Showing papers by "Trinity College, Dublin published in 2011"

Two-Dimensional Nanosheets Produced by Liquid Exfoliation of Layered Materials

Abstract: If they could be easily exfoliated, layered materials would become a diverse source of two-dimensional crystals whose properties would be useful in applications ranging from electronics to energy storage. We show that layered compounds such as MoS2, WS2, MoSe2, MoTe2, TaSe2, NbSe2, NiTe2, BN, and Bi2Te3 can be efficiently dispersed in common solvents and can be deposited as individual flakes or formed into films. Electron microscopy strongly suggests that the material is exfoliated into individual layers. By blending this material with suspensions of other nanomaterials or polymer solutions, we can prepare hybrid dispersions or composites, which can be cast into films. We show that WS2 and MoS2 effectively reinforce polymers, whereas WS2/carbon nanotube hybrid films have high conductivity, leading to promising thermoelectric properties.

Crystal structure of the β2 adrenergic receptor-Gs protein complex.

Abstract: G protein-coupled receptors (GPCRs) are responsible for the majority of cellular responses to hormones and neurotransmitters as well as the senses of sight, olfaction and taste. The paradigm of GPCR signalling is the activation of a heterotrimeric GTP binding protein (G protein) by an agonist-occupied receptor. The b2 adrenergic receptor (b2AR) activation of Gs, the stimulatory G protein for adenylyl cyclase, has long been a model system for GPCR signalling. Here we present the crystal structure of the active state ternary complex composed of agonist-occupied monomericb2AR and nucleotide-free Gs heterotrimer. The principal interactions between the b2AR and Gs involve the amino- and carboxy-terminal a-helices of Gs, with conformational changes propagating to the nucleotide-binding pocket. The

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis

Abstract: Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.

Comparing isotopic niche widths among and within communities: SIBER - Stable Isotope Bayesian Ellipses in R.

Abstract: 1. The use of stable isotope data to infer characteristics of community structure and niche width of community members has become increasingly common. Although these developments have provided ecologists with new perspectives, their full impact has been hampered by an inability to statistically compare individual communities using descriptive metrics. 2. We solve these issues by reformulating the metrics in a Bayesian framework. This reformulation takes account of uncertainty in the sampled data and naturally incorporates error arising from the sampling process, propagating it through to the derived metrics. 3. Furthermore, we develop novel multivariate ellipse-based metrics as an alternative to the currently employed Convex Hull methods when applied to single community members. We show that unlike Convex Hulls, the ellipses are unbiased with respect to sample size, and their estimation via Bayesian inference allows robust comparison to be made among data sets comprising different sample sizes. 4. These new metrics, which we call SIBER (Stable Isotope Bayesian Ellipses in R), open up more avenues for direct comparison of isotopic niches across communities. The computational code to calculate the new metrics is implemented in the free-to-download package Stable Isotope Analysis for the R statistical environment.

Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease.

Abstract: We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ≤ 1 × 10−5. We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10−17; including ADGC data, meta P = 5.0 × 10−21) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10−14; including ADGC data, meta P = 1.2 × 10−16) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10−4; including ADGC data, meta P = 8.6 × 10−9), CD33 (GERAD+, P = 2.2 × 10−4; including ADGC data, meta P = 1.6 × 10−9) and EPHA1 (GERAD+, P = 3.4 × 10−4; including ADGC data, meta P = 6.0 × 10−10).

Genome-wide association study identifies five new schizophrenia loci

Abstract: We examined the role of common genetic variation in schizophrenia in a genome-wide association study of substantial size: a stage 1 discovery sample of 21,856 individuals of European ancestry and a stage 2 replication sample of 29,839 independent subjects. The combined stage 1 and 2 analysis yielded genome-wide significant associations with schizophrenia for seven loci, five of which are new (1p21.3, 2q32.3, 8p23.2, 8q21.3 and 10q24.32-q24.33) and two of which have been previously implicated (6p21.32-p22.1 and 18q21.2). The strongest new finding (P = 1.6 x 10(-11)) was with rs1625579 within an intron of a putative primary transcript for MIR137 (microRNA 137), a known regulator of neuronal development. Four other schizophrenia loci achieving genome-wide significance contain predicted targets of MIR137, suggesting MIR137-mediated dysregulation as a previously unknown etiologic mechanism in schizophrenia. In a joint analysis with a bipolar disorder sample (16,374 affected individuals and 14,044 controls), three loci reached genome-wide significance: CACNA1C (rs4765905, P = 7.0 x 10(-9)), ANK3 (rs10994359, P = 2.5 x 10(-8)) and the ITIH3-ITIH4 region (rs2239547, P = 7.8 x 10(-9)).

Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4

Abstract: We conducted a combined genome-wide association study (GWAS) of 7,481 individuals with bipolar disorder (cases) and 9,250 controls as part of the Psychiatric GWAS Consortium. Our replication study tested 34 SNPs in 4,496 independent cases with bipolar disorder and 42,422 independent controls and found that 18 of 34 SNPs had P < 0.05, with 31 of 34 SNPs having signals with the same direction of effect (P = 3.8 × 10−7). An analysis of all 11,974 bipolar disorder cases and 51,792 controls confirmed genome-wide significant evidence of association for CACNA1C and identified a new intronic variant in ODZ4. We identified a pathway comprised of subunits of calcium channels enriched in bipolar disorder association intervals. Finally, a combined GWAS analysis of schizophrenia and bipolar disorder yielded strong association evidence for SNPs in CACNA1C and in the region of NEK4-ITIH1-ITIH3-ITIH4. Our replication results imply that increasing sample sizes in bipolar disorder will confirm many additional loci.

Two-Dimensional Nanosheets Produced by Liquid Exfoliation of Layered Materials.

Abstract: Layered compounds such as MoS2, WS2, MoSe2, TaSe2, NbSe2, NiTe2, BN, and Bi2Te3 are exfoliated by sonication of powders of the materials in a number of solvents with varying surface tensions and deposited as individual flakes or formed into films.

Large-scale exfoliation of inorganic layered compounds in aqueous surfactant solutions

Abstract: Ronan J. Smith , Paul J. King , Mustafa Lotya , Christian Wirtz , Umar Khan , Sukanta De , Arlene O’Neill , Georg S. Duesberg , Jaime C. Grunlan , Gregory Moriarty , Jun Chen , Jiazhao Wang , Andrew I. Minett , Valeria Nicolosi , and Jonathan N. Coleman *

Filaggrin Mutations Associated with Skin and Allergic Diseases

Abstract: Mutations in the filaggrin gene are associated with a broad range of skin and allergic diseases. The biology of this molecule and the role of mutations in its altered function offer new insights into a range of conditions not previously thought to be related to one another.

Methodology in conducting a systematic review of systematic reviews of healthcare interventions

Abstract: Background: Hundreds of studies of maternity care interventions have been published, too many for most people involved in providing maternity care to identify and consider when making decisions. It became apparent that systematic reviews of individual studies were required to appraise, summarise and bring together existing studies in a single place. However, decision makers are increasingly faced by a plethora of such reviews and these are likely to be of variable quality and scope, with more than one review of important topics. Systematic reviews (or overviews) of reviews are a logical and appropriate next step, allowing the findings of separate reviews to be compared and contrasted, providing clinical decision makers with the evidence they need. Methods: The methods used to identify and appraise published and unpublished reviews systematically, drawing on our experiences and good practice in the conduct and reporting of systematic reviews are described. The process of identifying and appraising all published reviews allows researchers to describe the quality of this evidence base, summarise and compare the review’s conclusions and discuss the strength of these conclusions. Results: Methodological challenges and possible solutions are described within the context of (i) sources, (ii) study selection, (iii) quality assessment (i.e. the extent of searching undertaken for the reviews, description of study selection and inclusion criteria, comparability of included studies, assessment of publication bias and assessment of heterogeneity), (iv) presentation of results, and (v) implications for practice and research. Conclusion: Conducting a systematic review of reviews highlights the usefulness of bringing together a summary of reviews in one place, where there is more than one review on an important topic. The methods described here should help clinicians to review and appraise published reviews systematically, and aid evidence-based clinical decision-making.

