Background
The expression of chronic rhinosinusitis (CRS) is multidimensional. Disease heterogeneity in patients with CRS remains poorly understood. This study aimed to identify endotypes of CRS ...using cluster analysis by integrating multidimensional characteristics and to explore their association with treatment outcomes.
Methods
A total of 28 clinical variables and 39 mucosal cellular and molecular variables were analyzed using principal component analysis. Cluster analysis was performed on 246 prospectively recruited Chinese CRS patients with at least 1‐year postoperative follow‐up. Difficult‐to‐treat CRS was characterized in each generated cluster.
Results
Seven subject clusters were identified. Cluster 1 (13.01%) was comparable to the classic well‐defined eosinophilic CRS with polyps, having severe disease and the highest proportion of difficult‐to‐treat CRS. Patients in cluster 2 (16.26%) and cluster 4 (13.82%) had relatively lower proportions of presence of polyps and presented mild inflammation with moderate proportions of difficult‐to‐treat cases. Subjects in cluster 2 were highly atopic. Cluster 3 (7.31%) and cluster 6 (21.14%) were characterized by severe or moderate neutrophilic inflammation, respectively, and with elevated levels of IL‐8 and high proportions of difficult‐to‐treat CRS. Cluster 5 (4.07%) was a unique group characterized by the highest levels of IL‐10 and lacked difficult‐to‐treat cases. Cluster 7 (24.39%) demonstrated the lowest symptom severity, a low proportion of difficult‐to‐treat CRS, and low inflammation load. Finally, we found that difficult‐to‐treat CRS was associated with distinct clinical features and biomarkers in the different clusters.
Conclusions
Distinct clinicopathobiologic clusters of CRS display differences in clinical response to treatments and characteristics of difficult‐to‐treat CRS.
Summary
Background
Eosinophilic and non‐eosinophilic chronic rhinosinusitis with nasal polyps (CRSwNP) display distinct patterns of inflammation. However, the pathogenic mechanisms underlying the ...heterogeneity of CRSwNP need further investigation.
Objective
To investigate local immunoglobulin E (IgE) production and phenotype of mast cells in eosinophilic and non‐eosinophilic CRSwNP in Chinese.
Methods
Total and specific IgE levels were analysed by means of the ImmunoCAP system. The molecular steps involved in class‐switch recombination to IgE were investigated using RT‐PCR assays. Mast cell phenotypes, IgE‐ and high‐affinity IgE receptor (FcεRI)‐positive cells, and allergen binding to specific IgE in sinonasal mucosa were determined by means of immunohistochemistry.
Results
Compared with controls and non‐eosinophilic CRSwNP, local total IgE levels were increased, and local specific IgE to common aeroallergens was more frequently found, in Chinese eosinophilic CRSwNP independent of atopy and without significant association with Staphylococcus aureus enterotoxins. The ε germline gene transcript was also more frequently detected in eosinophilic CRSwNP. The number of IgE‐ and FcεRI‐positive cells was increased in eosinophilic CRSwNP. Most IgE‐ and FcεRI‐positive cells were mast cells. Dust mite antigens could bind to IgE on mast cells in situ. The number of mast cells positive for both tryptase and chymase and activated mast cells was increased in eosinophilic CRSwNP and the number of activated mast cells positively correlated with local IgE level, eotaxin‐1 level, and eosinophil count in CRSwNP.
Conclusions and Clinical Relevance
The local IgE induced by common aeroallergens may mediate mast cell activation and contribute to subsequent eosinophilic inflammation in Chinese CRSwNP. This study offers a rationale for considering intervention strategies designed to target ‘local allergy’ in eosinophilic CRSwNP.
Novel antibiotics are urgently needed to address the looming global crisis of antibiotic resistance. Historically, the primary source of clinically used antibiotics has been microbial secondary ...metabolism. Microbial genome sequencing has revealed a plethora of uncharacterized natural antibiotics that remain to be discovered. However, the isolation of these molecules is hindered by the challenge of linking sequence information to the chemical structures of the encoded molecules. Here, we present PRISM 4, a comprehensive platform for prediction of the chemical structures of genomically encoded antibiotics, including all classes of bacterial antibiotics currently in clinical use. The accuracy of chemical structure prediction enables the development of machine-learning methods to predict the likely biological activity of encoded molecules. We apply PRISM 4 to chart secondary metabolite biosynthesis in a collection of over 10,000 bacterial genomes from both cultured isolates and metagenomic datasets, revealing thousands of encoded antibiotics. PRISM 4 is freely available as an interactive web application at http://prism.adapsyn.com .
