Aspergillus fumigatus preexposure worsens pathology and improves control of Mycobacterium abscessus pulmonary infection in mice

ABSTRACT Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Mutations in this chloride channel lead to mucus accumulation, subsequent recurrent pulmonary infections, and inflammation, which, in turn, cause chronic lung disease and respiratory failure. Recently, rates of nontuberculous mycobacterial (NTM) infections in CF patients have been increasing. Of particular relevance is infection with Mycobacterium abscessus , which causes a serious, life-threatening disease and constitutes one of the most antibiotic-resistant NTM species. Interestingly, an increased prevalence of NTM infections is associated with worsening lung function in CF patients who are also coinfected with Aspergillus fumigatus . We established a new mouse model to investigate the relationship between A. fumigatus and M. abscessus pulmonary infections. In this model, animals exposed to A. fumigatus and coinfected with M. abscessus exhibited increased lung inflammation and decreased mycobacterial burden compared with those of mice infected with M. abscessus alone. This increased control of M. abscessus infection in coinfected mice was mucus independent but dependent on both transcription factors T-box 21 (Tbx21) and retinoic acid receptor (RAR)-related orphan receptor gamma t (RORγ-t), master regulators of type 1 and type 17 immune responses, respectively. These results implicate a role for both type 1 and type 17 responses in M. abscessus control in A. fumigatus -coinfected lungs. Our results demonstrate that A. fumigatus , an organism found commonly in CF patients with NTM infection, can worsen pulmonary inflammation and impact M. abscessus control in a mouse model. </jats:p

Fake News and Indifference to Truth

State of the Union Addresses (SOUA) by two recent US Presidents, President Obama (2016) and President Trump (2018), and a series of recent of tweets by President Trump, are analysed by means of the data mining technique, sentiment analysis. The intention is to explore the contents and sentiments of the messages contained, the degree to which they dier, and their potential implications for the national mood and state of the economy. President Trump's 2018 SOUA and his sample tweets are identied as being more positive in sentiment than President Obama's 2016 SOUA. This is conrmed by bootstrapped t tests and non-parametric sign tests on components of the respective sentiment scores. The issue of whether overly positive pronouncements amount to self-promotion, rather than intrinsic merit or sentiment, is a topic for future research

Longitudinal evaluation of quality of life in 288 patients with neurofibromatosis 2

Advances in molecular biology have resulted in novel therapy for neurofibromatosis 2-related (NF2) tumours, highlighting the need for robust outcome measures. The disease-focused NF2 impact on quality of life (NFTI-QOL) patient questionnaire was assessed as an outcome measure for treatment in a multi-centre study. NFTI-QOL was related to clinician-rated severity (ClinSev) and genetic severity (GenSev) over repeated visits. Data were evaluated for 288 NF2 patients (n = 464 visits) attending the English national NF2 clinics from 2010 to 2012. The male-to-female ratio was equal and the mean age was 42.2 (SD 17.8) years. The analysis included NFTI-QOL eight-item score, ClinSev graded as mild, moderate, or severe, and GenSev as a rank order of the number of NF2 mutations (graded as mild, moderate, severe). The mean (SD) 8.7 (5.4) score for NFTI-QOL for either a first visit or all visits 9.2 (5.4) was similar to the published norm of 9.4 (5.5), with no significant relationships with age or gender. NFTI-QOL internal reliability was good, with a Cronbach's alpha score of 0.85 and test re-test reliability r = 0.84. NFTI related to ClinSev (r = 0.41, p &lt;0.001; r = 0.46 for all visits), but weakly to GenSev (r = 0.16, p &lt;0.05; r = 0.15 for all visits). ClinSev related to GenSev (r = 0.41, p &lt;0.001; r = 0.42 for all visits). NFTI-QOL showed a good reliability and ability to detect significant longitudinal changes in the QOL of individuals. The moderate relationships of NFTI-QOL with clinician- and genetic-rated severity suggest that NFTI-QOL taps into NF2 patient experiences that are not encompassed by ClinSev rating or genotype. © 2014 The Author(s)

Systemic and stratum corneum biomarkers of severity in infant atopic dermatitis include markers of innate and T helper cell-related immunity and angiogenesis

BACKGROUND: Biomarkers of atopic dermatitis (AD) are largely lacking, especially in infant AD. Those that have been examined to date have focused mostly on serum cytokines with few on non-invasive biomarkers in the skin. OBJECTIVES: We aimed to explore biomarkers obtainable from non-invasive sampling of infant skin. We compared these to plasma biomarkers and structural and functional measures of the skin barrier. METHODS: We recruited 100 infants at first presentation with AD, who were treatment naïve to topical or systemic anti-inflammatory therapies and 20 healthy children. We sampled clinically unaffected skin by tape stripping the stratum corneum (SC). Multiple cytokines and chemokines and natural moisturizing factors (NMF) were measured in the SC and plasma. We recorded disease severity and skin barrier function. RESULTS: 19 SC and 12 plasma biomarkers showed significant difference between healthy and AD skin. Some biomarkers were common to both the SC and plasma, and others were compartment-specific. Identified biomarkers of AD severity included Th2 skewed markers (IL-13, CCL17, CCL22, IL-5), markers of innate activation (IL-18, Il-1α, IL1β, CXCL8), angiogenesis (Flt-1, VEGF) and others (sICAM-1, vCAM-1, IL-16, IL-17A). CONCLUSIONS: We identified clinically relevant biomarkers of AD, including novel markers, easily sampled and typed in infants. These markers may provide objective assessment of disease severity and suggest new therapeutic targets, or response measurement targets for AD. Future studies will be required to determine if these biomarkers, seen in very early AD, can predict disease outcomes or comorbidities

Turning points: the personal and professional circumstances that lead academics to become middle managers

In the current higher education climate, there is a growing perception that the pressures associated with being an academic middle manager outweigh the perceived rewards of the position. This article investigates the personal and professional circumstances that lead academics to become middle managers by drawing on data from life history interviews undertaken with 17 male and female department heads from a range of disciplines, in a post-1992 UK university. The data suggests that experiencing conflict between personal and professional identities, manifested through different socialization experiences over time, can lead to a ‘turning point’ and a decision that affects a person’s career trajectory. Although the results of this study cannot be generalized, the findings may help other individuals and institutions move towards a firmer understanding of the academic who becomes head of department—in relation to theory, practice and research

Value at Risk models with long memory features and their economic performance

We study alternative dynamics for Value at Risk (VaR) that incorporate a slow moving component and information on recent aggregate returns in established quantile (auto) regression models. These models are compared on their economic performance, and also on metrics of first-order importance such as violation ratios. By better economic performance, we mean that changes in the VaR forecasts should have a lower variance to reduce transaction costs and should lead to lower exceedance sizes without raising the average level of the VaR. We find that, in combination with a targeted estimation strategy, our proposed models lead to improved performance in both statistical and economic terms

Photoproduction of phi(1020) mesons on the proton at large momentum transfer

The cross section for $\phi$ meson photoproduction on the proton has been measured for the first time up to a four-momentum transfer -t = 4 GeV^2, using the CLAS detector at the Thomas Jefferson National Accelerator Facility. At low four-momentum transfer, the differential cross section is well described by Pomeron exchange. At large four-momentum transfer, above -t = 1.8 GeV^2, the data support a model where the Pomeron is resolved into its simplest component, two gluons, which may couple to any quark in the proton and in the $\phi$.Comment: 5 pages; 7 figure

Clumping factor B promotes adherence of <i>Staphylococcus aureus </i>to corneocytes in atopic dermatitis

Staphylococcus aureus skin infection is a frequent and recurrent problem in children with the common inflammatory skin disease atopic dermatitis (AD). S. aureus colonizes the skin of the majority of children with AD and exacerbates the disease. The first step during colonization and infection is bacterial adhesion to the cornified envelope of corneocytes in the outer layer, the stratum corneum. Corneocytes from AD skin are structurally different from corneocytes from normal healthy skin. The objective of this study was to identify bacterial proteins that promote the adherence of S. aureus to AD corneocytes. S. aureus strains from clonal complexes 1 and 8 were more frequently isolated from infected AD skin than from the nasal cavity of healthy children. AD strains had increased ClfB ligand binding activity compared to normal nasal carriage strains. Adherence of single S. aureus bacteria to corneocytes from AD patients ex vivo was studied using atomic force microscopy. Bacteria expressing ClfB recognized ligands distributed over the entire corneocyte surface. The ability of an isogenic ClfB-deficient mutant to adhere to AD corneocytes compared to that of its parent clonal complex 1 clinical strain was greatly reduced. ClfB from clonal complex 1 strains had a slightly higher binding affinity for its ligand than ClfB from strains from other clonal complexes. Our results provide new insights into the first step in the establishment of S. aureus colonization in AD patients. ClfB is a key adhesion molecule for the interaction of S. aureus with AD corneocytes and represents a target for interventio

Measurement of the Polarized Structure Function σLT′\sigma_{LT^\prime} for p(e⃗,e′π+)np(\vec{e},e'\pi^+)n in the Δ(1232)\Delta(1232) Resonance Region

The polarized longitudinal-transverse structure function $\sigma_{LT^\prime}$ has been measured using the $p(\vec e,e'\pi^+)n$ reaction in the $\Delta(1232)$ resonance region at $Q^2=0.40$ and 0.65 GeV$^2$. No previous $\sigma_{LT^\prime}$ data exist for this reaction channel. The kinematically complete experiment was performed at Jefferson Lab with the CEBAF Large Acceptance Spectrometer (CLAS) using longitudinally polarized electrons at an energy of 1.515 GeV. A partial wave analysis of the data shows generally better agreement with recent phenomenological models of pion electroproduction compared to the previously measured $\pi^0 p$ channel. A fit to both $\pi^0 p$ and $\pi^+ n$ channels using a unitary isobar model suggests the unitarized Born terms provide a consistent description of the non-resonant background. The $t$-channel pion pole term is important in the $\pi^0 p$ channel through a rescattering correction, which could be model-dependent.Comment: 6 pages, LaTex, 5 eps figures: Submitted to PRC/Brief Reports v2: Updated referenc