A role for polyunsaturated fatty acids in Th1-mediated disease

The anti-inflammatory effects of polyunsaturated fatty acids (PUFA) have been well documented, however their exact method of action remains elusive. Dendritic cells (DC) are the most potent antigen presenting cell (APC) and we found that n-3 and n-6 PUFA suppressed IL-12p70 and enhanced IL-10 production rendering the DC less inflammatory. Furthermore, PUFA inhibited DC maturation by impeding the upregulation of co-stirnulatory markers and MHCII expression. Given the critical role of IL-12 and IL-10 in T helper cell differentiation we looked at the effects of PUFA-modified DC on subsequent T cell development and found them capable of inhibiting IFN-y, IL-17, IL-2, and IL-4 production from CD4' T cells. PUFA are reported to be natural ligands for PPARy, therefore we investigated whether they exerted their effects on DC maturation by activation of this nuclear receptor. We found PPARy expression was enhanced in PUFA-treated DC, and confocal microscopy revealed an increased association of PPARy with NFkB . However, the PUFA-induced changes in DC cytokine production and cell surface marker expression were not reversed in the presence of the specific PPARy antagonist (GW9662) and were therefore deemed PPARy independent. Finally we carried out a number of feeding studies in mice where a CLAincorporated diet was used to ascertain whether results we recorded in vitro were mirrored in an in vivo situation. Mice fed a CLA-rich diet had less circulating inflammatory cytokines (LL-12p70 and EN-y) following endotoxin challenge in an LPS-shock model. Furthermore, feeding animals a CLA-supplemented diet significantly protected against the development of colitis in a DSS-induced model of inflammatory bowel disease, thus indicating that PUFA can exert beneficial and protective effects in inflammatory disease

Bringing "The Moth" to Light: A Planet-Sculpting Scenario for the HD 61005 Debris Disk

The HD 61005 debris disk ("The Moth") stands out from the growing collection of spatially resolved circumstellar disks by virtue of its unusual swept-back morphology, brightness asymmetries, and dust ring offset. Despite several suggestions for the physical mechanisms creating these features, no definitive answer has been found. In this work, we demonstrate the plausibility of a scenario in which the disk material is shaped dynamically by an eccentric, inclined planet. We present new Keck NIRC2 scattered-light angular differential imaging of the disk at 1.2-2.3 microns that further constrains its outer morphology (projected separations of 27-135 AU). We also present complementary Gemini Planet Imager 1.6 micron total intensity and polarized light detections that probe down to projected separations less than 10 AU. To test our planet-sculpting hypothesis, we employed secular perturbation theory to construct parent body and dust distributions that informed scattered-light models. We found that this method produced models with morphological and photometric features similar to those seen in the data, supporting the premise of a planet-perturbed disk. Briefly, our results indicate a disk parent body population with a semimajor axis of 40-52 AU and an interior planet with an eccentricity of at least 0.2. Many permutations of planet mass and semimajor axis are allowed, ranging from an Earth mass at 35 AU to a Jupiter mass at 5 AU.Comment: Accepted to AJ; added Figure 5 and minor text edit

Ecosystem Restoration: What, Why, How, and Where?

Our world contains many ecosystems, from tropical forests to coral reefs to urban parks. Ecosystems help us in important ways, including cleaning our air and water, storing carbon, and producing food. People have been shaping most ecosystems for at least 12,000 years. Human impact has become so intense that many ecosystems are now threatened. That is why the United Nations has decided that the next 10 years are the Decade on Ecosystem Restoration. But what is ecosystem restoration and how do we do it? In this article, we will tell you why ecosystem restoration is important and why it can be difficult. We will explain how it can be done well, and give examples from a range of projects. Successful restoration must include local people and requires lots of data. Restoration should not always return ecosystems back to what they were like once before

FtsK-Dependent Dimer Resolution on Multiple Chromosomes in the Pathogen Vibrio cholerae

Unlike most bacteria, Vibrio cholerae harbors two distinct, nonhomologous circular chromosomes (chromosome I and II). Many features of chromosome II are plasmid-like, which raised questions concerning its chromosomal nature. Plasmid replication and segregation are generally not coordinated with the bacterial cell cycle, further calling into question the mechanisms ensuring the synchronous management of chromosome I and II. Maintenance of circular replicons requires the resolution of dimers created by homologous recombination events. In Escherichia coli, chromosome dimers are resolved by the addition of a crossover at a specific site, dif, by two tyrosine recombinases, XerC and XerD. The process is coordinated with cell division through the activity of a DNA translocase, FtsK. Many E. coli plasmids also use XerCD for dimer resolution. However, the process is FtsK-independent. The two chromosomes of the V. cholerae N16961 strain carry divergent dimer resolution sites, dif1 and dif2. Here, we show that V. cholerae FtsK controls the addition of a crossover at dif1 and dif2 by a common pair of Xer recombinases. In addition, we show that specific DNA motifs dictate its orientation of translocation, the distribution of these motifs on chromosome I and chromosome II supporting the idea that FtsK translocation serves to bring together the resolution sites carried by a dimer at the time of cell division. Taken together, these results suggest that the same FtsK-dependent mechanism coordinates dimer resolution with cell division for each of the two V. cholerae chromosomes. Chromosome II dimer resolution thus stands as a bona fide chromosomal process

A Role for TLR4 in Clostridium difficile Infection and the Recognition of Surface Layer Proteins

