Topological doping and the stability of stripe phases

We analyze the properties of a general Ginzburg-Landau free energy with competing order parameters, long-range interactions, and global constraints (e.g., a fixed value of a total ``charge'') to address the physics of stripe phases in underdoped high-Tc and related materials. For a local free energy limited to quadratic terms of the gradient expansion, only uniform or phase-separated configurations are thermodynamically stable. ``Stripe'' or other non-uniform phases can be stabilized by long-range forces, but can only have non-topological (in-phase) domain walls where the components of the antiferromagnetic order parameter never change sign, and the periods of charge and spin density waves coincide. The antiphase domain walls observed experimentally require physics on an intermediate lengthscale, and they are absent from a model that involves only long-distance physics. Dense stripe phases can be stable even in the absence of long-range forces, but domain walls always attract at large distances, i.e., there is a ubiquitous tendency to phase separation at small doping. The implications for the phase diagram of underdoped cuprates are discussed.Comment: 18 two-column pages, 2 figures, revtex+eps

Epithelial IL-6 trans-signaling defines a new asthma phenotype with increased airway inflammation

Background: Although several studies link high levels of IL-6 and soluble IL-6 receptor (sIL-6R) to asthma severity and decreased lung function, the role of IL-6 trans-signaling (IL-6TS) in asthmatic patients is unclear. Objective: We sought to explore the association between epithelial IL-6TS pathway activation and molecular and clinical phenotypes in asthmatic patients. Methods: An IL-6TS gene signature obtained from air-liquid interface cultures of human bronchial epithelial cells stimulated with IL-6 and sIL-6R was used to stratify lung epithelial transcriptomic data (Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes [U-BIOPRED] cohorts) by means of hierarchical clustering. IL-6TS-specific protein markers were used to stratify sputum biomarker data (Wessex cohort). Molecular phenotyping was based on transcriptional profiling of epithelial brushings, pathway analysis, and immunohistochemical analysis of bronchial biopsy specimens. Results: Activation of IL-6TS in air-liquid interface cultures reduced epithelial integrity and induced a specific gene signature enriched in genes associated with airway remodeling. The IL-6TS signature identified a subset of patients with IL-6TS-high asthma with increased epithelial expression of IL-6TS-inducible genes in the absence of systemic inflammation. The IL-6TS-high subset had an overrepresentation of frequent exacerbators, blood eosinophilia, and submucosal infiltration of T cells and macrophages. In bronchial brushings Toll-like receptor pathway genes were upregulated, whereas expression of cell junction genes was reduced. Sputum sIL-6R and IL-6 levels correlated with sputum markers of remodeling and innate immune activation, in particular YKL-40, matrix metalloproteinase 3, macrophage inflammatory protein 1 beta, IL-8, and IL-1 beta. Conclusions: Local lung epithelial IL-6TS activation in the absence of type 2 airway inflammation defines a novel subset of asthmatic patients and might drive airway inflammation and epithelial dysfunction in these patients.Peer reviewe

Biomarker discovery for asthma phenotyping: From gene expression to the clinic

Asthma is considered a complex respiratory disease of which various asthma phenotypes are being discovered. Clinical biomarkers have shown to be successful in the management of asthma phenotypes. High-throughput omics technologies are now available to allow further biomarker discovery for this complex disease, such as transcriptomics, proteomics, lipidomics, and breathomics. In this thesis, I discussed the strengths and limitations of transcriptomics by microarrays and next-generation RNA sequencing. Next, metabolomics in exhaled air is reviewed as a non-invasive tool for the clinic. To conclude, composite molecular fingerprints have the best prospect as biomarkers in the phenotyping of patients with complex respiratory diseases such as asthma. Furthermore, I studied the link between the upper and lower airways by analysing gene expression profiles of upper and lower airway epithelial cells in healthy individuals and examining the impact of allergic rhinitis and asthma on these expression profiles. Several new genes and pathways were identified that might be potential targets for future drug development. Next, I examined the responses of airway epithelium to double-stranded RNA (dsRNA) as a model of viral induced exacerbations. Potential targets for drug-discovery studies were identified, related to mitochondrial dysfunction and interferon signalling. In the next study, blood eosinophils represented an accurate biomarker for eosinophilic airway inflammation which can facilitate guidance of current and novel individualised asthma treatment. In the last chapter a composite electronic nose (eNose) platform was used to assess eosinophilic airway inflammation in patients with asthma in a quick and non-invasive way, thereby potentially facilitating personalized asthma management

