ASYMPTOTIC ALGEBRAS (Asymptotic Analysis and Microlocal Analysis of PDE)

CDC123 mRNA expression in human lung across Pseudoglandular and Canalicular stages of development. Expression of CDC123 gene probe 223503_at showed a decrease in mRNA expression with increasing fetal lung age. (JPG 43 kb

Additional file 9: Table S5. of Genes associated with polymorphic variants predicting lung function are differentially expressed during human lung development

Evidence of regulated expression (by LD and Lung eQTL) in 5 top differentially expressed genes associated with lung function. (XLSX 33 kb

Additional file 4: Table S3. of Genes associated with polymorphic variants predicting lung function are differentially expressed during human lung development

Lung function associated genes with significantly different expression during lung development. Affymetrix U133 Plus 2 array probe ID. Beta coefficient corresponds to the mean change in gene expression per day during the studied period (7-22 weeks of gestational age). (DOCX 22 kb

Additional file 8: Table S4. of Genes associated with polymorphic variants predicting lung function are differentially expressed during human lung development

Evidence of regulated expression (by LD and Blood eQTL) in 5 top differentially expressed genes associated with lung function. SNP = single nucleotide polymorphism, LD = linkage disequilibrium, Chr = chromosome, FDR = false discovery rate, eQTL = expression quantitative loci. (XLSX 28 kb

Additional file 2: Table S2. of Genes associated with polymorphic variants predicting lung function are differentially expressed during human lung development

Expression array probes and results annotated to 54 genes associated with lung function. Probe ID = Affymetrix U133 Plus 2 array probe ID, LogFC = log fold change, AveExpr = average expression throughout development, t = t-statistic describing differential expression, adj.P.Value = Adjusted p value controlling for false discovery rate. Beta coefficient corresponds to the mean change in gene expression per day during the studied period (7–22 weeks of gestational age). (XLSX 37 kb

Additional file 3: Figure S1. of Genes associated with polymorphic variants predicting lung function are differentially expressed during human lung development

Positive and isotype control immunohistochemical staining for CDC123, TMEM163, HHIP, PTCH1 and FAM13A proteins. Lung tissue was immunopositive for CDC123 (A) and TMEM163 (C), Tonsil tissue was immunopositive for HHIP (E) and PTCH1 (G) and Bronchus was immunopositive for FAM13A (I). All isotype controls were negative (B, D, F, H and J). (JPG 19349 kb

Additional file 5: Figures S2. of Genes associated with polymorphic variants predicting lung function are differentially expressed during human lung development

FAM13A mRNA expression in human lung across Pseudoglandular and Canalicular stages of development. Expression of FAM13A gene probe 201725_at showed an increase in mRNA expression with increasing fetal lung age. (JPG 43 kb

Additional file 6: Figures S3. of Genes associated with polymorphic variants predicting lung function are differentially expressed during human lung development

HHIP mRNA expression in human lung across Pseudoglandular and Canalicular stages of development. Expression of HHIP gene probe 209815_at showed an increase in mRNA expression with increasing fetal lung age. (JPG 43 kb

Airway and peripheral uPAR is elevated in asthma, and identifies a severe, non-atopic subset of patients.

RATIONALE: Genetic polymorphisms in the asthma susceptibility gene, urokinase plasminogen activator receptor (uPAR/PLAUR) have been associated with lung function decline and uPAR blood levels in asthma subjects. Preliminary studies have identified uPAR elevation in asthma; however a definitive study regarding which clinical feature of asthma uPAR may be driving is currently lacking. OBJECTIVES: We aimed to comprehensively determine the uPAR expression profile in asthma and control subjects utilising bronchial biopsies and serum, and to relate uPAR expression to asthma clinical features. METHODS: uPAR levels were determined in control (n=9) and asthmatic (n=27) bronchial biopsies using immunohistochemistry, with a semi-quantitative score defining intensity in multiple cell types. Soluble cleaved (sc)uPAR levels were determined in serum through ELISA in UK (cases n=129; controls n=39) and Dutch (cases n=441; controls n=96) cohorts. MEASUREMENTS AND MAIN RESULTS: In bronchial tissue, uPAR was elevated in inflammatory cells in the lamina propria (P=0.0019), bronchial epithelial (P=0.0002) and airway smooth muscle cells (P=0.0352) of asthma patients, with uPAR levels correlated between the cell types. No correlation with disease severity or asthma clinical features was identified. scuPAR serum levels were elevated in asthma patients (1.5 fold; P=0.0008) and we identified an association between high uPAR serum levels and severe, non-atopic disease. CONCLUSIONS: This study provides novel data that elevated airway and blood uPAR in asthma is particularly related to severe, non-atopic asthma. The findings warrant further investigation and may provide a therapeutic opportunity for this refractory population

The Ser82 RAGE Variant Affects Lung Function and Serum RAGE in Smokers and sRAGE Production In Vitro

Introduction Genome-Wide Association Studies have identified associations between lung function measures and Chronic Obstructive Pulmonary Disease (COPD) and chromosome region 6p21 containing the gene for the Advanced Glycation End Product Receptor (AGER, encoding RAGE). We aimed to (i) characterise RAGE expression in the lung, (ii) identify AGER transcripts, (iii) ascertain if SNP rs2070600 (Gly82Ser C/T) is associated with lung function and serum sRAGE levels and (iv) identify whether the Gly82Ser variant is functionally important in altering sRAGE levels in an airway epithelial cell model. Methods Immunohistochemistry was used to identify RAGE protein expression in 26 human tissues and qPCR was used to quantify AGER mRNA in lung cells. Gene expression array data was used to identify AGER expression during lung development in 38 fetal lung samples. RNA-Seq was used to identify AGER transcripts in lung cells. sRAGE levels were assessed in cells and patient serum by ELISA. BEAS2B-R1 cells were transfected to overexpress RAGE protein with either the Gly82 or Ser82 variant and sRAGE levels identified. Results Immunohistochemical assessment of 6 adult lung samples identified high RAGE expression in the alveoli of healthy adults and individuals with COPD. AGER/RAGE expression increased across developmental stages in human fetal lung at both the mRNA (38 samples) and protein levels (20 samples). Extensive AGER splicing was identified. The rs2070600T (Ser82) allele is associated with higher FEV1, FEV1/FVC and lower serum sRAGE levels in UK smokers. Using an airway epithelium model overexpressing the Gly82 or Ser82 variants we found that HMGB1 activation of the RAGE-Ser82 receptor results in lower sRAGE production. Conclusions This study provides new information regarding the expression profile and potential role of RAGE in the human lung and shows a functional role of the Gly82Ser variant. These findings advance our understanding of the potential mechanisms underlying COPD particularly for carriers of this AGER polymorphism