IL-17 can be protective or deleterious in murine pneumococcal pneumonia

Streptococcus pneumoniae is the major bacterial cause of community-acquired pneumonia, and the leading agent of childhood pneumonia deaths worldwide. Nasal colonization is an essential step prior to infection. The cytokine IL-17 protects against such colonization and vaccines that enhance IL-17 responses to pneumococcal colonization are being developed. The role of IL-17 in host defence against pneumonia is not known. To address this issue, we have utilized a murine model of pneumococcal pneumonia in which the gene for the IL-17 cytokine family receptor, Il17ra, has been inactivated. Using this model, we show that IL-17 produced predominantly from γδ T cells protects mice against death from the invasive TIGR4 strain (serotype 4) which expresses a relatively thin capsule. However, in pneumonia produced by two heavily encapsulated strains with low invasive potential (serotypes 3 and 6B), IL-17 significantly enhanced mortality. Neutrophil uptake and killing of the serotype 3 strain was significantly impaired compared to the serotype 4 strain and depletion of neutrophils with antibody enhanced survival of mice infected with the highly encapsulated SRL1 strain. These data strongly suggest that IL-17 mediated neutrophil recruitment to the lungs clears infection from the invasive TIGR4 strain but that lung neutrophils exacerbate disease caused by the highly encapsulated pneumococcal strains. Thus, whilst augmenting IL-17 immune responses against pneumococci may decrease nasal colonization, this may worsen outcome during pneumonia caused by some strains

Limitations of predicting substrate classes on a sedimentary complex but morphologically simple seabed

The ocean floor, its species and habitats are under pressure from various human activities. Marine spatial planning and nature conservation aim to address these threats but require sufficiently detailed and accurate maps of the distribution of seabed substrates and habitats. Benthic habitat mapping has markedly evolved as a discipline over the last decade, but important challenges remain. To test the adequacy of current data products and classification approaches, we carried out a comparative study based on a common dataset of multibeam echosounder bathymetry and backscatter data, supplemented with groundtruth observations. The task was to predict the spatial distribution of five substrate classes (coarse sediments, mixed sediments, mud, sand, and rock) in a highly heterogeneous area of the south-western continental shelf of the United Kingdom. Five different supervised classification methods were employed, and their accuracy estimated with a set of samples that were withheld. We found that all methods achieved overall accuracies of around 50%. Errors of commission and omission were acceptable for rocky substrates, but high for all sediment types. We predominantly attribute the low map accuracy regardless of mapping approach to inadequacies of the selected classification system, which is required to fit gradually changing substrate types into a rigid scheme, low discriminatory power of the available predictors, and high spatial complexity of the site relative to the positioning accuracy of the groundtruth equipment. Some of these issues might be alleviated by creating an ensemble map that aggregates the individual outputs into one map showing the modal substrate class and its associated confidence or by adopting a quantitative approach that models the spatial distribution of sediment fractions. We conclude that further incremental improvements to the collection, processing and analysis of remote sensing and sample data are required to improve map accuracy. To assess the progress in benthic habitat mapping we propose the creation of benchmark datasets

Histone deacetylase 4 interacts with 53BP1 to mediate the DNA damage response

Anumber of proteins are recruited to nuclear foci upon exposure to double-strand DNA damage, including 53BP1 and Rad51, but the precise role of these DNA damage–induced foci remain unclear. Here we show in a variety of human cell lines that histone deacetylase (HDAC) 4 is recruited to foci with kinetics similar to, and colocalizes with, 53BP1 after exposure to agents causing double-stranded DNA breaks. HDAC4 foci gradually disappeared in repair-proficient cells but persisted in repair-deficient cell lines or cells irradiated with a lethal dose, suggesting that resolution of HDAC4 foci is linked to repair. Silencing of HDAC4 via RNA interference surprisingly also decreased levels of 53BP1 protein, abrogated the DNA damage–induced G2 delay, and radiosensitized HeLa cells. Our combined results suggest that HDAC4 is a critical component of the DNA damage response pathway that acts through 53BP1 and perhaps contributes in maintaining the G2 cell cycle checkpoint

Mapping the Design Process for Urban Ecology Researchers

The integration of research into the design process is an opportunity to build ecologically informed urban design solutions. To date, designers have traditionally relied on environmental consultants to provide the best available science; however, serious gaps in our understanding of urban ecosystems remain. To evaluate ecosystem processes and services for sustainable urban design and to further advance our understanding of social-ecological processes within the urban context, we need to integrate primary research into the urban design process. In this article, we develop a road map for such a synthesis. Supporting our proposals by case studies, we identify strategic entry points at which urban ecology researchers can integrate their work into the design process

Death or survival from invasive pneumococcal disease in Scotland: associations with serogroups and multilocus sequence types

