Exendin-4 protects against post-myocardial infarction remodelling via specific actions on inflammation and the extracellular matrix

Glucagon-like peptide-1 (GLP-1) is an insulin-releasing hormone clinically exploited for glycaemic control in diabetes, which also confers acute cardioprotection and benefits in experimental/clinical heart failure. We specifically investigated the role of the GLP-1 mimetic, exendin-4, in post-myocardial infarction (MI) remodelling, which is a key contributor to heart failure. Adult female normoglycaemic mice underwent coronary artery ligation/sham surgery prior to infusion with exendin-4/vehicle for 4 weeks. Metabolic parameters and infarct sizes were comparable between groups. Exendin-4 protected against cardiac dysfunction and chamber dilatation post-MI and improved survival. Furthermore, exendin-4 modestly decreased cardiomyocyte hypertrophy/apoptosis but markedly attenuated interstitial fibrosis and myocardial inflammation post-MI. This was associated with altered extracellular matrix (procollagen IαI/IIIαI, connective tissue growth factor, fibronectin, TGF-β3) and inflammatory (IL-10, IL-1β, IL-6) gene expression in exendin-4-treated mice, together with modulation of both Akt/GSK-3β and Smad2/3 signalling. Exendin-4 also altered macrophage response gene expression in the absence of direct actions on cardiac fibroblast differentiation, suggesting cardioprotective effects occurring secondary to modulation of inflammation. Our findings indicate that exendin-4 protects against post-MI remodelling via preferential actions on inflammation and the extracellular matrix independently of its established actions on glycaemic control, thereby suggesting that selective targeting of GLP-1 signalling may be required to realise its clear therapeutic potential for post-MI heart failure.

Susceptibility to Invasive Meningococcal Disease: Polymorphism of Complement System Genes and Neisseria meningitidis Factor H Binding Protein

BACKGROUND: Neisseria meningitidis can cause severe infection in humans. Polymorphism of Complement Factor H (CFH) is associated with altered risk of invasive meningococcal disease (IMD). We aimed to find whether polymorphism of other complement genes altered risk and whether variation of N. meningitidis factor H binding protein (fHBP) affected the risk association.

METHODS: We undertook a case-control study with 309 European cases and 5,200 1958 Birth Cohort and National Blood Service cohort controls. We used additive model logistic regression, accepting P<0.05 as significant after correction for multiple testing. The effects of fHBP subfamily on the age at infection and severity of disease was tested using the independent samples median test and Student's T test. The effect of CFH polymorphism on the N. meningitidis fHBP subfamily was investigated by logistic regression and Chi squared test.

RESULTS: Rs12085435 A in C8B was associated with odds ratio (OR) of IMD (0.35 [95% CI 0.19-0.67]; P = 0.03 after correction). A CFH haplotype tagged by rs3753396 G was associated with IMD (OR 0.56 [95% CI 0.42-0.76], P = 1.6x10-4). There was no bacterial load (CtrA cycle threshold) difference associated with carriage of this haplotype. Host CFH haplotype and meningococcal fHBP subfamily were not associated. Individuals infected with meningococci expressing subfamily A fHBP were younger than those with subfamily B fHBP meningococci (median 1 vs 2 years; P = 0.025).

DISCUSSION: The protective CFH haplotype alters odds of IMD without affecting bacterial load for affected heterozygotes. CFH haplotype did not affect the likelihood of infecting meningococci having either fHBP subfamily. The association between C8B rs12085435 and IMD requires independent replication. The CFH association is of interest because it is independent of known functional polymorphisms in CFH. As fHBP-containing vaccines are now in use, relationships between CFH polymorphism and vaccine effectiveness and side-effects may become important.