A field guide to pandemic, epidemic and sporadic clones of methicillin-resistant Staphylococcus aureus

Abstract: In recent years, methicillin-resistant Staphylococcus aureus (MRSA) have become a truly global challenge. In addition to the long-known healthcare-associated clones, novel strains have also emerged outside of the hospital settings, in the community as well as in livestock. The emergence and spread of virulent clones expressing Panton-Valentine leukocidin (PVL) is an additional cause for concern. In order to provide an overview of pandemic, epidemic and sporadic strains, more than 3,000 clinical and veterinary isolates of MRSA mainly from Germany, the United Kingdom, Ireland, France, Malta, Abu Dhabi, Hong Kong, Australia, Trinidad & Tobago as well as some reference strains from the United States have been genotyped by DNA microarray analysis. This technique allowed the assignment of the MRSA isolates to 34 distinct lineages which can be clearly defined based on non-mobile genes. The results were in accordance with data from multilocus sequence typing. More than 100 different strains were distinguished based on affiliation to these lineages, SCCmec type and the presence or absence of PVL. These strains are described here mainly with regard to clinically relevant antimicrobial resistance- and virulence-associated markers, but also in relation to epidemiology and geographic distribution. The findings of the study show a high level of biodiversity among MRSA, especially among strains harbouring SCCmec IV and V elements. The data also indicate a high rate of genetic recombination in MRSA involving SCC elements, bacteriophages or other mobile genetic elements and large-scale chromosomal replacements.

MicroRNAs: the fine-tuners of Toll-like receptor signalling

Abstract: Toll-like receptors (TLRs) are central to the induction of pro-inflammatory responses, but their signalling pathways must be tightly regulated. As discussed in this article, an emerging level of fine-tuning is mediated by microRNAs, several of which are induced by TLR signalling. Toll-like receptor (TLR) signalling must be tightly regulated to avoid excessive inflammation and to allow for tissue repair and the return to homeostasis after infection and tissue injury. MicroRNAs (miRNAs) have emerged as important controllers of TLR signalling. Several miRNAs are induced by TLR activation in innate immune cells and these and other miRNAs target the 3′ untranslated regions of mRNAs encoding components of the TLR signalling system. miRNAs are also proving to be an important link between the innate and adaptive immune systems, and their dysregulation might have a role in the pathogenesis of inflammatory diseases.

Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility

Abstract: Ankylosing spondylitis is a common form of inflammatory arthritis predominantly affecting the spine and pelvis that occurs in approximately 5 out of 1,000 adults of European descent. Here we report the identification of three variants in the RUNX3, LTBR-TNFRSF1A and IL12B regions convincingly associated with ankylosing spondylitis (P < 5 x 10(-8) in the combined discovery and replication datasets) and a further four loci at PTGER4, TBKBP1, ANTXR2 and CARD9 that show strong association across all our datasets (P < 5 x 10(-6) overall, with support in each of the three datasets studied). We also show that polymorphisms of ERAP1, which encodes an endoplasmic reticulum aminopeptidase involved in peptide trimming before HLA class I presentation, only affect ankylosing spondylitis risk in HLA-B27-positive individuals. These findings provide strong evidence that HLA-B27 operates in ankylosing spondylitis through a mechanism involving aberrant processing of antigenic peptides.

An Observational Overview of Solar Flares

Abstract: We present an overview of solar flares and associated phenomena, drawing upon a wide range of observational data primarily from the RHESSI era Following an introductory discussion and overview of the status of observational capabilities, the article is split into topical sections which deal with different areas of flare phenomena (footpoints and ribbons, coronal sources, relationship to coronal mass ejections) and their interconnections We also discuss flare soft X-ray spectroscopy and the energetics of the process The emphasis is to describe the observations from multiple points of view, while bearing in mind the models that link them to each other and to theory The present theoretical and observational understanding of solar flares is far from complete, so we conclude with a brief discussion of models, and a list of missing but important observations

