Spontaneous protein crystallization is a rare event, yet protein crystals are frequently found in eosinophil-rich inflammation. In humans, Charcot-Leyden crystals (CLCs) are made from galectin-10 ...(Gal10) protein, an abundant protein in eosinophils. Although mice do not encode Gal10 in their genome, they do form pseudo-CLCs, made from the chitinase-like proteins Ym1 and/or Ym2, encoded by
and
and made by myeloid and epithelial cells respectively. Here, we investigated the biological effects of pseudo-CLCs since their function is currently unknown. We produced recombinant Ym1 crystals which were shown to have identical crystal packing and structure by X-ray crystallography as in vivo native crystals derived from murine lung. When administered to the airways of mice, crystalline but not soluble Ym1 stimulated innate and adaptive immunity and acted as a type 2 immune adjuvant for eosinophilic inflammation via triggering of dendritic cells (DCs). Murine Ym1 protein crystals found at sites of eosinophilic inflammation reinforce type 2 immunity and could serve as a surrogate model for studying the biology of human CLCs.
Allergic diseases asthma, rhinitis and atopic dermatitis (AD) are complex. They are associated with allergen‐specific IgE and nonallergic mechanisms that may coexist in the same patient. In addition, ...these diseases tend to cluster and patients present concomitant or consecutive diseases (multimorbidity). IgE sensitization should be considered as a quantitative trait. Important clinical and immunological differences exist between mono‐ and polysensitized subjects. Multimorbidities of allergic diseases share common causal mechanisms that are only partly IgE‐mediated. Persistence of allergic diseases over time is associated with multimorbidity and/or IgE polysensitization. The importance of the family history of allergy may decrease with age. This review puts forward the hypothesis that allergic multimorbidities and IgE polysensitization are associated and related to the persistence or re‐occurrence of foetal type 2 signalling. Asthma, rhinitis and AD are manifestations of a common systemic immune imbalance (mesodermal origin) with specific patterns of remodelling (ectodermal or endodermal origin). This study proposes a new classification of IgE‐mediated allergic diseases that allows the definition of novel phenotypes to (i) better understand genetic and epigenetic mechanisms, (ii) better stratify allergic preschool children for prognosis and (iii) propose novel strategies of treatment and prevention.
To cite this article: Bousquet J, Anto J, Auffray C, Akdis M, Cambon‐Thomsen A, Keil T, Haahtela T, Lambrecht BN, Postma DS, Sunyer J, Valenta R, Akdis CA, Annesi‐Maesano I, Arno A, Bachert C, ...Ballester F, Basagana X, Baumgartner U, Bindslev‐Jensen C, Brunekreef B, Carlsen KH, Chatzi L, Crameri R, Eveno E, Forastiere F, Garcia‐Aymerich J, Guerra S, Hammad H, Heinrich J, Hirsch D, Jacquemin B, Kauffmann F, Kerkhof M, Kogevinas M, Koppelman GH, Kowalski ML, Lau S, Lodrup‐Carlsen KC, Lopez‐Botet M, Lotvall J, Lupinek C, Maier D, Makela MJ, Martinez FD, Mestres J, Momas I, Nawijn MC, Neubauer A, Oddie S, Palkonen S, Pin I, Pison C, Rancé F, Reitamo S, Rial‐Sebbag E, Salapatas M, Siroux V, Smagghe D, Torrent M, Toskala E, van Cauwenberge P, van Oosterhout AJM, Varraso R, von Hertzen L, Wickman M, Wijmenga C, Worm M, Wright J, Zuberbier T. MeDALL (Mechanisms of the Development of ALLergy): an integrated approach from phenotypes to systems medicine. Allergy 2011; 66: 596–604.