Reactions of nitrogen nucleophiles with enantiopure cyclohexenyl electrophiles:a stereo- and regio- selective study

The reactions of enantiopure cyclohexene epoxides and trans-1,2-bromoacetates, derived from the corresponding substituted benzene cis-dihydrodiol metabolites, with nitrogen nucleophiles, were examined and possible mechanisms proposed. An initial objective was the synthesis of new 1,2-aminoalcohol enantiomers as potential chiral ligands and synthetic scaffolds for library generation. These apparently simple substitution reactions proved to be more complex than initially anticipated and were found to involve a combination of different reaction mechanisms. Allylic trans-1,2-azidohydrins were prepared by Lewis acid-catalysed ring-opening of cyclic vinyl epoxides with sodium azide via an S(N)2 mechanism. On heating, these trans-1,2-azidohydrins isomerized to the corresponding trans-1,4-azidohydrins via a suprafacial allyl azide [3,3]-sigmatropic rearrangement mechanism. Conversion of a 1,2-azidohydrin to a 1,2-azidoacetate moved the equilibrium position in favour of the 1,4-substitution product. Allylic trans-1,2-bromoacetates reacted with sodium azide at room temperature to give C-2 and C-4 substituted products. A clean inversion of configuration at C-2 was found, as expected, from a concerted S(N)2-pathway. However, substitution at C-4 was not stereoselective and resulted in mixtures of 1,4-cis and 1,4-trans products. This observation can be rationalized in terms of competitive S(N)2 and S(N)2 reactions allied to a [3,3]-sigmatropic rearrangement. cis-1,2-Azidohydrins and cis-1,2-azidoacetates were much more prone to rearrange than the corresponding trans-isomers. Reaction of the softer tosamide nucleophile with trans-1,2-bromoacetates resulted, predominantly, in C-4 substitution via a syn-S(N)2 mechanism. One application of the reaction of secondary amines with allylic cyclohexene epoxides, to give trans-1,2-aminoalcohols, is in the synthesis of the anticholinergic drug vesamicol, via an S(N)2 mechanism. Copyright (c) 2013 John Wiley & Sons, Ltd.

"'Nothing but a printer's devil ever drives me into finishing': the Genesis of Thomas Moore's Irish Melodies'

This chapter outlines the working methods of the prolific writer and lyricist Thomas Moore—which were characterized by the unfortunate combination of a perfectionist streak, a tendency to release material to the publishers while still in the creative mode, and a tendency to re-visit previously-published material. The Gibson-Massie Moore collection at Queen's University Belfast teaches us a great deal about Moore’s creative processes, and also records the nineteenth-century publishing industry’s response to one of its most prolific and popular creative artists. This chapter is illustrated by an online Exhibition, the 'Thomas Moore Project', Digital Collections, Special Collections, McClay library (see URL below).

Toluene Dioxygenase Catalysed synthesis and reactions of cis-diol metabolites derived from 2 and 3-methoxy phenols

Using toluene dioxygenase as biocatalyst, enantiopure cisdihydrodiol and cis-tetrahydrodiol metabolites, isolated as their ketone tautomers, were obtained from meta and ortho methoxyphenols. Although these isomeric phenol substrates are structurally similar, the major bioproducts from each of these biotransformations were found at different oxidation levels. The relatively stable cyclohexenone cis-diol metabolite from meta methoxyphenol was isolated, while the corresponding metabolite from ortho methoxyphenol was rapidly bioreduced to a cyclohexanone cis-diol. The chemistry of the 3-methoxycyclohexenone cis-diol product was investigated and elimination, aromatization, hydrogenation, regioselective O-exchange, Stork−Danheiser transposition and O-methylation reactions were observed. An offshoot of this technology provided a two-step chemoenzymatic synthesis, from meta methoxyphenol, of a recently reported chiral fungal metabolite; this synthesis also established the previously unassigned absolute configuration.

Free Improvisation in Europe:Lecture and Hands-on Workshop, given at 5 different universities in Brazil during February - June 2014

The lecture traces the beginnings of the free improvisation scene in Europe, commencing in the 1960. I present a multitude of video and audio examples of some of the most prominent improvisers of the time.
I focus specifically on the scene that developed around John Stevens and his SME (Spontaneous Music Ensemble). The work of Derek Bailey, specifically his writings in “Improvisation: its nature and practice in music” (1980), will feature.

The practical workshop invites improvisers (beginners to advanced with any instruments) to work with me on several listening and improvisation exercises.
Many of the exercises will be based on the innovative methods as developed by John Stevens in his work “Search and Reflect”. Participants will be able to experiment with a few essential ‘sound/listening’ exercises, guided by myself.
It is envisaged that a small ensemble is formed which will explore several improvisatory strategies. This part is open to all skill levels, all ages and any instrumental groupings.