We describe associations between death from invasive pneumococcal disease (IPD) and particular serogroups and sequence types (STs) determined by multilocus sequence typing (MLST) using data from Scotland. All IPD episodes where blood or cerebrospinal fluid (CSF) culture isolates were referred to the Scottish Haemophilus, Legionella, Meningococcal and Pneumococcal Reference Laboratory (SHLMPRL) from January 1992 to February 2007 were matched to death certification records by the General Register Office for Scotland. This represented 5959 patients. The median number of IPD cases in Scotland each year was 292. Deaths, from any cause, within 30 days of pneumococcal culture from blood or CSF were considered to have IPD as a contributing factor. Eight hundred and thirty-three patients died within 30 days of culture of Streptococcus pneumoniae from blood or CSF [13.95%; 95% confidence interval (13.10, 14.80)]. The highest death rates were in patients over the age of 75. Serotyping data exist for all years but MLST data were only available from 2001 onward. The risk ratio of dying from infection due to particular serogroups or STs compared to dying from IPD due to all other serogroups or STs was calculated. Fisher's exact test with Bonferroni adjustment for multiple testing was used. Age adjustment was accomplished using the Cochran-Mantel-Haenszel test and 95% confidence intervals were reported. Serogroups 3, 11 and 16 have increased probability of causing fatal IPD in Scotland while serogroup 1 IPD has a reduced probability of causing death. None of the 20 most common STs were significantly associated with death within 30 days of pneumococcal culture, after age adjustment. We conclude that there is a stronger association between a fatal outcome and pneumococcal capsular serogroup than there is between a fatal outcome and ST

Reversal of aging-induced increases in aortic stiffness by targeting cytoskeletal protein-protein interfaces

Background: The proximal aorta normally functions as a critical shock absorber that protects small downstream vessels from damage by pressure and flow pulsatility generated by the heart during systole. This shock absorber function is impaired with age because of aortic stiffening. Methods and Results: We examined the contribution of common genetic variation to aortic stiffness in humans by interrogating results from the AortaGen Consortium genome-wide association study of carotid-femoral pulse wave velocity. Common genetic variation in the N-WASP (WASL) locus is associated with carotid-femoral pulse wave velocity (rs600420, P=0.0051). Thus, we tested the hypothesis that decoy proteins designed to disrupt the interaction of cytoskeletal proteins such as N-WASP with its binding partners in the vascular smooth muscle cytoskeleton could decrease ex vivo stiffness of aortas from a mouse model of aging. A synthetic decoy peptide construct of N-WASP significantly reduced activated stiffness in ex vivo aortas of aged mice. Two other cytoskeletal constructs targeted to VASP and talin-vinculin interfaces similarly decreased aging-induced ex vivo active stiffness by on-target specific actions. Furthermore, packaging these decoy peptides into microbubbles enables the peptides to be ultrasound-targeted to the wall of the proximal aorta to attenuate ex vivo active stiffness. Conclusions: We conclude that decoy peptides targeted to vascular smooth muscle cytoskeletal protein-protein interfaces and microbubble packaged can decrease aortic stiffness ex vivo. Our results provide proof of concept at the ex vivo level that decoy peptides targeted to cytoskeletal protein-protein interfaces may lead to substantive dynamic modulation of aortic stiffness

Tomographic image of melt storage beneath Askja Volcano, Iceland using local microseismicity

We use P wave and S wave arrivals from microseismic earthquakes to construct 3-D tomographic Vp and Vs images of the magma storage region beneath Askja's central volcano in the Northern Volcanic Zone of Iceland. A distinctive ellipsoidal low-velocity anomaly, with both Vp and Vsvelocities 8-12% below the background, is imaged at 6-11 km depth beneath the caldera. The presence of a shallow magma chamber is corroborated by geodetic and gravity studies. The small Vp/Vs anomaly suggests a lack of pervasive melt. We interpret this anomaly as a region of multiple sills, some frozen but hot, others containing partial melt. A second, smaller low-velocity anomaly beneath the main magma storage region may represent a magma migration pathway. This interpretation is supported by the close proximity to the anomaly of clusters of deep, magmatically induced earthquakes. However, the location and shape of this deep anomaly are poorly constrained by the current data set

The 'Matters' of Science Diplomacy:Transversal Analysis of the S4D4C Case Studies

What matters in science diplomacy? That is the question that the publication of the S4D4C project (see www.s4d4c.eu) “The 'Matters' of Science Diplomacy: Transversal Analysis of the S4D4C Case Studies” aims to answer. To do so, the transversal analysis critically analyses the content of the project's nine case studies and identifies insights to foster and advance the understanding and the practice of science diplomacy. Each matter addresses a piece from the larger picture; together they form a mosaic depicting the complex and wide-ranging concept of science diplomacy. The 10 “matters” are the result of the collaborative work between 11 S4D4C team members, coordinated by Mitchell Young, S4D4C lead for empirical work