The 20 GHz circularly polarized, high temperature superconducting microstrip antenna array

The primary goal was to design and characterize a four-element, 20 GHz, circularly polarized microstrip patch antenna fabricated from YBa2Cu3O(x) superconductor. The purpose is to support a high temperature superconductivity flight communications experiment between the space shuttle orbiter and the ACTS satellite. This study is intended to provide information into the design, construction, and feasibility of a circularly polarized superconducting 20 GHz downlink or cross-link antenna. We have demonstrated that significant gain improvements can be realized by using superconducting materials for large corporate fed array antennas. In addition, we have shown that when constructed from superconducting materials, the efficiency, and therefore the gain, of microstrip patches increases if the substrate is not so thick that the dominant loss mechanism for the patch is radiation into the surface waves of the conductor-backed substrate. We have considered two design configurations for a superconducting 20 GHz four-element circularly polarized microstrip antenna array. The first is the Huang array that uses properly oriented and phased linearly polarized microstrip patch elements to realize a circularly polarized pattern. The second is a gap-coupled array of circularly polarized elements. In this study we determined that although the Huang array operates well on low dielectric constant substrates, its performance becomes extremely sensitive to mismatches, interelement coupling, and design imperfections for substrates with high dielectric constants. For the gap-coupled microstrip array, we were able to fabricate and test circularly polarized elements and four-element arrays on LaAlO3 using sputtered copper films. These antennas were found to perform well, with relatively good circular polarization. In addition, we realized a four-element YBa2Cu3O(x) array of the same design and measured its pattern and gain relative to a room temperature copper array. The patterns were essentially the same as that for the copper array. The measured gain of the YBCO antenna was greater than that for the room temperature copper design at temperatures below 82K, reaching a value of 3.4 dB at the lowest temperatures

Do sputum or circulating blood samples reflect the pulmonary transcriptomic differences of COPD patients? A multi-tissue transcriptomic network META-analysis

BACKGROUND: Previous studies have identified lung, sputum or blood transcriptomic biomarkers associated with the severity of airflow limitation in COPD. Yet, it is not clear whether the lung pathobiology is mirrored by these surrogate tissues. The aim of this study was to explore this question. METHODS: We used Weighted Gene Co-expression Network Analysis (WGCNA) to identify shared pathological mechanisms across four COPD gene-expression datasets: two sets of lung tissues (L1 n = 70; L2 n = 124), and one each of induced sputum (S; n = 121) and peripheral blood (B; n = 121). RESULTS: WGCNA analysis identified twenty-one gene co-expression modules in L1. A robust module preservation between the two L datasets was observed (86%), with less preservation in S (33%) and even less in B (23%). Three modules preserved across lung tissues and sputum (not blood) were associated with the severity of airflow limitation. Ontology enrichment analysis showed that these modules included genes related to mitochondrial function, ion-homeostasis, T cells and RNA processing. These findings were largely reproduced using the consensus WGCNA network approach. CONCLUSIONS: These observations indicate that major differences in lung tissue transcriptomics in patients with COPD are poorly mirrored in sputum and are unrelated to those determined in blood, suggesting that the systemic component in COPD is independently regulated. Finally, the fact that one of the preserved modules associated with FEV1 was enriched in mitochondria-related genes supports a role for mitochondrial dysfunction in the pathobiology of COPD

Heme metabolism genes Downregulated in COPD Cachexia.

IntroductionCachexia contributes to increased mortality and reduced quality of life in Chronic Obstructive Pulmonary Disease (COPD) and may be associated with underlying gene expression changes. Our goal was to identify differential gene expression signatures associated with COPD cachexia in current and former smokers.MethodsWe analyzed whole-blood gene expression data from participants with COPD in a discovery cohort (COPDGene, N = 400) and assessed replication (ECLIPSE, N = 114). To approximate the consensus definition using available criteria, cachexia was defined as weight-loss > 5% in the past 12 months or low body mass index (BMI) (< 20 kg/m2) and 1/3 criteria: decreased muscle strength (six-minute walk distance < 350 m), anemia (hemoglobin < 12 g/dl), and low fat-free mass index (FFMI) (< 15 kg/m2 among women and < 17 kg/m2 among men) in COPDGene. In ECLIPSE, cachexia was defined as weight-loss > 5% in the past 12 months or low BMI and 3/5 criteria: decreased muscle strength, anorexia, abnormal biochemistry (anemia or high c-reactive protein (> 5 mg/l)), fatigue, and low FFMI. Differential gene expression was assessed between cachectic and non-cachectic subjects, adjusting for age, sex, white blood cell counts, and technical covariates. Gene set enrichment analysis was performed using MSigDB.ResultsThe prevalence of COPD cachexia was 13.7% in COPDGene and 7.9% in ECLIPSE. Fourteen genes were differentially downregulated in cachectic versus non-cachectic COPD patients in COPDGene (FDR < 0.05) and ECLIPSE (FDR < 0.05).DiscussionSeveral replicated genes regulating heme metabolism were downregulated among participants with COPD cachexia. Impaired heme biosynthesis may contribute to cachexia development through free-iron buildup and oxidative tissue damage