The origin of the epidemic of IgE‐associated (allergic) diseases is unclear. MeDALL (Mechanisms of the Development of ALLergy), an FP7 European Union project (No. 264357), aims to generate novel knowledge on the mechanisms of initiation of allergy and to propose early diagnosis, prevention, and targets for therapy. A novel phenotype definition and an integrative translational approach are needed to understand how a network of molecular and environmental factors can lead to complex allergic diseases. A novel, stepwise, large‐scale, and integrative approach will be led by a network of complementary experts in allergy, epidemiology, allergen biochemistry, immunology, molecular biology, epigenetics, functional genomics, bioinformatics, computational and systems biology. The following steps are proposed: (i) Identification of ‘classical’ and ‘novel’ phenotypes in existing birth cohorts; (ii) Building discovery of the relevant mechanisms in IgE‐associated allergic diseases in existing longitudinal birth cohorts and Karelian children; (iii) Validation and redefinition of classical and novel phenotypes of IgE‐associated allergic diseases; and (iv) Translational integration of systems biology outcomes into health care, including societal aspects. MeDALL will lead to: (i) A better understanding of allergic phenotypes, thus expanding current knowledge of the genomic and environmental determinants of allergic diseases in an integrative way; (ii) Novel diagnostic tools for the early diagnosis of allergy, targets for the development of novel treatment modalities, and prevention of allergic diseases; (iii) Improving the health of European citizens as well as increasing the competitiveness and boosting the innovative capacity of Europe, while addressing global health issues and ethical issues.
Although spontaneous protein crystallization is a rare event in vivo, Charcot-Leyden crystals (CLCs) consisting of galectin-10 (Gal10) protein are frequently observed in eosinophilic diseases, such ...as asthma. We found that CLCs derived from patients showed crystal packing and Gal10 structure identical to those of Gal10 crystals grown in vitro. When administered to the airways, crystalline Gal10 stimulated innate and adaptive immunity and acted as a type 2 adjuvant. By contrast, a soluble Gal10 mutein was inert. Antibodies directed against key epitopes of the CLC crystallization interface dissolved preexisting CLCs in patient-derived mucus within hours and reversed crystal-driven inflammation, goblet-cell metaplasia, immunoglobulin E (IgE) synthesis, and bronchial hyperreactivity (BHR) in a humanized mouse model of asthma. Thus, protein crystals may promote hallmark features of asthma and are targetable by crystal-dissolving antibodies.
Although the central role of the immune system for tumor prognosis is generally accepted, a single robust marker is not yet available.
On the basis of receiver operating characteristic analyses, ...robust markers were identified from a 60-gene B cell-derived metagene and analyzed in gene expression profiles of 1,810 breast cancer; 1,056 non-small cell lung carcinoma (NSCLC); 513 colorectal; and 426 ovarian cancer patients. Protein and RNA levels were examined in paraffin-embedded tissue of 330 breast cancer patients. The cell types were identified with immunohistochemical costaining and confocal fluorescence microscopy.
We identified immunoglobulin κ C (IGKC) which as a single marker is similarly predictive and prognostic as the entire B-cell metagene. IGKC was consistently associated with metastasis-free survival across different molecular subtypes in node-negative breast cancer (n = 965) and predicted response to anthracycline-based neoadjuvant chemotherapy (n = 845; P < 0.001). In addition, IGKC gene expression was prognostic in NSCLC and colorectal cancer. No association was observed in ovarian cancer. IGKC protein expression was significantly associated with survival in paraffin-embedded tissues of 330 breast cancer patients. Tumor-infiltrating plasma cells were identified as the source of IGKC expression.
Our findings provide IGKC as a novel diagnostic marker for risk stratification in human cancer and support concepts to exploit the humoral immune response for anticancer therapy. It could be validated in several independent cohorts and carried out similarly well in RNA from fresh frozen as well as from paraffin tissue and on protein level by immunostaining.
