Gene-based association study of rare variants in children of diverse ancestries implicates TNFRSF21 in the development of allergic asthma

BACKGROUND: Most genetic studies of asthma and allergy have focused on common variation in individuals primarily of European ancestry. Studying the role of rare variation in quantitative phenotypes and in asthma phenotypes in populations of diverse ancestries can provide additional, important insights into the development of these traits. OBJECTIVE: We sought to examine the contribution of rare variants to different asthma- or allergy-associated quantitative traits in children with diverse ancestries and explore their role in asthma phenotypes. METHODS: We examined whole-genome sequencing data from children participants in longitudinal studies of asthma (n = 1035; parent-identified as 67% Black and 25% Hispanic) to identify rare variants (minor allele frequency \u3c 0.01). We assigned variants to genes and tested for associations using an omnibus variant-set test between each of 24,902 genes and 8 asthma-associated quantitative traits. On combining our results with external data on predicted gene expression in humans and mouse knockout studies, we identified 3 candidate genes. A burden of rare variants in each gene and in a combined 3-gene score was tested for its associations with clinical phenotypes of asthma. Finally, published single-cell gene expression data in lower airway mucosal cells after allergen challenge were used to assess transcriptional responses to allergen. RESULTS: Rare variants in USF1 were significantly associated with blood neutrophil count (P = 2.18 × 10 CONCLUSIONS: We report novel associations between rare variants in genes and allergic and inflammatory phenotypes in children with diverse ancestries, highlighting TNFRSF21 as contributing to the development of allergic asthma

A functional genomics pipeline to identify high-value asthma and allergy CpGs in the human methylome

BACKGROUND: DNA methylation of cytosines at cytosine-phosphate-guanine (CpG) dinucleotides (CpGs) is a widespread epigenetic mark, but genome-wide variation has been relatively unexplored due to the limited representation of variable CpGs on commercial high-throughput arrays. OBJECTIVES: To explore this hidden portion of the epigenome, this study combined whole-genome bisulfite sequencing with in silico evidence of gene regulatory regions to design a custom array of high-value CpGs. This study focused on airway epithelial cells from children with and without allergic asthma because these cells mediate the effects of inhaled microbes, pollution, and allergens on asthma and allergic disease risk. METHODS: This study identified differentially methylated regions from whole-genome bisulfite sequencing in nasal epithelial cell DNA from a total of 39 children with and without allergic asthma of both European and African ancestries. This study selected CpGs from differentially methylated regions, previous allergy or asthma epigenome-wide association studies (EWAS), or genome-wide association study loci, and overlapped them with functional annotations for inclusion on a custom Asthma&Allergy array. This study used both the custom and EPIC arrays to perform EWAS of allergic sensitization (AS) in nasal epithelial cell DNA from children in the URECA (Urban Environment and Childhood Asthma) birth cohort and using the custom array in the INSPIRE [Infant Susceptibility to Pulmonary Infections and Asthma Following RSV Exposure] birth cohort. Each CpG on the arrays was assigned to its nearest gene and its promotor capture Hi-C interacting gene and performed expression quantitative trait methylation (eQTM) studies for both sets of genes. RESULTS: Custom array CpGs were enriched for intermediate methylation levels compared to EPIC CpGs. Intermediate methylation CpGs were further enriched among those associated with AS and for eQTMs on both arrays. CONCLUSIONS: This study revealed signature features of high-value CpGs and evidence for epigenetic regulation of genes at AS EWAS loci that are robust to race/ethnicity, ascertainment, age, and geography

Characterizing Quasar C iv Emission-line Measurements from Time-resolved Spectroscopy

We use multi-epoch quasar spectroscopy to determine how accurately single-epoch spectroscopy can locate quasars in emission-line parameter space in order to inform investigations where time-resolved spectroscopy is not available. We explore the improvements in emission-line characterization that result from using non-parametric information from many lines as opposed to a small number of parameters for a single line, utilizing reconstructions based on an independent component analysis applied to the data from the Sloan Digital Sky Survey Reverberation Mapping project. We find that most of the quasars are well described by just two components, while more components signal a quasar likely to yield a successful reverberation mapping analysis. In single-epoch spectroscopy the apparent variability of equivalent width is exaggerated because it is dependent on the continuum. Multi-epoch spectroscopy reveals that single-epoch results do not significantly change where quasars are located in CIV parameter space and do not have a significant impact on investigations of the global Baldwin Effect. Quasars with emission line properties indicative of higher $L/L_{Edd}$ are less variable, consistent with models with enhanced accretion disk density. Narrow absorption features at the systemic redshift may be indicative of orientation (including radio-quiet quasars) and may appear in as much as 20% of the quasar sample. Future work applying these techniques to lower luminosity quasars will be important for understanding the nature of accretion disk winds

RNA Interference in Marine and Freshwater Sponges: Actin Knockdown in \u3cem\u3eTethya wilhelma\u3c/em\u3e and \u3cem\u3eEphydatia muelleri\u3c/em\u3e by Ingested dsRNA Expressing Bacteria

Background: The marine sponge Tethya wilhelma and the freshwater sponge Ephydatia muelleri are emerging model organisms to study evolution, gene regulation, development, and physiology in non-bilaterian animal systems. Thus far, functional methods (i.e., loss or gain of function) for these organisms have not been available. Results: We show that soaking developing freshwater sponges in double-stranded RNA and/or feeding marine and freshwater sponges bacteria expressing double-stranded RNA can lead to RNA interference and reduction of targeted transcript levels. These methods, first utilized in C. elegans, have been adapted for the development and feeding style of easily cultured marine and freshwater poriferans. We demonstrate phenotypic changes result from \u27knocking down\u27 expression of the actin gene. Conclusion: This technique provides an easy, efficient loss-of-function manipulation for developmental and gene regulatory studies in these important non-bilaterian animals

