Unravelling the therapeutic potential of IL-33 for atrophic AMD

Age-related macular degeneration (AMD), a degenerative disease affecting the retinal pigment epithelium (RPE) and photoreceptors in the macula, is the leading cause of central blindness in the elderly. AMD progresses to advanced stages of the disease, atrophic AMD (aAMD), or in 15% of cases “wet” or neovascular AMD (nAMD), associated with substantial vision loss. Whilst there has been advancement in therapies treating nAMD, to date, there are no licenced effective treatments for the 85% affected by aAMD, with disease managed by changes to diet, vitamin supplements, and regular monitoring. AMD has a complex pathogenesis, involving highly integrated and common age-related disease pathways, including dysregulated complement/inflammation, impaired autophagy, and oxidative stress. The intricacy of AMD pathogenesis makes therapeutic development challenging and identifying a target that combats the converging disease pathways is essential to provide a globally effective treatment. Interleukin-33 is a cytokine, classically known for the proinflammatory role it plays in allergic disease. Recent evidence across degenerative and inflammatory disease conditions reveals a diverse immune-modulatory role for IL-33, with promising therapeutic potential. Here, we will review IL-33 function in disease and discuss the future potential for this homeostatic cytokine in treating AMD

Microcanonical studies on isoscaling

The exponential scaling of isotopic yields is investigated for sources of different sizes over a broad range of excitation energies and freeze-out volumes, in both primary and asymptotic stages of the decay in the framework of a microcanonical multifragmentation model. It was found that the scaling parameters have a strong dependence on the considered pair of equilibrated sources and excitation energy and are affected by the secondary particle emission of the break-up fragments. No significant influence of the freeze-out volume on the considered isotopic ratios has been observed. Deviations of microcanonical results from grandcanonical expectations are discussed.Comment: 19 pages, 6 figure

Optical properties of ferroelectric nanocrystal-containing polymer BaTiO₃/polycarbonate films

Author name used in this publication: C. L. MakAuthor name used in this publication: K. H. Wong2005-2006 > Academic research: refereed > Publication in refereed journalVersion of RecordPublishe

Joint profiling of DNA methylation and chromatin architecture in single cells.

We report a molecular assay, Methyl-HiC, that can simultaneously capture the chromosome conformation and DNA methylome in a cell. Methyl-HiC reveals coordinated DNA methylation status between distal genomic segments that are in spatial proximity in the nucleus, and delineates heterogeneity of both the chromatin architecture and DNA methylome in a mixed population. It enables simultaneous characterization of cell-type-specific chromatin organization and epigenome in complex tissues

Global distribution of two fungal pathogens threatening endangered sea turtles

This work was supported by grants of Ministerio de Ciencia e Innovación, Spain (CGL2009-10032, CGL2012-32934). J.M.S.R was supported by PhD fellowship of the CSIC (JAEPre 0901804). The Natural Environment Research Council and the Biotechnology and Biological Sciences Research Council supported P.V.W. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Thanks Machalilla National Park in Ecuador, Pacuare Nature Reserve in Costa Rica, Foundations Natura 2000 in Cape Verde and Equilibrio Azul in Ecuador, Dr. Jesus Muñoz, Dr. Ian Bell, Dr. Juan Patiño for help and technical support during samplingPeer reviewedPublisher PD

SteC is a Salmonella kinase required for SPI-2-dependent F-actin remodelling

Salmonella enterica serovar Typhimurium (S. Typhimurium) replicates inside mammalian cells within membrane-bound compartments called Salmonella-containing vacuoles. Intracellular replication is dependent on the activities of several effector proteins translocated across the vacuolar membrane by the Salmonella pathogenicity island 2 (SPI-2)-type III secretion system (T3SS). This is accompanied by the formation in the vicinity of bacterial vacuoles of an F-actin meshwork, thought to be involved in maintaining the integrity of vacuolar membranes. In this study, we investigated the function of the SPI-2 T3SS effector SteC. An steC mutant strain was not defective for intracellular replication or attenuated for virulence in mice. However, the steC mutant was defective for SPI-2-dependent F-actin meshwork formation in host cells, although the vacuolar membranes surrounding mutant bacteria appeared to be normal. Expression of SteC in fibroblast cells following transfection caused extensive rearrangements of the F-actin cytoskeleton. Sequence analysis identified amino acid similarity between SteC and the human kinase Raf-1. A His-tagged SteC fusion protein had kinase activity in vitro and a point mutant lacking kinase activity was unable to induce F-actin rearrangements in vivo. We conclude that SPI-2-dependent F-actin meshwork formation depends on the kinase activity of SteC, which resembles more closely eukaryotic than prokaryotic kinases

