity of traits), the model fit better when the anxiety syndromes were specified than when no specific syndromes were specified (convergent validity), and the methods of assessment yielded distinguishable, unique types of information about child anxiety (discriminant validity of methods). Using a multi-informant approach, these findings support the distinctions between childhood anxiety disorders as delineated in the current classification system, suggesting that disagreement between informants in psychometric studies of child anxiety measures is not due to poor construct validity of these anxiety syndromes

The Bacterial Intimins and Invasins: A Large and Novel Family of Secreted Proteins

Gram-negative bacteria have developed a limited repertoire of solutions for secreting proteins from the cytoplasmic compartment to the exterior of the cell. Amongst the spectrum of secreted proteins are the intimins and invasins (the Int/Inv family; TC# 1.B.54) which are characterized by an N-terminal β-barrel domain and a C-terminal surface localized passenger domain. Despite the important role played by members of this family in diseases mediated by several species of the Enterobacteriaceae, there has been little appreciation for the distribution and diversity of these proteins amongst Gram-negative bacteria. Furthermore, there is little understanding of the molecular events governing secretion of these proteins to the extracellular milieu.In silico approaches were used to analyze the domain organization and diversity of members of this secretion family. Proteins belonging to this family are predominantly associated with organisms from the γ-proteobacteria. Whilst proteins from the Chlamydia, γ-, β- and ε-proteobacteria possess β-barrel domains and passenger domains of various sizes, Int/Inv proteins from the α-proteobacteria, cyanobacteria and chlorobi possess only the predicted β-barrel domains. Phylogenetic analyses revealed that with few exceptions these proteins cluster according to organismal type, indicating that divergence occurred contemporaneously with speciation, and that horizontal transfer was limited. Clustering patterns of the β-barrel domains correlate well with those of the full-length proteins although the passenger domains do so with much less consistency. The modular subdomain design of the passenger domains suggests that subdomain duplication and deletion have occurred with high frequency over evolutionary time. However, all repeated subdomains are found in tandem, suggesting that subdomain shuffling occurred rarely if at all. Topological predictions for the β-barrel domains are presented.Based on our in silico analyses we present a model for the biogenesis of these proteins. This study is the first of its kind to describe this unusual family of bacterial adhesins

Animal Ca2+ release-activated Ca2+ (CRAC) channels appear to be homologous to and derived from the ubiquitous cation diffusion facilitators

<p>Abstract</p> <p>Background</p> <p>Antigen stimulation of immune cells triggers Ca²⁺entry through Ca²⁺release-activated Ca²⁺(CRAC) channels, promoting an immune response to pathogens. Defects in a CRAC (Orai) channel in humans gives rise to the hereditary Severe Combined Immune Deficiency (SCID) syndrome. We here report results that define the evolutionary relationship of the CRAC channel proteins of animals, and the ubiquitous Cation Diffusion Facilitator (CDF) carrier proteins.</p> <p>Findings</p> <p>CDF antiporters derived from a primordial 2 transmembrane spanner (TMS) hairpin structure by intragenic triplication to yield 6 TMS proteins. Four programs (IC/GAP, GGSEARCH, HMMER and SAM) were evaluated for identifying sequence similarity and establishing homology using statistical means. Overall, the order of sensitivity (similarity detection) was IC/GAP = GGSEARCH > HMMER > SAM, but the use of all four programs was superior to the use of any two or three of them. Members of the CDF family appeared to be homologous to members of the 4 TMS Orai channel proteins.</p> <p>Conclusions</p> <p>CRAC channels derived from CDF carriers by loss of the first two TMSs of the latter. Based on statistical analyses with multiple programs, TMSs 3-6 in CDF carriers are homologous to TMSs 1-4 in CRAC channels, and the former was the precursor of the latter. This is an unusual example of how a functionally and structurally more complex protein may have predated a simpler one.</p