REMOVED: High Performance Gas Separation Membrane from a Polymer of Intrinsic Microporosity by Photochemical Surface Modification

This article has been removed: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy).This article has been removed at the request of the Executive Publisher.This article has been removed because it was published without the permission of the author(s)

CritCom: Assessment of quality of interdisciplinary communication around deterioration in pediatric oncologic patients

BACKGROUND: High-quality clinical care requires excellent interdisciplinary communication, especially during emergencies, and no tools exist to evaluate communication in critical care. We describe the development of a pragmatic tool focusing on interdisciplinary communication during patient deterioration (CritCom). METHODS: The preliminary CritCom tool was developed after a literature review and consultation with a multidisciplinary panel of global experts in communication, pediatric oncology, and critical care to review the domains and establish content validity iteratively. Face and linguistic validity were established through cognitive interviews, translation, and linguistic synthesis. We conducted a pilot study among an international group of clinicians to establish reliability and usability. RESULTS: After reviewing 105 potential survey items, we identified 52 items across seven domains. These were refined through cognitive interviews with 36 clinicians from 15 countries. CritCom was piloted with 433 clinicians (58% nurses, 36% physicians, and 6% other) from 42 hospitals in 22 countries. Psychometric testing guided the refinement of the items for the final tool. CritCom comprised six domains with five items each (30 total). The final tool has excellent reliability (Cronbach\u27s alpha 0.81-0.86), usability (93% agree or strongly agree that the tool is easy to use), and similar performance between English and Spanish tools. Confirmatory factor analysis was used to establish the final 6-domain structure. CONCLUSIONS: CritCom is a reliable and pragmatic bilingual tool to assess the quality of interdisciplinary communication around patient deterioration for children in diverse resource levels globally. Critcom results can be used to design and evaluate interventions to improve team communication

Prototyping the Semantics of a DSL using ASF+SDF: Link to Formal Verification of DSL Models

A formal definition of the semantics of a domain-specific language (DSL) is a key prerequisite for the verification of the correctness of models specified using such a DSL and of transformations applied to these models. For this reason, we implemented a prototype of the semantics of a DSL for the specification of systems consisting of concurrent, communicating objects. Using this prototype, models specified in the DSL can be transformed to labeled transition systems (LTS). This approach of transforming models to LTSs allows us to apply existing tools for visualization and verification to models with little or no further effort. The prototype is implemented using the ASF+SDF Meta-Environment, an IDE for the algebraic specification language ASF+SDF, which offers efficient execution of the transformation as well as the ability to read models and produce LTSs without any additional pre or post processing.Comment: In Proceedings AMMSE 2011, arXiv:1106.596

Some studies on the deformation of the membrane in an RF MEMS switch

Radio Frequency (RF) switches of Micro Electro Mechanical Systems (MEMS) are appealing to the mobile industry because of their energy efficiency and ability to accommodate more frequency bands. However, the electromechanical coupling of the electrical circuit to the mechanical components in RF MEMS switches is not fully understood. In this paper, we consider the problem of mechanical deformation of electrodes in RF MEMS switch due to the electrostatic forces caused by the difference in voltage between the electrodes. It is known from previous studies of this problem, that the solution exhibits multiple deformation states for a given electrostatic force. Subsequently, the capacity of the switch that depends on the deformation of electrodes displays a hysteresis behaviour against the voltage in the switch. We investigate the present problem along two lines of attack. First, we solve for the deformation states of electrodes using numerical methods such as finite difference and shooting methods. Subsequently, a relationship between capacity and voltage of the RF MEMS switch is constructed. The solutions obtained are exemplified using the continuation and bifurcation package AUTO. Second, we focus on the analytical methods for a simplified version of the problem and on the stability analysis for the solutions of deformation states. The stability analysis shows that there exists a continuous path of equilibrium deformation states between the open and closed state

A Randomized Controlled Trial of Sertraline in Young Children With Autism Spectrum Disorder.

Objective: Selective serotonin reuptake inhibitors like sertraline have been shown in observational studies and anecdotal reports to improve language development in young children with fragile X syndrome (FXS). A previous controlled trial of sertraline in young children with FXS found significant improvement in expressive language development as measured by the Mullen Scales of Early Learning (MSEL) among those with comorbid autism spectrum disorder (ASD) in post hoc analysis, prompting the authors to probe whether sertraline is also indicated in nonsyndromic ASD. Methods: The authors evaluated the efficacy of 6 months of treatment with low-dose sertraline in a randomized, double-blind, placebo-controlled trial in 58 children with ASD aged 24 to 72 months. Results: 179 subjects were screened for eligibility, and 58 were randomized to sertraline (32) or placebo (26). Eight subjects from the sertraline arm and five from the placebo arm discontinued. Intent-to-treat analysis showed no significant difference from placebo on the primary outcomes (MSEL expressive language raw score and age equivalent combined score) or secondary outcomes. Sertraline was well tolerated, with no difference in side effects between sertraline and placebo groups. No serious adverse events possibly related to study treatment occurred. Conclusion: This randomized controlled trial of sertraline treatment showed no benefit with respect to primary or secondary outcome measures. For the 6-month period, treatment in young children with ASD appears safe, although the long-term side effects of low-dose sertraline in early childhood are unknown. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02385799