The Interdependence Theory links grain formation and nucleant selection to improve the ability to reveal the mechanisms of grain refinement, predict as-cast grain size and account for observations ...that only a small proportion of added inoculant particles nucleate grains. The Interdependence Theory addresses these issues from a different fundamental perspective, which assumes that grain formation is the result of the interdependence between nucleation and growth acting in concert within an environment dictated by the alloy chemistry. The final grain size is determined by three components: (i) the distance that a previously nucleated grain must grow in order to establish sufficient constitutional supercooling (CS) ahead of a solid–liquid (S–L) interface to enable nucleation of the next grain; (ii) the distance from this S–L interface to the point where this critical amount of CS has been generated; and (iii) the additional distance to the nearest most potent nucleant particle. The first and second components together represent a nucleation-free zone where nucleation is completely suppressed. The relative significance of each component is assessed using experimental data on magnesium and aluminium alloys. To improve particle efficacy and promote nucleation and grain refinement it is critical to minimize the size of the nucleation-free zone by controlling alloy chemistry and/or growth rate. The Interdependence Theory clearly explains why only a small proportion of added inoculants particles are operative.
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•Precise design of Pd-decorated vertically aligned ZnO nanorod architectures.•Pd@ZnO sensors exhibit excellent selectivity towards C2H5OH @260 °C.•C2H5OH performance of ZnO sensor ...increased by the order of 4 after Pd-decoration.•Excellent C2H5OH response reproducibility of Pd@ZnO sensors @260 °C.•Plausible gas sensing mechanism of Pd@ZnO sensors is proposed.
The development of defined hierarchical transition metal oxide nanostructures has attracted remarkable attention due to their superior chemiresistive gas sensing performances. In the present study, vertically aligned zinc oxide nanorods (ZnO-NRs) were grown by chemical vapor deposition (CVD) and precise decoration with palladium nanoparticles (Pd-NPs) on their surfaces, at different deposition times, was done through unique RF magnetic sputtering followed by annealing. The effect of different Pd-NPs loadings on structure, surface morphology, elemental composition, and chemiresistive C2H5OH gas sensing properties of CVD-mediated pristine ZnO-NRs was elucidated thoroughly and accounted. As-fabricated pristine and Pd-loaded ZnO-NRs sensors are sensitive towards ethanol (C2H5OH) at 260 °C. Moreover, gas sensing investigations revealed that the C2H5OH response of pristine ZnO NRs was enhanced strongly due to Pd-decoration. Such a response enhancement is mainly attributed to the catalytic activity of Pd-NPs. It is confirmed that the influence of Pd-NPs on ZnO-NRs sensor is normally to strengthen the amount of chemisorbed oxygen on ZnO-NRs surface and enhance the C2H5OH response. Present work can motivate research advancement on precise designing of innovative one dimensional and related nanostructures for the application of selective chemiresistive gas sensors.
Background
Thymic stromal lymphopoietin (TSLP), IL‐25, and IL‐33 system contribute to the initiation and development of Th2 responses. This study aimed to explore the involvement of TSLP, IL‐25, ...IL‐33, and their receptors in type 2 T‐helper (Th) responses in chronic rhinosinusitis with nasal polyps (CRSwNPs) and their cross‐regulation in human nasal epithelial cells (HNECs).
Methods
Immunohistochemistry, quantitative RT‐PCR, ELISA, Bio‐Plex assay, and flow cytometry were used to detect the expression of TSLP/common γ‐like TSLP receptor (TSLPR)/IL‐7 receptor α (IL‐7Rα), IL‐25/IL‐17B receptor (IL‐17RB), and IL‐33/membrane‐bound ST2 (ST2L)/soluble ST2 (sST2) in sinonasal mucosa and HNECs. HNECs cultured at an air–liquid interface were used to explore the expression in regulation of these cytokine systems.