Extreme precipitation events are among the most severe weather hazards. Knowledge about the spatial patterns underlying such events in the Upper Indus Basin is limited because estimating ...precipitation is very challenging due to the data scarcity and the complex orography. Numerical weather prediction models can be applied at a fine resolution to overcome this issue. The Advanced Research Weather Research and Forecasting (WRF) model version 3.8.1 was applied over the Kabul River Basin to simulate the temperature and precipitation of monsoon season 2010, i.e., 1st May to 16th September 2010. We considered the May month as a spin-up period. The initial and boundary conditions were derived from the National Oceanic and Atmospheric Administration, Climate Forecast System Reanalysis data. The model was set up by using two-nested domains with increasing horizontal resolution moving inward from 15km on domain d01 to 5km on domain d02. The simulations were compared with TRMM 3B42, and station data collected from the Pakistan Meteorological Department and Water and the Power Development Authority using bias, percentage bias, root mean square error, and Pearson correlation. The results revealed that the simulated precipitation was improved from d01 to d02. However, the model showed mixed results with overestimation of precipitation at some stations and underestimations at others. Simulated precipitation generally agreed better with TRMM than with station data. Overall, the results indicate that the WRF model can be used to simulate heavy precipitation in complex terrain.
Aim:
The study was conducted to investigate the obtained external and internal porosity and the pore-interconnectivity of specific fabricated bioactive composite tissue engineering scaffolds for bone ...regeneration in dental applications.
Materials and Methods:
In this study, the bioactive glass M was elaborated as a quaternary system to be incorporated into the chitosan C scaffold preparation on a magnetic stirrer to provide bioactivity and better strength properties for the attempted composite scaffolds C/ M of variable compositions. The homogenous chitosan/bioactive glass mix was poured into tailor-made cylindrical molds 10cm×10cm; a freeze-dryer program was used for the creation of uniform and interconnected macropores for all prepared chitosan-based scaffolds. The morphology of fabricated chitosan C and chitosan-bioactive glass C/ M composite scaffolds was studied by a scanning electron microscope SEM and a mercury porosimeter. In addition, the in-vitro biodegradation rate of all elaborated scaffolds was reported after immersing the prepared scaffolds in a simulated body fluid SBF solution. Furthermore, for every prepared scaffold composition, characterization was performed for phase identification, microstructure, porosity, bioactivity, and mechanical properties using an X-ray diffraction analysis XRD, an X-ray Fourier transfer infrared spectroscopy FTIR, a mercury porosimetry, a scanning electron microscopy SEM coupled to an energy-dispersive X-ray spectrometry EDS and a universal testing machine, respectively.
Results:
All the prepared porous chitosan-based composite materials showed pore sizes suitable for osteoblasts seeding, with relatively larger pore sizes for the C scaffolds.
Conclusion:
The smart blending of the prepared bioactive glass M with the chitosan matrix offered some advantages, such as the formation of an apatite layer for cell adhesion upon the scaffold surfaces, the reasonable decrease in scaffold pore size, and the relative increase in compressive strength that were enhanced by the incorporation of M. Therefore, the morphology, microstructure, and mechanical behavior of the elaborated stress loaded biocomposite tissue engineering scaffolds seem highly dependent on their critical contented bioactive glass.
Spontaneous protein crystallization is a rare event, yet protein crystals are frequently found in eosinophil-rich inflammation. In humans, Charcot-Leyden crystals (CLCs) are made from galectin-10 ...(Gal10) protein, an abundant protein in eosinophils. Although mice do not encode Gal10 in their genome, they do form pseudo-CLCs, made from the chitinase-like proteins Ym1 and/or Ym2, encoded by
Chil3
and
Chil4
and made by myeloid and epithelial cells respectively. Here, we investigated the biological effects of pseudo-CLCs since their function is currently unknown. We produced recombinant Ym1 crystals which were shown to have identical crystal packing and structure by X-ray crystallography as in vivo native crystals derived from murine lung. When administered to the airways of mice, crystalline but not soluble Ym1 stimulated innate and adaptive immunity and acted as a type 2 immune adjuvant for eosinophilic inflammation via triggering of dendritic cells (DCs). Murine Ym1 protein crystals found at sites of eosinophilic inflammation reinforce type 2 immunity and could serve as a surrogate model for studying the biology of human CLCs.
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