Structure and function of an irreversible agonist-β2 adrenoceptor complex

Abstract: G-protein-coupled receptors (GPCRs) are eukaryotic integral membrane proteins that modulate biological function by initiating cellular signalling in response to chemically diverse agonists. Despite recent progress in the structural biology of GPCRs, the molecular basis for agonist binding and allosteric modulation of these proteins is poorly understood. Structural knowledge of agonist-bound states is essential for deciphering the mechanism of receptor activation, and for structure-guided design and optimization of ligands. However, the crystallization of agonist-bound GPCRs has been hampered by modest affinities and rapid off-rates of available agonists. Using the inactive structure of the human β(2) adrenergic receptor (β(2)AR) as a guide, we designed a β(2)AR agonist that can be covalently tethered to a specific site on the receptor through a disulphide bond. The covalent β(2)AR-agonist complex forms efficiently, and is capable of activating a heterotrimeric G protein. We crystallized a covalent agonist-bound β(2)AR-T4L fusion protein in lipid bilayers through the use of the lipidic mesophase method, and determined its structure at 3.5 A resolution. A comparison to the inactive structure and an antibody-stabilized active structure (companion paper) shows how binding events at both the extracellular and intracellular surfaces are required to stabilize an active conformation of the receptor. The structures are in agreement with long-timescale (up to 30 μs) molecular dynamics simulations showing that an agonist-bound active conformation spontaneously relaxes to an inactive-like conformation in the absence of a G protein or stabilizing antibody.

Extra-pleural pneumonectomy versus no extra-pleural pneumonectomy for patients with malignant pleural mesothelioma: clinical outcomes of the Mesothelioma and Radical Surgery (MARS) randomised feasibility study

Abstract: Background The eff ects of extra-pleural pneumonectomy (EPP) on survival and quality of life in patients with malignant pleural mesothelioma have, to our knowledge, not been assessed in a randomised trial. We aimed to assess the clinical outcomes of patients who were randomly assigned to EPP or no EPP in the context of trimodal therapy in the Mesothelioma and Radical S urgery (MARS) feasibility study. Methods MARS was a multicentre randomised controlled trial in 12 UK hospitals. Patients aged 18 years or older who had pathologically confi rmed mesothelioma and were deemed fi t enough to undergo trimodal therapy were included. In a prerandomisation registration phase, all patients underwent induction platinum-based chemotherapy followed by clinical review. Af ter further consent, patients were randomly assigned (1:1) to EPP followed by postoperative hemithorax irradiation or to no EPP. Randomisation was done centrally with computer-generated permuted blocks stratifi ed by surgical centre. The main endpoints were feasibility of randomly assigning 50 patients in 1 year (results detailed in another report), proportion randomised who received treatment, proportion eligible (registered) who proceeded to randomisation, perioperative mortality, and quality of life. Patients and investigators were not masked to treatment allocation. This is the principal report of the MARS study; all patients have been recruited. Analyses were by intention to treat. This trial is registered, number ISRCTN95583524. Findings Between Oct 1, 2005, and Nov 3, 2008, 112 patients were registered and 50 were subsequently randomly assigned: 24 to EPP and 26 to no EPP. The main reasons for not proceeding to randomisation were disease progression (33 patients), inoperability (fi ve patients), and patient choice (19 patients). EPP was completed satisfactorily in 16 of 24 patients assigned to EPP; in fi ve patients EPP was not started and in three patients it was abandoned. Two patients in the EPP group died within 30 days and a further patient died without leaving hospital. One patient in the no EPP group died perioperatively af ter receiving EPP off trial in a non-MARS centre. The hazard ratio [HR] for overall survival between the EPP and no EPP groups was 1·90 (95% CI 0·92–3·93; exact p=0·082), and after adjustment for sex, histological subtype, stage, and age at randomisation the HR was 2·75 (1·21–6·26; p=0·016). Median survival was 14·4 months (5·3–18·7) for the EPP group and 19·5 months (13·4 to time not yet reached) for the no EPP group. Of the 49 randomly assigned patients who consented to quality of life assessment (EPP n=23; no EPP n=26), 12 patients in the EPP group and 19 in the no EPP group completed the quality of life questionnaires. Although median quality of life scores were lower in the EPP group than the no EPP group, no signifi cant diff erences between groups were reported in the quality of life analyses. There were ten serious adverse events reported in the EPP group and two in the no EPP group. Interpretation In view of the high morbidity associated with EPP in this trial and in other non-randomised studies a larger study is not feasible. These data, although limited, suggest that radical surgery in the form of EPP within trimodal therapy off ers no benefi t and possibly harms patients.