Results
Compared with controls and noneosinophilic CRSwNP, the expression of TSLP/TSLPR/IL‐7Rα and ST2L/sST2 was significantly increased in eosinophilic CRSwNP, predominantly in epithelial cells. In contrast, the expression of IL‐33 and IL‐25/IL‐17RB was enhanced in epithelial cells in both eosinophilic and noneosinophilic CRSwNP compared to controls. The expression of TSLP, TSLPR, and ST2L was positively correlated with symptom and computer tomography scan scores in eosinophilic CRSwNP and with Th2 cytokine expression in sinonasal mucosa. The expression of ST2L was correlated with TSLP and its receptor expression. TSLP could induce ST2L expression that promoted IL‐33‐induced TSLP expression in HNECs. In addition, TSLP/TSLPR/IL‐7Rα and ST2L could be induced by Th2 cytokines, while IL‐25/IL‐17RB and IL‐33 could be upregulated by Th1/Th17 cytokines, in HNECs.
Conclusions
The positive feedback loop between TSLP, IL‐33 and their receptors, and Th2 cytokines may facilitate Th2‐skewed inflammation in eosinophilic CRSwNP.
Background
The remodeling patterns in different types of chronic rhinosinusitis (CRS) have rarely been compared, particularly the difference between eosinophilic and noneosinophilic CRS with nasal ...polyps (CRSwNP). Moreover, whether there is a link between remodeling and inflammation remains controversial.
Objective
To directly compare the remodeling features of different CRS and to explore their relationship with inflammation in Chinese patients.
Methods
Histologic characteristics of surgical samples were analyzed in 33 controls, 72 eosinophilic and 76 noneosinophilic CRSwNP, and 72 CRS without nasal polyps (CRSsNP) patients. Tissue samples from 38 controls, 26 eosinophilic and 26 noneosinophilic CRSwNP, and 32 CRSsNP patients were measured for mRNA and/or protein expression of profibrotic growth factors, metalloproteinases (MMPs), tissue inhibitor of metalloproteinases (TIMPs), hypoxia‐inducible factor (HIF)‐1α, interleukin (IL)‐8, eosinophil cationic protein (ECP), and myeloperoxidase (MPO).
Results
The amount of collagen decreased, whereas the edema scores increased, from CRSsNP to noneosinophilic CRSwNP and to eosinophilic CRSwNP. Transforming growth factor (TGF)‐β2 protein levels were enhanced in CRSsNP compared with CRSwNP. TIMP‐4 protein levels decreased in eosinophilic CRSwNP compared with noneosinophilic CRSwNP and CRSsNP. The number of neutrophils decreased from CRSsNP to noneosinophilic CRSwNP and to eosinophilic CRSwNP. ECP levels were only up‐regulated in eosinophilic CRSwNP. ECP levels and neutrophil number correlated positively with the severity of edema and fibrosis, respectively. Neutrophils were the major sources of TGF‐β2 in CRSsNP and noneosinophilic CRSwNP.
Conclusion
Distinct remodeling patterns are revealed for different types of CRS, particularly for eosinophilic and noneosinophilic CRSwNP. Tissue remodeling associates with inflammation in CRS.
Summary
Background
CD8+ T cells are important effectors of cell‐mediated immunity; however, their contribution to the pathogenesis of CRS is unclear.
Objective
This study aimed to characterize the ...cytokine‐producing features and cytotoxic activity of CD8+ T cells, and their correlation with inflammation patterns in CRS with nasal polyps.
Methods
The expression of IFN‐γ, IL‐4, IL‐5, IL‐17A, forkhead box P3 (FOXP3), perforin, and granzyme B in CD8+ T cells was studied by means of flow cytometry, immunohistochemistry, and immunofluorescence. The expression of CD8+ T‐cell subset relevant chemokines and chemokine receptors was detected by means of real‐time RT‐PCR or ELISA. The cytotoxic activity of sorted CD8+ T cells was defined by anti‐CD3‐redirected killing assay.
Results
Compared with controls, elevated percentages of total CD8+ T cells and cytotoxic T lymphocyte (Tc) 1 (IFN‐γ+), Tc2 (IL‐4+), and Tc17 (IL‐17A+) cell subset, and decreased percentages of FOXP3+CD8+ regulatory T cells, were found in both eosinophilic and non‐eosinophilic polyps with a Tc2‐skewed and Tc1/Tc17‐dominated response in eosinophilic and non‐eosinophilic polyps, respectively. Nasal CD8+ T cells were found to produce similar or even higher levels of IFN‐γ and IL‐4 compared with CD4+ T cells. Tc1 and Tc17, and Tc2 (IL‐4+ and IL‐5+) cell subset percentages positively correlated with neutrophil and eosinophil counts in sinonasal mucosa, respectively. Strikingly, the expression of perforin and granzyme B and cytotoxic activity were significantly reduced in nasal CD8+ T cells compared with their counterparts in peripheral blood. The expression of CXCL16, CCL17, and CCL20 positively correlated with Tc1, Tc2, and Tc17 cell subset number in sinonasal mucosa, respectively.
