Toll-like receptor and IL-12 signaling control susceptibility to contact hypersensitivity.

Allergic contact hypersensitivity (CHS) is a T cell-mediated inflammatory skin disease. Interleukin (IL)-12 is considered to be important in the generation of the allergen-specific T cell response. Loss of IL-12 function in IL-12Rbeta2-deficient mice, however, did not ameliorate the allergic immune response, suggesting alternate IL-12-independent pathways in the induction of CHS. Because exposure to contact allergens always takes place in the presence of microbial skin flora, we investigated the potential role of Toll-like receptors (TLRs) in the induction of CHS. Using mice deficient in TLR4, the receptor for bacterial lipopolysaccharide (LPS), IL-12 receptor (R) beta2, or both, we show that the concomitant absence of TLR4 and IL-12Rbeta2, but not the absence of TLR4 or IL-12Rbeta2 alone, prevented DC-mediated sensitization, generation of effector T cells, and the subsequent CHS response to 2,4,6-trinitro-1-chlorobenzene (TNCB), oxazolone, and fluorescein isothiocyanate. Introduction of the TLR4 transgene into the TLR4/IL-12Rbeta2 mutant restored the CHS inducibility, showing a requirement for TLR4 in IL-12-independent CHS induction. Furthermore, the concomitant absence of TLR2 and TLR4 prevented the induction of CHS to TNCB in IL-12-competent mice. Finally, CHS was inducible in germ-free wild-type and IL-12Rbeta2-deficient mice, but not in germ-free TLR4/IL-12Rbeta2 double deficient mice, suggesting that the necessary TLR activation may proceed via endogenous ligands

Integrated analysis of dermal blister fluid proteomics and genome-wide skin gene expression in systemic sclerosis: an observational study

Background: Skin fibrosis is a hallmark feature of systemic sclerosis. Skin biopsy transcriptomics and blister fluid proteomics give insight into the local environment of the skin. We have integrated these modalities with the aim of developing a surrogate for the modified Rodnan skin score (mRSS), using candidate genes and proteins from the skin and blister fluid as anchors to identify key analytes in the plasma. Methods: In this single-centre, prospective observational study at the Royal Free Campus, University College London, London, UK, transcriptional and proteomic analyses of blood and skin were performed in a cohort of patients with systemic sclerosis (n=52) and healthy controls (n=16). Weighted gene co-expression network analysis was used to explore the association of skin transcriptomics data, clinical traits, and blister fluid proteomic results. Candidate hub analytes were identified as those present in both blister and skin gene sets (modules), and which correlated with plasma (module membership >0·7 and gene significance >0·6). Hub analytes were confirmed using RNA transcript data obtained from skin biopsy samples from patients with early diffuse cutaneous systemic sclerosis at 12 months. Findings: We identified three modules in the skin, and two in blister fluid, which correlated with a diagnosis of early diffuse cutaneous systemic sclerosis. From these modules, 11 key hub analytes were identified, present in both skin and blister fluid modules, whose transcript and protein levels correlated with plasma protein concentrations, mRSS, and showed statistically significant correlation on repeat transcriptomic samples taken at 12 months. Multivariate analysis identified four plasma analytes as correlates of mRSS (COL4A1, COMP, SPON1, and TNC), which can be used to differentiate disease subtype. Interpretation: This unbiased approach has identified potential biological candidates that might be drivers of local skin pathogenesis in systemic sclerosis. By focusing on measurable analytes in the plasma, we generated a promising composite plasma protein biomarker that could be used for assessment of skin severity, case stratification, and as a potential outcome measure for clinical trials and practice. Once fully validated, the biomarker score could replace a clinical score such as the mRSS, which carries substantial variability. Funding: GlaxoSmithKline and UK Medical Research Council

A Simple Method for Analyzing Exome Sequencing Data Shows Distinct Levels of Nonsynonymous Variation for Human Immune and Nervous System Genes

To measure the strength of natural selection that acts upon single nucleotide variants (SNVs) in a set of human genes, we calculate the ratio between nonsynonymous SNVs (nsSNVs) per nonsynonymous site and synonymous SNVs (sSNVs) per synonymous site. We transform this ratio with a respective factor f that corrects for the bias of synonymous sites towards transitions in the genetic code and different mutation rates for transitions and transversions. This method approximates the relative density of nsSNVs (rdnsv) in comparison with the neutral expectation as inferred from the density of sSNVs. Using SNVs from a diploid genome and 200 exomes, we apply our method to immune system genes (ISGs), nervous system genes (NSGs), randomly sampled genes (RSGs), and gene ontology annotated genes. The estimate of rdnsv in an individual exome is around 20% for NSGs and 30–40% for ISGs and RSGs. This smaller rdnsv of NSGs indicates overall stronger purifying selection. To quantify the relative shift of nsSNVs towards rare variants, we next fit a linear regression model to the estimates of rdnsv over different SNV allele frequency bins. The obtained regression models show a negative slope for NSGs, ISGs and RSGs, supporting an influence of purifying selection on the frequency spectrum of segregating nsSNVs. The y-intercept of the model predicts rdnsv for an allele frequency close to 0. This parameter can be interpreted as the proportion of nonsynonymous sites where mutations are tolerated to segregate with an allele frequency notably greater than 0 in the population, given the performed normalization of the observed nsSNV to sSNV ratio. A smaller y-intercept is displayed by NSGs, indicating more nonsynonymous sites under strong negative selection. This predicts more monogenically inherited or de-novo mutation diseases that affect the nervous system