Clostridium difficile is the etiological agent of antibiotic-associated diarrhoea (AAD) and pseudomembranous colitis in humans. The role of the surface layer proteins (SLPs) in this disease has not yet been fully explored. The aim of this study was to investigate a role for SLPs in the recognition of C. difficile and the subsequent activation of the immune system. Bone marrow derived dendritic cells (DCs) exposed to SLPs were assessed for production of inflammatory cytokines, expression of cell surface markers and their ability to generate T helper (Th) cell responses. DCs isolated from C3H/HeN and C3H/HeJ mice were used in order to examine whether SLPs are recognised by TLR4. The role of TLR4 in infection was examined in TLR4-deficient mice. SLPs induced maturation of DCs characterised by production of IL-12, TNFα and IL-10 and expression of MHC class II, CD40, CD80 and CD86. Furthermore, SLP-activated DCs generated Th cells producing IFNγ and IL-17. SLPs were unable to activate DCs isolated from TLR4-mutant C3H/HeJ mice and failed to induce a subsequent Th cell response. TLR4−/− and Myd88−/−, but not TRIF−/− mice were more susceptible than wild-type mice to C. difficile infection. Furthermore, SLPs activated NFκB, but not IRF3, downstream of TLR4. Our results indicate that SLPs isolated from C. difficile can activate innate and adaptive immunity and that these effects are mediated by TLR4, with TLR4 having a functional role in experimental C. difficile infection. This suggests an important role for SLPs in the recognition of C. difficile by the immune system

A randomized, observer-blinded immunogenicity trial of Cervarix(®) and Gardasil(®) Human Papillomavirus vaccines in 12-15 year old girls.

BACKGROUND: The current generation of Human Papillomavirus (HPV) vaccines, Cervarix® and Gardasil®, exhibit a high degree of efficacy in clinical trials against the two high-risk (HR) genotypes represented in the vaccines (HPV16 and HPV18). High levels of neutralizing antibodies are elicited against the vaccine types, consistent with preclinical data showing that neutralizing antibodies can mediate type-specific protection in the absence of other immune effectors. The vaccines also confer protection against some closely related non-vaccine HR HPV types, although the vaccines appear to differ in their degree of cross-protection. The mechanism of vaccine-induced cross-protection is unknown. This study sought to compare the breadth and magnitudes of neutralizing antibodies against non-vaccine types elicited by both vaccines and establish whether such antibodies could be detected in the genital secretions of vaccinated individuals. METHODS AND FINDINGS: Serum and genital samples were collected from 12-15 year old girls following vaccination with either Cervarix® (n = 96) or Gardasil® (n = 102) HPV vaccine. Serum-neutralizing antibody responses against non-vaccine HPV types were broader and of higher magnitude in the Cervarix®, compared to the Gardasil®, vaccinated individuals. Levels of neutralizing and binding antibodies in genital secretions were closely associated with those found in the serum (r = 0.869), with Cervarix® having a median 2.5 (inter-quartile range, 1.7-3.5) fold higher geometric mean HPV-specific IgG ratio in serum and genital samples than Gardasil® (p = 0.0047). There was a strong positive association between cross-neutralizing antibody seropositivity and available HPV vaccine trial efficacy data against non-vaccine types. CONCLUSIONS: These data demonstrate for the first time that cross-neutralizing antibodies can be detected at the genital site of infection and support the possibility that cross-neutralizing antibodies play a role in the cross-protection against HPV infection and disease that has been reported for the current HPV vaccines. TRIAL REGISTRATION: ClinicalTrials.gov NCT00956553

Estimating background concentrations of PM2.5 for urban air quality modelling in a data poor environment

Atmospheric dispersion models are widely applied to simulate pollutant concentrations such as PM2.5 for use in long- and short-term health studies. A significant proportion of PM2.5 originates outside urban areas in which many people live. It is important to reflect this ‘background’ component in the modelling process in order to provide an accurate representation of the total pollution load experienced by human populations. To be credible, model outputs must be verified against available monitoring data, which, in the case of PM2.5, may be limited to a small number of monitoring sites across a large urban area. Here we evaluate four different approaches to representing background PM2.5 in an atmospheric dispersion model (ADMS-Urban) for Nottingham, UK. A directional approach, based on multiple urban background monitoring sites located outside the study area provides the most robust estimates. Our adopted approach allows us to model both short- and long-term air quality conditions, whilst accounting for local- and regional-scale variations in the pollution burden, and will ultimately enable us to assess short- and long-term effects of air pollution on health

Estimating background concentrations of PM2.5 for urban air quality modelling in a data poor environment

Atmospheric dispersion models are widely applied to simulate pollutant concentrations such as PM2.5 for use in long- and short-term health studies. A significant proportion of PM2.5 originates outside urban areas in which many people live. It is important to reflect this ‘background’ component in the modelling process in order to provide an accurate representation of the total pollution load experienced by human populations. To be credible, model outputs must be verified against available monitoring data, which, in the case of PM2.5, may be limited to a small number of monitoring sites across a large urban area. Here we evaluate four different approaches to representing background PM2.5 in an atmospheric dispersion model (ADMS-Urban) for Nottingham, UK. A directional approach, based on multiple urban background monitoring sites located outside the study area provides the most robust estimates. Our adopted approach allows us to model both short- and long-term air quality conditions, whilst accounting for local- and regional-scale variations in the pollution burden, and will ultimately enable us to assess short- and long-term effects of air pollution on health