Interleukin-27 inhibits ectopic lymphoid-like structure development in early inflammatory arthritis

Ectopic lymphoid-like structures (ELSs) reminiscent of secondary lymphoid organs often develop at sites of chronic inflammation where they contribute to immune-mediated pathology. Through evaluation of synovial tissues from rheumatoid arthritis (RA) patients, we now show that low interleukin-27 (IL-27) expression corresponds with an increased incidence of ELS and gene signatures associated with their development and activity. The presence of synovial ELS was also noted in mice deficient in the IL-27 receptor (IL-27R) after the onset of inflammatory arthritis. Here, pathology was associated with increased synovial expression of pro-inflammatory cytokines, homeostatic chemokines, and transcriptional regulators linked with lymphoid neogenesis. In both clinical and experimental RA, synovial ELS coincided with the heightened local expression of cytokines and transcription factors of the Th17 and T follicular helper (Tfh) cell lineages, and included podoplanin-expressing T cells within lymphoid aggregates. IL-27 inhibited the differentiation of podoplanin-expressing Th17 cells, and an increased number of these cells were observed in IL-27R–deficient mice with inflammatory arthritis. Thus, IL-27 appears to negatively regulate ELS development in RA through control of effector T cells. These studies open new opportunities for patient stratification and treatment

Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes

SO₂ Phototriggered Crystalline Nanomechanical Transduction of Aromatic Rotors in Tosylates: Rationalization via Photocrystallography of [Ru(NH₃)₄SO₂X]tosylate₂ (X = pyridine, 3‑Cl-pyridine, 4‑Cl-pyridine)

Thermally reversible solid-state linkage SO₂ photoisomers of three complexes in the [Ru­(NH₃)₄SO₂<b>X</b>]­tosylate₂ family are captured in their metastable states using photocrystallography, where <b>X</b> = pyridine (<b>1</b>), 3-Cl-pyridine (<b>2</b>), and 4-Cl-pyridine (<b>3</b>). This photoisomerism exists only in the single-crystal form; accordingly, the nature of the crystalline environment surrounding the photoactive species controls its properties. In particular, the structural role of the tosylate anion needs to be understood against possible chemical influences due to varying the <i>trans</i> ligand, <b>X</b>. The photoexcited geometries, photoconversion levels, and thermal stabilities of the photoisomers that form in <b>1</b>–<b>3</b> are therefore studied. <b>1</b> and <b>2</b> yield two photoisomers at 100 K: the O-bound end-on η¹-SO₂ (MS1) configuration and the side-bound η²-SO₂ (MS2); <b>3</b> exhibits only the more thermally stable MS2 geometry. The decay kinetics of the MS2 geometry for <b>1</b>–<b>3</b> demonstrate that the greater the free volume of the GS SO₂ ligand for a given counterion, the greater the MS2 thermal stability. Furthermore, a rationalization is sought for the SO₂ phototriggered molecular rotation of the phenyl ring in the tosylate anion; this is selectively observed in <b>2</b>, manifesting as nanomechanical molecular transduction. This molecular transduction was not observed in <b>1</b>, despite the presence of the MS1 geometry due to the close intermolecular interactions between the MS1 SO₂ and the neighboring tosylate ion. The decay of this anionic molecular rotor in <b>2</b>, however, follows a nontraditional decay pathway, as determined by time-resolved crystallographic analysis; this contrasts with the well-behaved first-order kinetic decay of its MS1 SO₂ phototrigger

Quest Volume 6 Number 1

Maths, engineering and soccer stadiums; Why do you need to understand maths and science to build soccer stadia? An examination of the way in which geometry, trigonometry and mathematics are used in the building of these wonderful structures; Getting to the match: Transport is not something that you usually associate with science, but there is a lot of careful analysis used in working out the best way to transport large numbers of people; Sustainability - the key to the future of our soccer stadia: QUEST spoke to the experts who are making sure that the money spent on building our soccer stadia is being used wisely; The mathematics of soccer: How mathematics and statistics can be used to go some way towards answering the question, 'will my team win?'; Kicking a soccer ball QUEST shows you the anatomy behind that vital kick; Earth explorers: The Earth explorer satellites promise to revolutionise our understanding of the world around us; Restoration in South Africa - a case study; Ecological restoration is one approach to saving our changing landscape; Understanding the ocean floor: Seamount ecosystems are crucial to our understanding of the ocean floor; A life on the ocean wave: Riaan describes the excitement of working with global experts on oceanography; The birth of a fish: The fascinating journey from egg to larva; Mercury exposure - are we at risk?: Mercury is more a part of our everyday environment than you might realise;Academy of Science of South Africa: Department of Science and Innovatio

Rhythm in Twentieth-Century British Poetry

Les articles réunis dans le présent volume ont été originellement présentés sous forme de communications dans le cadre du colloque de la SÉAC organisé en novembre 2009 à l’ENS-LSH de Lyon. Cette manifestation a été organisée par Lacy Rumsey, en collaboration avec Simon Jarvis et Paul Volsik à qui nous adressons tous nos remerciements. The articles collected in this volume developed from oral presentations originally delivered during the SEAC conference hosted the ENS-LSH, in Lyon in November 2009, and convened by Lacy Rumsey, in association with Simon Jarvis and Paul Volsik. Our thanks go to the organisers of the conference who were instrumental in the publication of this volume

Cross-Amplification and Validation of SNPs Conserved over 44 Million Years between Seals and Dogs

Hoffman J, Thorne MAS, McEwing R, Forcada J, Ogden R. Cross-Amplification and Validation of SNPs Conserved over 44 Million Years between Seals and Dogs. PLoS ONE. 2013;8(7): e68365.High-density SNP arrays developed for humans and their companion species provide a rapid and convenient tool for generating SNP data in closely-related non-model organisms, but have not yet been widely applied to phylogenetically divergent taxa. Consequently, we used the CanineHD BeadChip to genotype 24 Antarctic fur seal (Arctocephalus gazella) individuals. Despite seals and dogs having diverged around 44 million years ago, 33,324 out of 173,662 loci (19.2%) could be genotyped, of which 173 were polymorphic and clearly interpretable. Two SNPs were validated using KASP genotyping assays, with the resulting genotypes being 100% concordant with those obtained from the high-density array. Two loci were also confirmed through in silico visualisation after mapping them to the fur seal transcriptome. Polymorphic SNPs were distributed broadly throughout the dog genome and did not differ significantly in proximity to genes from either monomorphic SNPs or those that failed to cross-amplify in seals. However, the nearest genes to polymorphic SNPs were significantly enriched for functional annotations relating to energy metabolism, suggesting a possible bias towards conserved regions of the genome