Conclusion and Clinical Relevance
CD8+ T cells have low cytotoxic activity; nevertheless, they are a significant and previously underappreciated source of inflammatory cytokine production in polyps. Different Tc cell subset domination may contribute to distinctly biased granulocyte inflammation in eosinophilic and non‐eosinophilic polyps.
The AP2/ERF family includes a large number of developmentally and physiologically important transcription factors sharing an AP2 DNA-binding domain. Among them DREB1/CBF and DREB2 factors are known ...as master regulators respectively of cold and heat/osmotic stress responses.
The manual annotation of AP2/ERF family from Eucalyptus grandis, Malus, Populus and Vitis genomes allowed a complete phylogenetic study for comparing the structure of this family in woody species and the model Arabidopsis thaliana. Expression profiles of the whole groups of EgrDREB1 and EgrDREB2 were investigated through RNAseq database survey and RT-qPCR analyses.
The structure and the size of the AP2/ERF family show a global conservation for the plant species under comparison. In addition to an expansion of the ERF subfamily, the tree genomes mainly differ with respect to the group representation within the subfamilies. With regard to the E. grandis DREB subfamily, an obvious feature is the presence of 17 DREB1/CBF genes, the maximum reported to date for dicotyledons. In contrast, only six DREB2 have been identified, which is similar to the other plants species under study, except for Malus. All the DREB1/CBF and DREB2 genes from E. grandis are expressed in at least one condition and all are heat-responsive. Regulation by cold and drought depends on the genes but is not specific of one group; DREB1/CBF group is more cold-inducible than DREB2 which is mainly drought responsive.
These features suggest that the dramatic expansion of the DREB1/CBF group might be related to the adaptation of this evergreen tree to climate changes when it expanded in Australia.
Background
Autophagy is a lysosomal degradation pathway that is essential for cell survival, differentiation, and homeostasis. This study aimed to investigate the contribution of autophagy to the ...pathogenesis of CRS with nasal polyps (CRSwNP).
Methods
The expression of autophagic proteins microtubule‐associated protein 1 light chain 3B (LC3B)‐II, autophagy‐related proteins (Atg), and Beclin 1, substrate proteins (p62 and ubiquitinated proteins), and apoptotic signaling molecules cysteine‐aspartic protease‐3 and cysteine‐aspartic protease‐8, and poly‐ADP‐ribose polymerase in the sinonasal mucosa and nasal epithelial cells (NECs) was detected by immunohistochemistry and Western blotting. Autophagic vacuoles were observed with transmission electron microscopy. BEAS‐2B cells and NECs were treated with rapamycin, bafilomycin A1, or various cytokines. In some experiments, cultured NECs were transfected with small interfering RNA targeting p62 (sip62) or Atg5 (siAtg5). Cultured cells were analyzed with Western blotting and flow cytometry.
Results
Although autophagic protein expression and autophagic vacuole formation were increased in both eosinophilic and noneosinophilic CRSwNP, particularly in NECs, there was also an up‐regulation of substrate proteins and apoptotic signaling molecules. IFN‐γ, but not IL‐4, IL‐13, or IL‐17A, simultaneously enhanced LC3B‐II and p62 levels as well as cell apoptosis in BEAS‐2B cells and/or normal NECs. Bafilomycin A1 up‐regulated the levels of LC3B‐II and p62 in polyp NECs and IFN‐γ‐treated normal NECs. IFN‐γ‐induced apoptosis of normal NECs was exaggerated by bafilomycin A1 and siAtg5. Sip62 suppressed apoptosis of polyp NECs and IFN‐γ‐treated NECs. IFN‐γ protein levels were increased in both eosinophilic and noneosinophilic CRSwNP.
Conclusions
IFN‐γ induces activated but insufficient autophagy and thus contributes to a degree to p62‐dependent apoptosis of NECs in CRSwNP.
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