Epidemiology of Nontuberculous Mycobacteria Infection in Children and Young People With Cystic Fibrosis: Analysis of UK Cystic Fibrosis Registry

Background Infection with nontuberculous mycobacteria (NTM) is of growing clinical concern in people with cystic fibrosis (CF). The epidemiology of infection in children and young people remains poorly understood. Our goal was to investigate the epidemiology of NTM infection in the pediatric age group using data from the UK CF Registry. Methods Data from 2010–2015 for individuals aged <16 years (23200 observations from 5333 unique individuals) were obtained. Univariate analysis of unique individuals comparing all key clinical factors and health outcomes to NTM status was performed. The significant factors that were identified were used to generate a multivariate logistic regression model that, following step-wise removal, generated a final parsimonious model. Results The prevalence of individuals with a NTM-positive respiratory culture increased every year from 2010 (45 [1.3%]) to 2015 (156 [3.8%]). Allergic bronchopulmonary aspergillosis (odds ratio [OR], 2.66; P = 5.0 × 10−8), age (OR, 1.08; P = 3.4 × 10−10), and intermittent Pseudomonas aeruginosa infection (OR, 1.51; P = .004) were significantly associated with NTM infection. Conclusions NTM infection is of increasing prevalence in the UK pediatric CF population. This study highlights the urgent need for work to establish effective treatment and prevention strategies for NTM infection in young people with CF

Recombinant Acid Ceramidase Reduces Inflammation and Infection in Cystic Fibrosis.

Rationale: In cystic fibrosis the major cause of morbidity and mortality is lung disease characterized by inflammation and infection. The influence of sphingolipid metabolism is poorly understood with a lack of studies using human airway model systems. Objectives: To investigate sphingolipid metabolism in cystic fibrosis and the effects of treatment with recombinant human acid ceramidase on inflammation and infection. Methods: Sphingolipids were measured using mass spectrometry in fully-differentiated cultures of primary human airway epithelial cells and co-cultures with Pseudomonas aeruginosa. In situ activity assays, Western blotting and quantitative polymerase chain reaction were used to investigate function and expression of ceramidase and sphingomyelinase. Effects of treatment with recombinant human acid ceramidase on sphingolipid profile and inflammatory mediator production were assessed in cell cultures and murine models. Measurements and Main Results: Ceramide is increased in cystic fibrosis airway epithelium due to differential function of enzymes regulating sphingolipid metabolism. Sphingosine, a metabolite of ceramide with antimicrobial properties, is not upregulated in response to Pseudomonas aeruginosa by cystic fibrosis airway epithelia. Tumor necrosis factor receptor 1 is increased in the apical membrane of cystic fibrosis epithelia and activates NF-κB signaling, generating inflammation. Treatment with recombinant human acid ceramidase, to decrease ceramide, reduced both inflammatory mediator production and susceptibility to infection. Conclusions: Sphingolipid metabolism is altered in airway epithelial cells cultured from people with cystic fibrosis. Treatment with recombinant acid ceramidase ameliorates the two pivotal features of cystic fibrosis lung disease, inflammation and infection, and thus represents a therapeutic approach worthy of further exploration. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)

The Hubble Space Telescope Wide Field Camera 3 Early Release Science data: Panchromatic Faint Object Counts for 0.2-2 microns wavelength

We describe the Hubble Space Telescope (HST) Wide Field Camera 3 (WFC3) Early Release Science (ERS) observations in the Great Observatories Origins Deep Survey (GOODS) South field. The new WFC3 ERS data provide calibrated, drizzled mosaics in the UV filters F225W, F275W, and F336W, as well as in the near-IR filters F098M (Ys), F125W (J), and F160W (H) with 1-2 HST orbits per filter. Together with the existing HST Advanced Camera for Surveys (ACS) GOODS-South mosaics in the BViz filters, these panchromatic 10-band ERS data cover 40-50 square arcmin at 0.2-1.7 {\mu}m in wavelength at 0.07-0.15" FWHM resolution and 0.090" Multidrizzled pixels to depths of AB\simeq 26.0-27.0 mag (5-{\sigma}) for point sources, and AB\simeq 25.5-26.5 mag for compact galaxies. In this paper, we describe: a) the scientific rationale, and the data taking plus reduction procedures of the panchromatic 10-band ERS mosaics; b) the procedure of generating object catalogs across the 10 different ERS filters, and the specific star-galaxy separation techniques used; and c) the reliability and completeness of the object catalogs from the WFC3 ERS mosaics. The excellent 0.07-0.15" FWHM resolution of HST/WFC3 and ACS makes star- galaxy separation straightforward over a factor of 10 in wavelength to AB\simeq 25-26 mag from the UV to the near-IR, respectively.Comment: 51 pages, 71 figures Accepted to ApJS 2011.01.2