Nowhere to go: How stigma limits the options of female drug users after release from jail

<p>Abstract</p> <p>Background</p> <p>Drug and alcohol using women leaving prison or jail face many challenges to successful re-integration in the community and are severely hampered in their efforts by the stigma of drug or alcohol use compounded by the stigma of incarceration.</p> <p>Methods</p> <p>This qualitative study is based on individual semi-structured interviews and focus groups with 17 women who had recently left jail about the challenges they faced on reentry.</p> <p>Results</p> <p>Our analysis identified three major themes, which are related by the overarching influence of stigma: survival (jobs and housing), access to treatment services, and family and community reintegration.</p> <p>Conclusion</p> <p>Stigma based on drug use and incarceration works to increase the needs of women for health and social services and at the same time, restricts their access to these services. These specific forms of stigma may amplify gender and race-based stigma. Punitive drug and social policies related to employment, housing, education, welfare, and mental health and substance abuse treatment make it extremely difficult for women to succeed.</p

Epitaxial growth and anisotropy of La(O,F)FeAs thin films deposited by Pulsed Laser Deposition

LaFeAsO1-xFx thin films were deposited successfully on (001)-oriented LaAlO3 and MgO substrates from stoichiometric LaFeAsO1-xFx polycrystalline targets with fluorine concentrations up to x = 0.25 by PLD. Room temperature deposition and post annealing of the films yield nearly phase pure films with a pronounced c-axis texture and a strong biaxial in-plane orientation. Transport measurements show metallic resistance and onset of superconductivity at 11 K. Hc2(T) was determined by resistive measurements and yield Hc2 values of 3 T at 3.6 K for B||c and 6 T at 6.4 K for B||ab.Comment: 11 pages, 5 figure

Towards environmentally sustainable human behaviour: targeting non-conscious and conscious processes for effective and acceptable policies.

Meeting climate change targets to limit global warming to 2°C requires rapid and large reductions in demand for products that most contribute to greenhouse gas (GHG) emissions. These include production of bulk materials (e.g. steel and cement), energy supply (e.g. fossil fuels) and animal source foods (particularly ruminants and their products). Effective strategies to meet these targets require transformative changes in supply as well as demand, involving changes in economic, political and legal systems at local, national and international levels, building on evidence from many disciplines. This paper outlines contributions from behavioural science in reducing demand. Grounded in dual-process models of human behaviour (involving non-conscious and conscious processes) this paper considers first why interventions aimed at changing population values towards the environment are usually insufficient or unnecessary for reducing demand although they may be important in increasing public acceptability of policies that could reduce demand. It then outlines two sets of evidence from behavioural science towards effective systems-based strategies, to identify interventions likely to be effective at: (i) reducing demand for products that contribute most to GHG emissions, mainly targeting non-conscious processes and (ii) increasing public acceptability for policy changes to enable these interventions, targeting conscious processes.This article is part of the themed issue 'Material demand reduction'

Is health coaching effective in changing the health status and behaviour of prisoners?-a systematic review protocol

Abstract Background This is a protocol for a systematic review of the impact of health coaching on changing the health behaviour of offenders. Prisoners are more likely to suffer from health-related issues when compared to the general population. Health coaching has been shown to influence health outcomes of patients with chronic conditions. This review, therefore, aims to assess the effectiveness of health coaching interventions on the health of adolescent and adult offenders in custodial institutions. Methods We plan to conduct a systematic review of the current literature on health coaching interventions delivered in the prison setting. We will include randomised controlled trials and observational studies that compare health coaching to the usual care or other alternative interventions. The ideal interventions will be delivered either by health professionals or peer coaches, and the outcomes extracted in the data collection will be disease-specific, clients’ life and self-management skills, behavioural and psychosocial outcomes. If appropriate, a meta-analysis of the data collected will be carried out on the last stage of the review. Discussion This systematic review will identify and gather evidence on the impact of health coaching interventions delivered in the prison setting and can function as a supporting material for health professionals, prison staff, the healthcare system, and public health departments when considering delivering health coaching. Systematic review registration PROSPERO CRD42016053237

Using distinct molecular signatures of human monocytes and dendritic cells to predict adjuvant activity and pyrogenicity of TLR agonists

We present a systematic study that defines molecular profiles of adjuvanticity and pyrogenicity induced by agonists of human Toll-like receptor molecules in vitro. Using P3CSK4, Lipid A and Poly I:C as model adjuvants we show that all three molecules enhance the expansion of IFNγ+/CD4+ T cells from their naïve precursors following priming with allogeneic DC in vitro. In contrast, co-culture of naive CD4+ T cells with allogeneic monocytes and TLR2/TLR4 agonists only resulted in enhanced T cell proliferation. Distinct APC molecular signatures in response to each TLR agonist underline the dual effect observed on T cell responses. Using protein and gene expression assays, we show that TNF-α and CXCL10 represent DC-restricted molecular signatures of TLR2/TLR4 and TLR3 activation, respectively, in sharp contrast to IL-6 produced by monocytes upon stimulation with P3CSK4 and Lipid A. Furthermore, although all TLR agonists are able to up-regulate proIL-1β specific gene in both cell types, only monocyte activation with Lipid A results in detectable IL-1β release. These molecular profiles, provide a simple screen to select new immune enhancers of human Th1 responses suitable for clinical application