The hippocampus in major depression: evidence for the convergence of the bench and bedside in psychiatric research?

Abstract: Major depressive disorder (MDD) has until recently been conceptualized as an episodic disorder associated with 'chemical imbalances' but no permanent brain changes. Evidence has emerged in the past decade that MDD is associated with small hippocampal volumes. This paper reviews the clinical and biological correlates of small hippocampal volumes based on literature searches of PubMed and EMBASE and discusses the ways in which these data force a re-conceptualization of MDD. Preclinical data describe the molecular and cellular effects of chronic stress and antidepressant treatment on the hippocampus, providing plausible mechanisms through which MDD might be associated with small hippocampal volumes. Small hippocampal volumes are associated with poor clinical outcome and may be a mechanism through which MDD appears to be a risk factor for Alzheimer's disease. The pathways through which stress may be linked to MDD, the emergence of chronicity or treatment resistance in MDD and the association between MDD and memory problems may be at least partially understood by dissecting the association with depression and changes in the hippocampus. MDD must be re-conceived as a complex illness, associated with persistent morphological brain changes that are detectable before illness onset and which may be modified by clinical and treatment variables.

Stereochemistry of post-transition metal oxides: revision of the classical lone pair model.

Abstract: The chemistry of post transition metals is dominated by the group oxidation state N and a lower N-2 oxidation state, which is associated with occupation of a metal s2 lone pair, as found in compounds of Tl(I), Pb(II) and Bi(III). The preference of these cations for non-centrosymmetric coordination environments has previously been rationalised in terms of direct hybridisation of metal s and p valence orbitals, thus lowering the internal electronic energy of the N-2 ion. This explanation in terms of an on-site second-order Jahn–Teller effect remains the contemporary textbook explanation. In this tutorial review, we review recent progress in this area, based on quantum chemical calculations and X-ray spectroscopic measurements. This recent work has led to a revised model, which highlights the important role of covalent interaction with oxygen in mediating lone pair formation for metal oxides. The role of the anion p atomic orbital in chemical bonding is key to explaining why chalcogenides display a weaker preference for structural distortions in comparison to oxides and halides. The underlying chemical interactions are responsible for the unique physicochemical properties of oxides containing lone pairs and, in particular, to their application as photocatalysts (BiVO4), ferroelectrics (PbTiO3), multi-ferroics (BiFeO3) and p-type semiconductors (SnO). The exploration of lone pair systems remains a viable a venue for the design of functional multi-component oxide compounds.

Clinical diagnosis and management of amyotrophic lateral sclerosis

Abstract: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that results in progressive loss of bulbar and limb function. Patients typically die from respiratory failure within 3 years of symptom onset. The incidence of ALS in Europe is 2-3 cases per 100,000 individuals in the general population, and the overall lifetime risk of developing the disease is 1:400. ALS is familial in 5% of cases, and shows a Mendelian pattern of inheritance. ALS is recognized to overlap with frontotemporal dementia. Diagnosis is made on clinical grounds, using internationally recognized consensus criteria, after exclusion of conditions that can mimic ALS. The Revised ALS Functional Rating Scale is currently the most widely used assessment tool; scores are used to predict survival, and have been employed extensively in clinical trials. Riluzole remains the only effective drug, and extends the average survival of patients by 3-6 months. Optimal treatment is based on symptom management and preservation of quality of life, provided in a multidisciplinary setting. The discovery of further effective disease-modifying therapies remains a critical need for patients with this devastating condition.