Electronic Nose Breathprints Are Independent of Acute Changes in Airway Caliber in Asthma

Molecular profiling of exhaled volatile organic compounds (VOC) by electronic nose technology provides breathprints that discriminate between patients with different inflammatory airway diseases, such as asthma and COPD. However, it is unknown whether this is determined by differences in airway caliber. We hypothesized that breathprints obtained by electronic nose are independent of acute changes in airway caliber in asthma. Ten patients with stable asthma underwent methacholine provocation (Visit 1) and sham challenge with isotonic saline (Visit 2). At Visit 1, exhaled air was repetitively collected pre-challenge, after reaching the provocative concentration (PC20) causing 20% fall in forced expiratory volume in 1 second (FEV1) and after subsequent salbutamol inhalation. At Visit 2, breath was collected pre-challenge, post-saline and post-salbutamol. At each occasion, an expiratory vital capacity was collected after 5 min of tidal breathing through an inspiratory VOC-filter in a Tedlar bag and sampled by electronic nose (Cyranose 320). Breathprints were analyzed with principal component analysis and individual factors were compared with mixed model analysis followed by pairwise comparisons. Inhalation of methacholine led to a 30.8 ± 3.3% fall in FEV1 and was followed by a significant change in breathprint (p = 0.04). Saline inhalation did not induce a significant change in FEV1, but altered the breathprint (p = 0.01). However, the breathprint obtained after the methacholine provocation was not significantly different from that after saline challenge (p = 0.27). The molecular profile of exhaled air in patients with asthma is altered by nebulized aerosols, but is not affected by acute changes in airway caliber. Our data demonstrate that breathprints by electronic nose are not confounded by the level of airway obstruction

Persian

U-BIOPRED is a European Union consortium of 20 academic institutions, 11 pharmaceutical companies and six patient organisations with the objective of improving the understanding of asthma disease mechanisms using a systems biology approach.This cross-sectional assessment of adults with severe asthma, mild/moderate asthma and healthy controls from 11 European countries consisted of analyses of patient-reported outcomes, lung function, blood and airway inflammatory measurements.Patients with severe asthma (nonsmokers, n=311; smokers/ex-smokers, n=110) had more symptoms and exacerbations compared to patients with mild/moderate disease (n=88) (2.5 exacerbations versus 0.4 in the preceding 12?months; p<0.001), with worse quality of life, and higher levels of anxiety and depression. They also had a higher incidence of nasal polyps and gastro-oesophageal reflux with lower lung function. Sputum eosinophil count was higher in severe asthma compared to mild/moderate asthma (median count 2.99% versus 1.05%; p=0.004) despite treatment with higher doses of inhaled and/or oral corticosteroids.Consistent with other severe asthma cohorts, U-BIOPRED is characterised by poor symptom control, increased comorbidity and airway inflammation, despite high levels of treatment. It is well suited to identify asthma phenotypes using the array of “omic” datasets that are at the core of this systems medicine approach

Data from: Comparison of five methods for delimitating species in Ophion Fabricius, a diverse genus of parasitoid wasps (Hymenoptera, Ichneumonidae)

DNA taxonomy has been proposed as a method to quickly assess diversity and species limits in highly diverse, understudied taxa. Here we use five methods for species delimitation and two genetic markers (COI and ITS2) to assess species diversity within the parasitoid genus, Ophion. We searched for compensatory base changes (CBC’s) in ITS2, and determined that they are too rare to be of practical use in delimiting species in this genus. The other four methods used both COI and ITS2, and included distance-based (threshold analysis and ABGD) and tree-based (GMYC and PTP) models. We compared the results of these analyses to each other under various parameters and tested their performance with respect to 11 Nearctic species/morphospecies and 15 described Palearctic species. We also computed barcode accumulation curves of COI sequences to assess the completeness of sampling. The species count was highly variable depending on the method and parameters used, ranging from 47 to 168 species, with more conservative estimates of 89–121 species. Despite this range, many of the Nearctic test species were fairly robust with respect to method. We concluded that while there was often good congruence between methods, GMYC and PTP were less reliant on arbitrary parameters than the other two methods and more easily applied to genetic markers other than COI. However, PTP was less successful at delimiting test species than was GMYC. All methods, as well as the barcode accumulation curves, indicate that several Palearctic species remain undescribed and that we have scarcely begun to appreciate the Nearctic diversity within this genus