A genome-wide association study of bronchodilator response in participants of European and African ancestry from six independent cohorts

Introduction Bronchodilator response (BDR) is a measurement of acute bronchodilation in response to short-acting β2-agonists, with a heritability between 10 and 40%. Identifying genetic variants associated with BDR may lead to a better understanding of its complex pathophysiology. Methods We performed a genome-wide association study (GWAS) of BDR in six adult cohorts with participants of European ancestry (EA) and African ancestry (AA) including community cohorts and cohorts ascertained on the basis of obstructive pulmonary disease. Validation analysis was carried out in two paediatric asthma cohorts. Results A total of 10 623 EA and 3597 AA participants were included in the analyses. No single nucleotide polymorphism (SNP) was associated with BDR at the conventional genome-wide significance threshold (p<5×10−8). Performing fine mapping and using a threshold of p<5×10−6 to identify suggestive variants of interest, we identified three SNPs with possible biological relevance: rs35870000 (within FREM1), which may be involved in IgE- and IL5-induced changes in airway smooth muscle cell responsiveness; rs10426116 (within ZNF284), a zinc finger protein, which has been implicated in asthma and BDR previously; and rs4782614 (near ATP2C2), involved in calcium transmembrane transport. Validation in paediatric cohorts yielded no significant SNPs, possibly due to age–genotype interaction effects. Conclusion Ancestry-stratified and ancestry-combined GWAS meta-analyses of over 14 000 participants did not identify genetic variants associated with BDR at the genome-wide significance threshold, although a less stringent threshold identified three variants showing suggestive evidence of association. A common definition and protocol for measuring BDR in research may improve future efforts to identify variants associated with BDR.publishedVersio

Meta-analysis of peripheral blood gene expression modules for COPD phenotypes.

Chronic obstructive pulmonary disease (COPD) occurs typically in current or former smokers, but only a minority of people with smoking history develops the disease. Besides environmental factors, genetics is an important risk factor for COPD. However, the relationship between genetics, environment and phenotypes is not well understood. Sample sizes for genome-wide expression studies based on lung tissue have been small due to the invasive nature of sample collection. Increasing evidence for the systemic nature of the disease makes blood a good alternative source to study the disease, but there have also been few large-scale blood genomic studies in COPD. Due to the complexity and heterogeneity of COPD, examining groups of interacting genes may have more relevance than identifying individual genes. Therefore, we used Weighted Gene Co-expression Network Analysis to find groups of genes (modules) that are highly connected. However, module definitions may vary between individual data sets. To alleviate this problem, we used a consensus module definition based on two cohorts, COPDGene and ECLIPSE. We studied the relationship between the consensus modules and COPD phenotypes airflow obstruction and emphysema. We also used these consensus module definitions on an independent cohort (TESRA) and performed a meta analysis involving all data sets. We found several modules that are associated with COPD phenotypes, are enriched in functional categories and are overrepresented for cell-type specific genes. Of the 14 consensus modules, three were strongly associated with airflow obstruction (meta p ≤ 0.0002), and two had some association with emphysema (meta p ≤ 0.06); some associations were stronger in the case-control cohorts, and others in the cases-only subcohorts. Gene Ontology terms that were overrepresented included "immune response" and "defense response." The cell types whose type-specific genes were overrepresented in modules (p < 0.05) included natural killer cells, dendritic cells, and neutrophils. Together, this is the largest investigation of gene blood expression in COPD with 469 cases in COPDGene, ECLIPSE and TESRA combined, with 6267 genes common to all data sets. Additional, we have 42 and 83 controls in COPDGene and ECLIPSE, respectively

The impact of genetic variation and cigarette smoke on DNA methylation in current and former smokers from the COPDGene study