Graphene Dispersion and Exfoliation in Low Boiling Point Solvents

Abstract: One of the problems with solvent exfoliation of graphene is that the best solvents tend to have high boiling points and so are difficult to remove and can present problems for flake deposition and composite formation. Here, we demonstrate the exfoliation of graphene at relatively high concentration in low boiling point solvents such as chloroform and isopropanol. It is possible to achieve concentrations of up to 0.5 mg/mL, just under half that which can be achieved with high boiling point solvents such as N-methyl-pyrrolidone. These dispersions consist of graphene flakes of ∼1 μm length and with a thickness of less than 10 layers (≤5 layers for isopropanol). For both solvents, >75% of the graphene remains dispersed indefinitely. Raman spectroscopy shows the flakes to be relatively defect-free. A significant advantage of low boiling point solvents is that they allow individual flakes to be spray cast onto substrates. Deposited densities of >10 flakes with length >1 μm per 10 μm × 10 μm square have been con...

Beta Blockers and Breast Cancer Mortality: A Population- Based Study

Abstract: Purpose Preclinical studies have demonstrated that antagonism of β2-adrenergic signaling inhibits several pathways necessary for breast tumor progression and metastasis. A series of population-based observational studies were conducted to examine associations between beta blocker use and breast tumor characteristics at diagnosis or breast cancer–specific mortality. Patients and Methods Linked national cancer registry and prescription dispensing data were used to identify women with a diagnosis of stage I to IV invasive breast cancer between January 1, 2001, and December 31, 2006. Women taking propranolol (β1/β2 antagonist; n = 70) or atenolol (β1 antagonist; n = 525), in the year before breast cancer diagnosis were matched (1:2) to women not taking a beta blocker (n = 4,738). Associations between use of propranolol or atenolol and risk of local tumor invasion at diagnosis (T4 tumor), nodal or metastatic involvement at diagnosis (N2/N3/M1 tumor), and time to breast cancer–specific mortality were assessed. ...

Hard Magnetic Materials: A Perspective

Abstract: The principles of operation of permanent magnets are summarized, and their development is reviewed. The key figure of merit, the energy product, improved exponentially over much of the 20th century, doubling roughly every 12 years. Yet it has not improved significantly in the last 20 years. Constraints on further development are explained, together with the limits of 1/4 μ0/Ms2 on energy product and 2K1/μ0Ms on coercivity, where K1 is the uniaxial anisotropy constant and Ms is the spontaneous magnetization. The challenge of making rare-earth free magnets with a large energy product is discussed, as well as nanocomposite megajoule magnets and the development of new magnetically hard thin-films with perpendicular anisotropy which are potentially interesting for spin electronics or magnetic recording.

Loss-of-function variants in the filaggrin gene are a significant risk factor for peanut allergy

Abstract: Background IgE-mediated peanut allergy is a complex trait with strong heritability, but its genetic basis is currently unknown. Loss-of-function mutations within the filaggrin gene are associated with atopic dermatitis and other atopic diseases; therefore, filaggrin is a candidate gene in the etiology of peanut allergy. Objective To investigate the association between filaggrin loss-of-function mutations and peanut allergy. Methods Case-control study of 71 English, Dutch, and Irish oral food challenge–positive patients with peanut allergy and 1000 non peanut-sensitized English population controls. Replication was tested in 390 white Canadian patients with peanut allergy (defined by food challenge, or clinical history and skin prick test wheal to peanut ≥8 mm and/or peanut-specific IgE ≥15 kUL −1 ) and 891 white Canadian population controls. The most prevalent filaggrin loss-of-function mutations were assayed in each population: R501X and 2282del4 in the Europeans, and R501X, 2282del4, R2447X, and S3247X in the Canadians. The Fisher exact test and logistic regression were used to test for association; covariate analysis controlled for coexistent atopic dermatitis. Results Filaggrin loss-of-function mutations showed a strong and significant association with peanut allergy in the food challenge–positive patients ( P = 3.0 × 10 −6 ; odds ratio, 5.3; 95% CI, 2.8-10.2), and this association was replicated in the Canadian study ( P = 5.4 × 10 −5 ; odds ratio, 1.9; 95% CI, 1.4-2.6). The association of filaggrin mutations with peanut allergy remains significant ( P = .0008) after controlling for coexistent atopic dermatitis. Conclusion Filaggrin mutations represent a significant risk factor for IgE-mediated peanut allergy, indicating a role for epithelial barrier dysfunction in the pathogenesis of this disease.