Enabling Others in Social Work: Reflexivity and the Theory of Social Domains

This paper sets out a framework to structure reflexivity in social work practice. Based on the thinking of the sociologist, Derek Layder, it comprises five domains that impact on the individual and social life, namely: (i) psycho-biography – referring to a person’s unique experience throughout the life-course; (ii) situated activity – highlighting the impact of every day social interaction; (iii) social settings – addressing the role of organizations in social life; (iv) culture – covering the influence of attitudes, beliefs, tastes and ideas on symbolic meaning; and (v) politico-economy – alluding to the ramifications of political and economic forces on people’s lives. It is contended that power circulates throughout each domain as an enabling and constraining force. The paper then outlines a process for using the reflexive framework in ‘enabling’ activities such as practice learning, supervision, mentoring and coaching. By applying the framework in these contexts, it is argued that social workers can reflect critically on their role and develop emancipatory forms of practice.

Haunted Seasons: Television Ghost Stories for Christmas and Horror for Halloween

Why do the English have ghost stories at Christmas? Why does US television have special Halloween episodes? Is this all down to Dickens, or is it a hangover of an ancient, pagan past? Why does it survive? Haunted Seasons explores these and related questions, examining the history and meaning of seasonal horror. It reaches back through archaeological evidence of ancient beliefs, through Shakespeare, and Victorian ghost stories, and the works of M.R.James, and onwards to radio and television. The broader genre of supernatural television is considered in relation to the irruptions of abnormality into the normal, along with the significance of time and the seasons in these narratives and their telling. Particular focus is placed on the BBC Ghost Story for Christmas strand and the Halloween episodes of The Simpsons to help us interpret the continued use of these seasonal horror stories and their place in society, from fireside to television.

Antimicrobial efficacy of tobramycin polymeric nanoparticles for Pseudomonas aeruginosa infections in cystic fibrosis: formulation, characterisation and functionalisation with dornase alfa (DNase).

Inhaled antibiotics, such as tobramycin, for the treatment of Pseudomonas aeruginosa pulmonary infections are associated with the increase in life expectancy seen in cystic fibrosis (CF) patients over recent years. However, the effectiveness of this aminoglycoside is still limited by its inability to penetrate the thick DNA-rich mucus in the lungs of these patients, leading to low antibiotic exposure to resident bacteria. In this study, we created novel polymeric nanoparticle (NP) delivery vehicles for tobramycin. Using isothermal titration calorimetry, we showed that tobramycin binds with alginate polymer and, by exploiting this interaction, optimised the production of tobramycin alginate/chitosan NPs. It was established that NP antimicrobial activity against P. aeruginosa PA01 was equivalent to unencapsulated tobramycin (minimum inhibitory concentration 0.625 mg/L). Galleria mellonella was employed as an in vivo model for P. aeruginosa infection. Survival rates of 90% were observed following injection of NPs, inferring low NP toxicity. After infection with P. aeruginosa, we showed that a lethal inoculum was effectively cleared by tobramycin NPs in a dose dependent manner. Crucially, a treatment with NPs prior to infection provided a longer window of antibiotic protection, doubling survival rates from 40% with free tobramycin to 80% with NP treatment. Tobramycin NPs were then functionalised with dornase alfa (recombinant human deoxyribonuclease I, DNase), demonstrating DNA degradation and improved NP penetration of CF sputum. Following incubation with CF sputum, tobramycin NPs both with and without DNase functionalisation, exhibited anti-pseudomonal effects. Overall, this work demonstrates the production of effective antimicrobial NPs, which may have clinical utility as mucus-penetrating tobramycin delivery vehicles, combining two widely used CF therapeutics into a single NP formulation. This nano-antibiotic represents a strategy to overcome the mucus barrier, increase local drug concentrations, avoid systemic adverse effects and improve outcomes for pulmonary infections in CF.