Imaging based uveitis surveillance in juvenile idiopathic arthritis: feasibility, acceptability and diagnostic performance

OBJECTIVE: Children with juvenile idiopathic arthritis need regular examinations for uveitis to avoid visual morbidity from the most common extra-articular manifestation of disease. We investigated the feasibility, acceptability and performance of optical coherence tomography (OCT) imaging based diagnosis of uveitis. METHODS: Observational cross-sectional study involving children with and without uveitis. Children underwent routine clinical examination and acquisition of anterior segment (AS) OCT scans images of intraocular inflammatory cells. Acceptability of image acquisition was assessed using a visual analogue scale, and duration of image acquisition. Inter and intra-observer variability of manual counting of acquired images (Bland-Altman limits of agreement), correlation between imaging and routine assessment, and sensitivity and specificity of AS-OCT detection of active inflammation were assessed. RESULTS: Of 26 children aged 3yrs to 15yrs (median 8yrs) who underwent imaging, 12 had active inflammation. All patients rated acceptability of image acquisition as at least 8·5/10. Time taken to acquire images ranged from 1·5mins to 22mins (median 8mins). There was good positive correlation between clinical assessment and image based cell quantification (R2 =0·63, p=0·002). Sensitivity of AS-OCT manual image cell count for diagnosis of active inflammation was 92% (95% Confidence interval 62%-99%), specificity 86% (58%-98%), and negative predictive value ('ruling-out' uveitis) 92% (65%-99%). CONCLUSION: Non-contact, high-resolution imaging for JIA uveitis surveillance is feasible, acceptable to patients, and holds the promise of transforming paediatric practice. Further work is needed to determine the analytic and clinical validity of AS-OCT quantification of active inflammation, and the clinical and cost-effectiveness of imaging based disease monitoring

New gold nanostructures for sensor applications: a review

Gold based structures such as nanoparticles (NPs) and nanowires (NWs) have widely been used as building blocks for sensing devices in chemistry and biochemistry fields because of their unusual optical, electrical and mechanical properties. This article gives a detailed review of the new properties and fabrication methods for gold nanostructures, especially gold nanowires (GNWs), and recent developments for their use in optical and electrochemical sensing tools, such as surface enhanced Raman spectroscopy (SERS). © 2014 by the authors; licensee MDPI, Basel, Switzerland

Interleukin-33 regulates tissue remodelling and inhibits angiogenesis in the eye

Age-related macular degeneration (AMD) is the leading cause of central vision loss worldwide. Loss of retinal pigment epithelium (RPE) is a major pathological hallmark in AMD with or without pathological neovascularization. Although activation of the immune system is implicated in disease progression, pathological pathways remain diverse and unclear. Here, we report an unexpected protective role of a pro-inflammatory cytokine, interleukin-33 (IL-33) in ocular angiogenesis. IL-33 and its receptor (ST2) are expressed constitutively in human and murine retina and choroid. When RPE was activated, IL-33 expression was markedly elevated in vitro. We found that IL-33 regulated tissue remodelling by attenuating wound-healing responses, including reduction in migration of choroidal fibroblasts and retinal microvascular endothelial cells, and inhibition of collagen gel contraction. In vivo, local administration of recombinant IL-33 inhibited murine choroidal neovascularization (CNV) formation, a surrogate of human neovascular AMD, and this effect was ST2-dependent. Collectively, these data demonstrate IL-33 as a potential immunotherapy and distinguishes pathways for subverting AMD pathology