<p>DNA methylation can be affected by systemic exposures, such as cigarette smoking and genetic sequence variation; however, the relative impact of each on the epigenome is unknown. We aimed to assess if cigarette smoking and genetic variation are associated with overlapping or distinct sets of DNA methylation marks and pathways. We selected 85 Caucasian current and former smokers with genome-wide single nucleotide polymorphism (SNP) genotyping available from the COPDGene study.  Genome-wide methylation was obtained on DNA from whole blood using the Illumina HumanMethylation27 platform. To determine the impact of local sequence variation on DNA methylation (mQTL), we examined the association between methylation and SNPs within 50 kb of each CpG site.  To examine the impact of cigarette smoking on DNA methylation, we examined the differences in methylation by current cigarette smoking status. We detected 770 CpG sites annotated to 708 genes associated at an FDR < 0.05 in the cis-mQTL analysis and 1,287 CpG sites annotated to 1,242 genes, which were nominally associated in the smoking-CpG association analysis (<i>P</i>_unadjusted < 0.05). Forty-three CpG sites annotated to 40 genes were associated with both SNP variation and current smoking; this overlap was not greater than that expected by chance. Our results suggest that cigarette smoking and genetic variants impact distinct sets of DNA methylation marks, the further elucidation of which may partially explain the variable susceptibility to the health effects of cigarette smoking. Ascertaining how genetic variation and systemic exposures differentially impact the human epigenome has relevance for both biomarker identification and therapeutic target development for smoking-related diseases.</p

RNA-sequencing across three matched tissues reveals shared and tissue-specific gene expression and pathway signatures of COPD

Abstract Background Multiple gene expression studies have been performed separately in peripheral blood, lung, and airway tissues to study COPD. We performed RNA-sequencing gene expression profiling of large-airway epithelium, alveolar macrophage and peripheral blood samples from the same subset of COPD cases and controls from the COPDGene study who underwent bronchoscopy at a single center. Using statistical and gene set enrichment approaches, we sought to improve the understanding of COPD by studying gene sets and pathways across these tissues, beyond the individual genomic determinants. Methods We performed differential expression analysis using RNA-seq data obtained from 63 samples from 21 COPD cases and controls (includes four non-smokers) via the R package DESeq2. We tested associations between gene expression and variables related to lung function, smoking history, and CT scan measures of emphysema and airway disease. We examined the correlation of differential gene expression across the tissues and phenotypes, hypothesizing that this would reveal preserved and private gene expression signatures. We performed gene set enrichment analyses using curated databases and findings from prior COPD studies to provide biological and disease relevance. Results The known smoking-related genes CYP1B1 and AHRR were among the top differential expression results for smoking status in the large-airway epithelium data. We observed a significant overlap of genes primarily across large-airway and macrophage results for smoking and airway disease phenotypes. We did not observe specific genes differentially expressed in all three tissues for any of the phenotypes. However, we did observe hemostasis and immune signaling pathways in the overlaps across all three tissues for emphysema, and amyloid and telomere-related pathways for smoking. In peripheral blood, the emphysema results were enriched for B cell related genes previously identified in lung tissue studies. Conclusions Our integrative analyses across COPD-relevant tissues and prior studies revealed shared and tissue-specific disease biology. These replicated and novel findings in the airway and peripheral blood have highlighted candidate genes and pathways for COPD pathogenesis

Integrating Genetics, Transcriptomics, and Proteomics in Lung Tissue to Investigate COPD.

The integration of transcriptomic and proteomic data from lung tissue with chronic obstructive pulmonary disease (COPD)-associated genetic variants could provide insight into the biological mechanisms for COPD. Here, we assessed associations between lung transcriptomics and proteomics with COPD in 98 subjects from the Lung Tissue Research Consortium. Low correlations between transcriptomics and proteomics were generally observed, but higher correlations were found for COPD-associated proteins. We integrated COPD risk SNPs or SNPs near COPD-associated proteins with lung transcripts and proteins to identify regulatory cis quantitative trait loci (QTLs). Significant expression QTLs (eQTLs) and protein QTLs (pQTLs) were found regulating multiple COPD-associated biomarkers. We investigated mediated associations from significant protein quantitative trait loci through transcripts to protein levels of COPD-associated proteins. We also attempted to identify colocalized effects between GWAS, eQTL, and pQTL signals. Evidence for colocalization between COPD GWAS signals and pQTL for RHOB and eQTL for DSP was found. We applied Weighted Gene Co-Expression Network Analysis (WGCNA) to find consensus COPD-associated network modules. Two network modules generated by consensus WGCNA were associated with COPD with FDR \u3c 0.05. One network module is related to the catenin complex, and the other module is related to plasma membrane components. In summary, multiple cis-acting effects for transcripts and proteins associated with COPD were identified. Colocalization analysis, mediation analysis, and correlation-based network analysis of multiple Omics data may identify key genes and proteins that work together to influence COPD pathogenesis