Implementation of an assessment and monitoring programme for Irish and British forests. BIOPLAN Final Report

A report describing in detail the scientific research that underpins the 30 specific recommendations are made for policy and practice in the Irish forestry sector made by the project.The four year BIOPLAN project ‘Implementation of an assessment and monitoring programme for biodiversity in Irish and British forests’ had the principal objective to identify ways in which forest policy and management can safeguard the future of forest biodiversity and associated ecosystem services, and inform environmentally sustainable expansion of Ireland’s forests. From the research findings, 30 specific recommendations are made for policy and practice in the Irish forestry sector to mitigate the effects of forest management on biodiversity. These recommendations are underpinned by sound scientific research to ensure that their implementation will help to deliver on Ireland’s commitment to sustainable forest management

Analysis combining correlated glaucoma traits identifies five new risk loci for open-angle glaucoma

Open-angle glaucoma (OAG) is a major cause of blindness worldwide. To identify new risk loci for OAG, we performed a genome-wide association study in 3,071 OAG cases and 6,750 unscreened controls, and meta-analysed the results with GWAS data for intraocular pressure (IOP) and optic disc parameters (the overall meta-analysis sample size varying between 32,000 to 48,000 participants), which are glaucoma-related traits. We identified and independently validated four novel genome-wide significant associations within or near MYOF and CYP26A1, LINC02052 and CRYGS, LMX1B, and LMO7 using single variant tests, one additional locus (C9) using gene-based tests, and two genetic pathways - “response to fluid shear stress” and “abnormal retina morphology” - in pathway-based tests. Interestingly, some of the new risk loci contribute to risk of other genetically-correlated eye diseases including myopia and age-related macular degeneration. To our knowledge, this study is the first integrative study to combine genetic data from OAG and its correlated traits to identify new risk variants and genetic pathways, highlighting the future potential of combining genetic data from genetically-correlated eye traits for the purpose of gene discovery and mapping

Genomic investigations of unexplained acute hepatitis in children

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children

Potent, synergistic inhibition of <em>Staphylococcus aureus</em> upon exposure to a combination of the endopeptidase lysostaphin and the cationic peptide ranalexin

Objectives: Successful treatment of infections involving multiply drug-resistant methicillin-resistant Staphylococcus aureus (MRSA) is becoming increasingly difficult. In this work, we have investigated the potential of combining lysostaphin with cationic antimicrobial peptides to effectively inhibit Staphylococcus aureus. Methods: S. aureus strains were grown in 96-well plates in the presence of increasing concentrations of lysostaphin and the peptides ranalexin, dermaseptin S3(1-16) or magainin 2. Growth was determined visually after 48 h and the plates imaged, or by automated optical density readings in a plate reader. Susceptibility to the combination of lysostaphin and ranalexin was also determined by viable cell counts. The efficacy of combined lysostaphin and ranalexin on a solid surface was tested via disc diffusion assays. Results and conclusions: Combination of lysostaphin with ranalexin resulted in potent, synergistic inhibition of S. aureus MSSA476 and MRSA252. Synergistic inhibition was specific for lysostaphin-susceptible staphylococci and was not observed with clinical isolates of the Gram-negative Escherichia coli, or other Gram-positive organisms, such as Enterococcus faecalis. Lysostaphin was not specifically synergistic with ranalexin alone. Synergy was also observed with two other cationic antimicrobial peptides, magainin 2 and dermaseptin s3(1-16); although combination with ranalexin was most potent. Synergistic inhibition by ranalexin in combination with lysostaphin resulted in an enhanced bactericidal effect. Importantly, synergy between lysostaphin and ranalexin was also observed after impregnation and drying in filter paper discs that clearly inhibited growth of S. aureus on the surface of agar; a solid, porous matrix. Thus, the combination could represent a novel route to target wounds infected with drug-resistant MRSA via dressings impregnated with the two compounds.</p

Bordetella pertussis commits human dendritic cells to promote a Th1/Th17 response through the activity of adenylate cyclase toxin and MAPK-pathways.

The complex pathology of B. pertussis infection is due to multiple virulence factors having disparate effects on different cell types. We focused our investigation on the ability of B. pertussis to modulate host immunity, in particular on the role played by adenylate cyclase toxin (CyaA), an important virulence factor of B. pertussis. As a tool, we used human monocyte derived dendritic cells (MDDC), an ex vivo model useful for the evaluation of the regulatory potential of DC on T cell immune responses. The work compared MDDC functions after encounter with wild-type B. pertussis (BpWT) or a mutant lacking CyaA (BpCyaA-), or the BpCyaA- strain supplemented with either the fully functional CyaA or a derivative, CyaA*, lacking adenylate cyclase activity. As a first step, MDDC maturation, cytokine production, and modulation of T helper cell polarization were evaluated. As a second step, engagement of Toll-like receptors (TLR) 2 and TLR4 by B. pertussis and the signaling events connected to this were analyzed. These approaches allowed us to demonstrate that CyaA expressed by B. pertussis strongly interferes with DC functions, by reducing the expression of phenotypic markers and immunomodulatory cytokines, and blocking IL-12p70 production. B. pertussis-treated MDDC promoted a mixed Th1/Th17 polarization, and the activity of CyaA altered the Th1/Th17 balance, enhancing Th17 and limiting Th1 expansion. We also demonstrated that Th1 effectors are induced by B. pertussis-MDDC in the absence of IL-12p70 through an ERK1/2 dependent mechanism, and that p38 MAPK is essential for MDDC-driven Th17 expansion. The data suggest that CyaA mediates an escape strategy for the bacterium, since it reduces Th1 immunity and increases Th17 responses thought to be responsible, when the response is exacerbated, for enhanced lung inflammation and injury

Competing S N 2 and E2 reaction pathways for hexachlorocyclohexane degradation in the gas phase, solution and enzymes

Quantum chemistry calculations have been used alongside experimental kinetic analysis to investigate the competition between SN2 and E2 mechanisms for the dechlorination of hexachlorocyclohexane isomers, revealing that enzyme specificity reflects the intrinsic reactivity of the various isomers