A spatially resolved analysis of star-formation burstiness by comparing UV and Hα\alpha in galaxies at z∼\sim1 with UVCANDELS

The UltraViolet imaging of the Cosmic Assembly Near-infrared Deep Extragalactic Legacy Survey Fields (UVCANDELS) program provides HST/UVIS F275W imaging for four CANDELS fields. We combine this UV imaging with existing HST/near-IR grism spectroscopy from 3D-HST+AGHAST to directly compare the resolved rest-frame UV and H$\alpha$ emission for a sample of 979 galaxies at $0.7<z<1.5$ spanning a range in stellar mass of $10^{8-11.5}~M_\odot$. Since both rest-UV and H$\alpha$ are sensitive to on-going star-formation but over different timescales, their resolved comparison allows us to infer the burstiness in star-formation as a function of galaxy structural parameters. We generate homogenized maps of rest-UV and H$\alpha$ emission for all galaxies in our sample and stack them to compute the average UV-to-H$\alpha$ luminosity ratio as a function of galactocentric radius. We find that galaxies below stellar mass of $\sim10^{9.5}~M_\odot$, at all radii, have a UV-to-H$\alpha$ ratio higher than the equilibrium value expected from constant star-formation, indicating a significant contribution from bursty star-formation. Even for galaxies with stellar mass $\gtrsim10^{9.5} M_\odot$, the UV-to-H$\alpha$ ratio is elevated towards in their outskirts ($R/R_{eff}>1.5$), suggesting that bursty star-formation is likely prevalent in the outskirts of even the most massive galaxies but is likely over-shadowed by their brighter cores. Furthermore, we present the UV-to-H$\alpha$ ratio as a function of galaxy surface brightness, a proxy for stellar mass surface density, and find that regions below $\sim10^8~M_\odot~kpc^{-2}$ are consistent with bursty star-formation, regardless of their galaxy stellar mass, potentially suggesting that local star-formation is independent of global galaxy properties at the smallest scales.Comment: 19 pages, 8 figures; submitted to Ap