Breaking the Intimate Screen: Pre-Recording, Special Effects and the Aesthetics of Early British Television

The technological constraints of early British television encouraged drama productions which emphasised the immediate, the enclosed and the close-up, an approach which Jason Jacobs described in the title of his seminal study as 'the intimate screen'. While Jacobs' book showed that this conception of early British television drama was only part of the reality, he did not focus on the role that special effects played in expanding the scope of the early television screen. This article will focus upon this role, showing that special effects were not only of use in expanding the temporal and spatial scope of television, but were also considered to be of interest to the audience as a way of exploring the new medium, receiving coverage in the popular press. These effects included pre-recorded film inserts, pre-recorded narration, multiple sets, model work and animation, combined with the live studio performances. Drawing upon archival research into television production files and scripts as well as audience responses and periodical coverage of television at the time of broadcast, this article will focus on telefantasy. This genre offered particular opportunities for utilising effects in ways that seemed appropriate for the experimentation with the form of television and for the drama narratives. This period also saw a variety of shifts within television as the BBC sought to determine a specific identity and understand the possibilities for the new medium.
This research also incorporates the BBC's own research and internal dialogue concerning audiences and how their tastes should best be met, at a time when the television audience was not only growing in terms of number but was also expanding geographically and socially beyond the moneyed Londoners who could afford the first television sets and were within range of the Alexandra Palace transmissions. The primary case study for this article will be the 1949 production of H.G.Wells’ The Time Machine, which incorporated pre-recorded audio and film inserts, which expanded the narrative out of the live studio performance both temporally and spatially, with the effects work receiving coverage in the popular magazine Illustrated. Other productions considered will be the 1938 and 1948 productions of RUR, the 1948 production of Blithe Spirit, and the 1950 adaptation of The Strange Case of Dr Jekyll and Mr Hyde. Despite the focus on telefantasy, this article will also include examples from other genres, both dramatic and factual, showing how the BBC's response to the changing television audience was to restrict drama to a more 'realistic' aesthetic and to move experimentation with televisual form to non-drama productions such as variety performances.

BMP signalling: agony and antagony in the family

Bone morphogenetic proteins (BMPs) are secreted extracellular matrix (ECM)-associated proteins that regulate a wide range of developmental processes, including limb and kidney formation. A critical element of BMP regulation is the presence of secreted antagonists that bind and inhibit BMP binding to their cognate Ser/Thr kinase receptors at the plasma membrane. Antagonists such as Noggin, Chordin, Gremlin (Grem1), and twisted gastrulation-1 (Twsg1) have been shown to inhibit BMP action in a range of different cell types and developmental stage-specific contexts. Here we review new developments in the field of BMP and BMP antagonist biology during mammalian development and suggest strategies for targeting these proteins in human disease.

Relative contributions of lipooligosaccharide inner and outer core modifications to nontypeable Haemophilus influenzae pathogenesis

Nontypeable Haemophilus influenzae (NTHi) is a frequent commensal of the human nasopharynx that causes opportunistic infection in immunocompromised individuals. Existing evidence associates lipooligosaccharide (LOS) with disease, but the specific and relative contributions of NTHi LOS modifications to virulence properties of the bacterium have not been comprehensively addressed. Using NTHi strain 375, an isolate for which the detailed LOS structure has been determined, we compared systematically a set of isogenic mutant strains expressing sequentially truncated LOS. The relative contributions of 2-keto-3-deoxyoctulosonic acid, the triheptose inner core, oligosaccharide extensions on heptoses I and III, phosphorylcholine, digalactose, and sialic acid to NTHi resistance to antimicrobial peptides (AMP), self-aggregation, biofilm formation, cultured human respiratory epithelial infection, and murine pulmonary infection were assessed. We show that opsX, lgtF, lpsA, lic1, and lic2A contribute to bacterial resistance to AMP; lic1 is related to NTHi self-aggregation; lgtF, lic1, and siaB are involved in biofilm growth; opsX and lgtF participate in epithelial infection; and opsX, lgtF, and lpsA contribute to lung infection. Depending on the phenotype, the involvement of these LOS modifications occurs at different extents, independently or having an additive effect in combination. We discuss the relative contribution of LOS epitopes to NTHi virulence and frame a range of pathogenic traits in the context of infection.