TLR-dependent T cell activation in autoimmunity

Abstract: Autoimmune disease can develop as a result of a breakdown in immunological tolerance, leading to the activation of self-reactive T cells. There is an established link between infection and human autoimmune diseases. Furthermore, experimental autoimmune diseases can be induced by autoantigens that are administered together with complete Freund's adjuvant, which contains killed Mycobacterium tuberculosis; in some cases, these bacteria can be replaced by individual pathogen-associated molecular patterns (PAMPs). Exogenous PAMPs and endogenous danger signals from necrotic cells bind to pattern recognition receptors (including Toll-like receptors) and activate signalling pathways in innate immune cells and in T cells. This leads to pro-inflammatory cytokine production and T cell activation, which are now considered to be major factors in the development of autoimmunity.

Increased soil emissions of potent greenhouse gases under increased atmospheric CO2

Abstract: Increasing concentrations of atmospheric carbon dioxide (CO(2)) can affect biotic and abiotic conditions in soil, such as microbial activity and water content. In turn, these changes might be expected to alter the production and consumption of the important greenhouse gases nitrous oxide (N(2)O) and methane (CH(4)) (refs 2, 3). However, studies on fluxes of N(2)O and CH(4) from soil under increased atmospheric CO(2) have not been quantitatively synthesized. Here we show, using meta-analysis, that increased CO(2) (ranging from 463 to 780 parts per million by volume) stimulates both N(2)O emissions from upland soils and CH(4) emissions from rice paddies and natural wetlands. Because enhanced greenhouse-gas emissions add to the radiative forcing of terrestrial ecosystems, these emissions are expected to negate at least 16.6 per cent of the climate change mitigation potential previously predicted from an increase in the terrestrial carbon sink under increased atmospheric CO(2) concentrations. Our results therefore suggest that the capacity of land ecosystems to slow climate warming has been overestimated.

Detection of Staphylococcal Cassette Chromosome mec Type XI Carrying Highly Divergent mecA, mecI, mecR1, blaZ, and ccr Genes in Human Clinical Isolates of Clonal Complex 130 Methicillin-Resistant Staphylococcus aureus

Abstract: Methicillin resistance in staphylococci is mediated by penicillin binding protein 2a (PBP 2a), encoded by mecA on mobile staphylococcal cassette chromosome mec (SCCmec) elements. In this study, two clonal complex 130 (CC130) methicillin-resistant Staphylococcus aureus (MRSA) isolates from patients in Irish hospitals were identified that were phenotypically PBP 2a positive but lacked mecA by conventional PCR and by DNA microarray screening. The isolates were identified as methicillin-susceptible S. aureus using the GeneXpert real-time PCR assay. Whole-genome sequencing of one isolate (M10/0061) revealed a 30-kb SCCmec element encoding a class E mec complex with highly divergent blaZ-mecA-mecR1-mecI, a type 8 cassette chromosome recombinase (ccr) complex consisting of ccrA1-ccrB3, an arsenic resistance operon, and flanking direct repeats (DRs). The SCCmec element was almost identical to that of SCCmec type XI (SCCmec XI) identified by the Sanger Institute in sequence type 425 bovine MRSA strain LGA251 listed on the website of the International Working Group on the Classification of Staphylococcal Cassette Chromosome Elements. The open reading frames (ORFs) identified within SCCmec XI of M10/0061 exhibited 21 to 93% amino acid identity to ORFs in GenBank. A third DR was identified ca. 3 kb downstream of SCCmec XI, indicating the presence of a possible SCC remnant. SCCmec XI was also identified in the second CC130 MRSA isolate by PCR and sequencing. The CC130 MRSA isolates may be of animal origin as previously reported CC130 S. aureus strains were predominantly from bovine sources. The highly divergent nature of SCCmec XI relative to other SCCmec elements indicates that it may have originated in another taxon.