Ecological Survey of Tauranga Harbour

This report summarises the results of biological and physical data collected from a broad scale intertidal survey of Tauranga Harbour conducted between December 2011 and February 2012. The survey was designed to understand more fully the role of various anthropogenic stressors on the ecology of the harbour. The research was conducted as part of the Manaaki Taha Moana (MTM) programme. The wider research project aims to restore and enhance coastal ecosystems and their services of importance to iwi/hapū, by working with iwi to improve knowledge of these ecosystems and the degradation processes that affect them. In this report we assess the health of macrofaunal benthic communities (bottom-dwelling animals) as well as trends in sediments, nutrients and contaminants. The results indicate that the sites identified as most impacted were generally located in the upper reaches of estuaries in some of the locations least exposed to wind, waves and currents. In addition, the biological community composition characterising sites with different sediment textures, nutrient and contaminant loadings were found to vary. Sediments within Tauranga Harbour were predominantly sandy with the percentage of mud within a similar range as measured for other New Zealand estuaries. The exceptions included Te Puna Estuary and Apata Estuary, which experience higher rates of sedimentation. Heavy metal contamination in sediments is often highly correlated with the percentage of mud content due to the adherence of chemicals to fine sediments and/or organic content. It is, therefore, not surprising that heavy metal concentrations were also highest in the depositional inner areas of the harbour, such as Te Puna Estuary. The heavy metal contaminant levels within Tauranga were well below relevant guideline thresholds and lower than concentrations measured in many other estuaries in New Zealand and overseas. Although the three metals recorded were found to be highly correlated, zinc levels tended to be closer to guideline thresholds for possible biological effects. Sediment nutrient concentrations in the harbour tended to decline with distance from the inner harbour and associated rivers. Te Puna Estuary showed comparatively high nitrogen and phosphorus loadings. Comparison of sediment nutrient concentrations with other New Zealand estuaries indicates that the Tauranga Harbour sits within a range typical for slightly to moderately enriched estuaries. Although total phosphorus was low compared with other estuaries, total N:P ratios suggest Tauranga Harbour is still limited by nitrogen. We developed a BHM using statistical ordination techniques to identify key stressors affecting the ‘health’ of macrofaunal communities. Sediments, nutrients and heavy metals were identified as key ‘stressors’, i.e. variables affecting the ecology of the harbour. Therefore, three multivariate models were developed based on the variability in community composition using canonical analysis of principal coordinates (CAP). The ecological assemblages generally reflected gradients of stress or pollution very well. However, the CAP models for sedimentation and contamination performed best. In general, the multivariate models were found to be more sensitive to changing ecological health than simple univariate measures (abundance, species diversity, evenness and Shannon-Wiener diversity). This finding has also been reported in the literature where univariate measures based on abundance and diversity were only able to detect significant differences between the most and least disturbed sites, but were not able to differentiate between smaller relative changes in ecological health. Hence univariate measures were less sensitive to smaller degradative changes in community composition. For Tauranga Harbour, ordination models based on community composition appear to be a more sensitive measure of ‘health’ along an ecological gradient and should enable long term degradative change from multiple disturbances to be assessed. This BHM approach can be used as a management or monitoring tool where sites are repeatedly sampled over time and tracked to determine whether the communities are moving towards a more healthy or unhealthy state. The key species at ‘healthy’ and ‘impacted’ sites as determined from the CAP models were also identified. Species at ‘impacted’ sites can be considered to be tolerant to the stressor (i.e. sediment, nutrients or contaminants), while species with high abundances at only ‘healthy’ sites are sensitive to increasing stressors. We developed species response models for 20 taxa. Although the type of response differed by taxa and stressor, variation in the abundance of most of the taxa modelled was most likely to be better predicted by sedimentation. Unimodal responses were almost always observed in response to nutrients, while declines or skewed unimodal responses were most often observed in response to sedimentation and metals. The results from this study are consistent with models of macrofaunal species occurrence with respect to sediment mud content developed across a range of New Zealand estuaries by Thrush et al. (2003). Within this report we extend this analysis by also developing models of macrofaunal species occurrence with respect to nutrient and contaminants loadings. Ultimately such statistical models provide a tool to forecast the distribution and abundance of species associated with habitat changes in sediments, nutrients and metals. In conclusion, Tauranga Harbour is a predominantly sandy harbour with slight to moderate enrichment and low levels of heavy metal contaminants. Sites identified as most impacted by elevated sediments, heavy metal contaminants and nutrients were generally located in the upper reaches of estuaries in some of the least exposed locations. To some extent, this reflects the natural progression of an estuary from land to sea; however, the rates of accumulation of sediments and nutrients have been accelerated as a result of anthropogenic land-based activities. Sediments and contaminants were found to explain the largest variance in benthic communities. Species response models suggest that taxa were either sensitive to elevated sediments, nutrients loading or contamination at all levels, or sensitive to these stressors beyond a critical point

Measurement of the production of a W boson in association with a charm quark in pp collisions at √s = 7 TeV with the ATLAS detector

The production of a W boson in association with a single charm quark is studied using 4.6 fb−1 of pp collision data at s√ = 7 TeV collected with the ATLAS detector at the Large Hadron Collider. In events in which a W boson decays to an electron or muon, the charm quark is tagged either by its semileptonic decay to a muon or by the presence of a charmed meson. The integrated and differential cross sections as a function of the pseudorapidity of the lepton from the W-boson decay are measured. Results are compared to the predictions of next-to-leading-order QCD calculations obtained from various parton distribution function parameterisations. The ratio of the strange-to-down sea-quark distributions is determined to be 0.96+0.26−0.30 at Q 2 = 1.9 GeV2, which supports the hypothesis of an SU(3)-symmetric composition of the light-quark sea. Additionally, the cross-section ratio σ(W + +c¯¯)/σ(W − + c) is compared to the predictions obtained using parton distribution function parameterisations with different assumptions about the s−s¯¯¯ quark asymmetry

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment