Heterogeneity of phenotypes in severe asthmatics. The Belgian Severe Asthma Registry (BSAR).

The Belgian severe asthma registry is a web-based registry encompassing demographic, clinical, functional and inflammatory data of severe asthmatics (SA), aiming at improving awareness, knowledge on its natural history and subphenotypes, and offering tools to optimize care of this asthma population. METHODS: The cross-sectional analyses of this registry included 350 SA as defined by the ATS (2000) from 9 Belgian centres, with at least one year follow up. RESULTS: Mean age was 55 +/- 14 yrs. SA were more frequently female (57%) and atopic (70%). Late-onset asthma (>/=40 yr) was observed in 31% of SA. Current smokers represented 12% while 31% were ex-smokers. In addition to high doses ICS + LABA, 65% of patients were receiving LTRA, 27% anti-IgE and 24% maintenance oral corticosteroids (8 mg (Interquartile range-IQR:4-8) methylprednisolone). Despite impaired airflow (median FEV1:67%; IQR: 52-81) only 65% had a post-bronchodilator FEV1/FVC ratio /= 50 ppb. Induced sputum was successful in 86 patients. Eosinophilic asthma (sputum Eos >/= 3%) was the predominant phenotype (55%) while neutrophilic (sputum Neu >/= 76%) and paucigranulocytic asthma accounted for 22% and 17% respectively. Comorbidities included rhinitis and chronic rhinosinusitis (49%), nasal polyposis (19%), oesophageal reflux (36%), overweight and obesity (47%) and depression (19%). In addition, 8% had aspirin-induced asthma and 3% ABPA. Asthma was not well-controlled in 83% according to ACT 1.5. CONCLUSION: In this cohort of patients with severe asthma, the majority displayed indices of persistent airflow limitation and eosinophilic inflammation despite high-dose corticosteroids, suggesting potential for eosinophil-targeted biotherapies

Use of the theory of index numbers for selection of fertilizer and seed drills of precision

The objectives of this work were to systemize the data contained in a set of technical catalogues referring to models of fertilizer and seed drills of precision to analyze the available information in order to prepare a database with technical characteristics and to propose a classification index for the models based on these characteristics. 93 catalogues of fertilizer and seed drills of precision supplied by Brazilian manufacturers were analyzed for generating information to characterize 250 models. On the basis of 31 technical characteristics available in catalogues, a database was prepared in which 9 of these characteristics were used in the formulation of an index number, called -Index of Adequacy- (IA). The application of IA allowed to classify the 250 models in five different categories (A, B, C, D and E), where 73% of the analyzed models composed the categories A and B, indicated for small and medium farms; 19% composed the category C, indicated for medium and large farms; and 8% of the models composed the categories D and E, indicated for large farms. It may be concluded that the adequacy index is a tool that could be used by producers in the decision-making to select most adequate fertilizer and seed drill for farm characteristics.Com este trabalho, objetivou-se sistematizar dados contidos em um conjunto de catálogos tecnológicos referentes aos modelos de semeadoras-adubadoras de precisão disponíveis no mercado nacional, analisar as informações disponíveis, construir um banco de dados com as características técnicas e propor um índice classificatório para os modelos. Analisaram-se 93 catálogos fornecidos por fabricantes nacionais, possibilitando caracterizar 250 modelos de semeadoras-adubadoras de precisão. Com base em 31 características técnicas disponíveis nos catálogos, construiu-se um banco de dados utilizando-se nove dessas características, na formulação de um número índice denominado -Índice de Adequação- (IA). A aplicação do IA permitiu que se classificassem os 250 modelos em cinco categorias (A, B, C, D e E), sendo que 73% dos modelos analisados integraram as categorias A e B, indicadas para pequenas e médias propriedades; 19% completaram a categoria C, indicada para médias e grandes propriedades e 8% dos modelos integraram as categorias D e E, indicadas para grandes propriedades. Conclui-se, portanto, que o IA é uma ferramenta que poderá ser utilizada por produtores na tomada de decisão, para escolha da semeadora-adubadora mais adequada às características da propriedade.22222

On universality of local edge regime for the deformed Gaussian Unitary Ensemble

We consider the deformed Gaussian ensemble $H_n=H_n^{(0)}+M_n$ in which $H_n^{(0)}$ is a hermitian matrix (possibly random) and $M_n$ is the Gaussian unitary random matrix (GUE) independent of $H_n^{(0)}$. Assuming that the Normalized Counting Measure of $H_n^{(0)}$ converges weakly (in probability if random) to a non-random measure $N^{(0)}$ with a bounded support and assuming some conditions on the convergence rate, we prove universality of the local eigenvalue statistics near the edge of the limiting spectrum of $H_n$.Comment: 25 pages, 2 figure

Impact‐based forecasting for pluvial floods

Pluvial floods in urban areas are caused by local, fast storm events with very high rainfall rates, which lead to inundation of streets and buildings before the storm water reaches a watercourse. An increase in frequency and intensity of heavy rainfall events and an ongoing urbanization may further increase the risk of pluvial flooding in many urban areas. Currently, warnings for pluvial floods are mostly limited to information on rainfall intensities and durations over larger areas, which is often not detailed enough to effectively protect people and goods. We present a proof-of-concept for an impact-based forecasting system for pluvial floods. Using a model chain consisting of a rainfall forecast, an inundation, a contaminant transport and a damage model, we are able to provide predictions for the expected rainfall, the inundated areas, spreading of potential contamination and the expected damage to residential buildings. We use a neural network-based inundation model, which significantly reduces the computation time of the model chain. To demonstrate the feasibility, we perform a hindcast of a recent pluvial flood event in an urban area in Germany. The required spatio-temporal accuracy of rainfall forecasts is still a major challenge, but our results show that reliable impact-based warnings can be forecasts are available up to 5 min before the peak of an extreme rainfall event. Based on our results, we discuss how the outputs of the impact-based forecast could be used to disseminate impact-based early warnings

Tumor-derived exosomes confer antigen-specific immunosuppression in a murine delayed-type hypersensitivity model

Exosomes are endosome-derived small membrane vesicles that are secreted by most cell types including tumor cells. Tumor-derived exosomes usually contain tumor antigens and have been used as a source of tumor antigens to stimulate anti-tumor immune responses. However, many reports also suggest that tumor-derived exosomes can facilitate tumor immune evasion through different mechanisms, most of which are antigen-independent. In the present study we used a mouse model of delayed-type hypersensitivity (DTH) and demonstrated that local administration of tumor-derived exosomes carrying the model antigen chicken ovalbumin (OVA) resulted in the suppression of DTH response in an antigen-specific manner. Analysis of exosome trafficking demonstrated that following local injection, tumor-derived exosomes were internalized by CD11c+ cells and transported to the draining LN. Exosome-mediated DTH suppression is associated with increased mRNA levels of TGF-β1 and IL-4 in the draining LN. The tumor-derived exosomes examined were also found to inhibit DC maturation. Taken together, our results suggest a role for tumor-derived exosomes in inducing tumor antigen-specific immunosuppression, possibly by modulating the function of APCs. © 2011 Yang et al

CD36 maintains the gastric mucosa and associates with gastric disease.

The gastric epithelium is often exposed to injurious elements and failure of appropriate healing predisposes to ulcers, hemorrhage, and ultimately cancer. We examined the gastric function of CD36, a protein linked to disease and homeostasis. We used the tamoxifen model of gastric injury in mice null for Cd36 (Cd36-/-), with Cd36 deletion in parietal cells (PC-Cd36-/-) or in endothelial cells (EC-Cd36-/-). CD36 expresses on corpus ECs, on PC basolateral membranes, and in gastrin and ghrelin cells. Stomachs of Cd36-/- mice have altered gland organization and secretion, more fibronectin, and inflammation. Tissue respiration and mitochondrial efficiency are reduced. Phospholipids increased and triglycerides decreased. Mucosal repair after injury is impaired in Cd36-/- and EC-Cd36-/-, not in PC-Cd36-/- mice, and is due to defect of progenitor differentiation to PCs, not of progenitor proliferation or mature PC dysfunction. Relevance to humans is explored in the Vanderbilt BioVu using PrediXcan that links genetically-determined gene expression to clinical phenotypes, which associates low CD36 mRNA with gastritis, gastric ulcer, and gastro-intestinal hemorrhage. A CD36 variant predicted to disrupt an enhancer site associates (p < 10-17) to death from gastro-intestinal hemorrhage in the UK Biobank. The findings support role of CD36 in gastric tissue repair, and its deletion associated with chronic diseases that can predispose to malignancy

MAGE-A cancer/testis antigens inhibit MDM2 ubiquitylation function and promote increased levels of MDM4

Melanoma antigen A (MAGE-A) proteins comprise a structurally and biochemically similar sub-family of Cancer/Testis antigens that are expressed in many cancer types and are thought to contribute actively to malignancy. MAGE-A proteins are established regulators of certain cancer-associated transcription factors, including p53, and are activators of several RING finger-dependent ubiquitin E3 ligases. Here, we show that MAGE-A2 associates with MDM2, a ubiquitin E3 ligase that mediates ubiquitylation of more than 20 substrates including mainly p53, MDM2 itself, and MDM4, a potent p53 inhibitor and MDM2 partner that is structurally related to MDM2. We find that MAGE-A2 interacts with MDM2 via the N-terminal p53-binding pocket and the RING finger domain of MDM2 that is required for homo/hetero-dimerization and for E2 ligase interaction. Consistent with these data, we show that MAGE-A2 is a potent inhibitor of the E3 ubiquitin ligase activity of MDM2, yet it does not have any significant effect on p53 turnover mediated by MDM2. Strikingly, however, increased MAGE-A2 expression leads to reduced ubiquitylation and increased levels of MDM4. Similarly, silencing of endogenous MAGE-A expression diminishes MDM4 levels in a manner that can be rescued by the proteasomal inhibitor, bortezomid, and permits increased MDM2/MDM4 association. These data suggest that MAGE-A proteins can: (i) uncouple the ubiquitin ligase and degradation functions of MDM2; (ii) act as potent inhibitors of E3 ligase function; and (iii) regulate the turnover of MDM4. We also find an association between the presence of MAGE-A and increased MDM4 levels in primary breast cancer, suggesting that MAGE-A-dependent control of MDM4 levels has relevance to cancer clinically

Impacts of large and small barriers on fish assemblage composition assessed using environmental DNA metabarcoding

River fragmentation caused by instream barriers is a leading cause of biodiversity loss, particularly for freshwater migratory fish, the vertebrate group that has suffered the steepest decline. However, most studies have tended to focus on the impacts of large dams on only a few taxa. We estimated the cumulative impact of both large and small barriers on fish species richness and relative abundance along an altitudinal gradient in the main stem of the River Allier (France). Using eDNA metabarcoding, we identified 24 fish zero-radius operational taxonomic units (zOTUs), corresponding to 26 species distributed along the main stem of the river. Elevation explained the greatest amount of variation in fish distribution, together with average flow, barrier density and its interaction with cumulative barrier height. Based on eDNA, the largest discontinuity in species richness was not related to the location of Poutès, the largest dam in the system, but located downstream from it. Our results indicate that, in addition to the more obvious effects of large dams on migratory fish such as the Atlantic salmon, the cumulative effects of small barriers can have widespread impacts on fish species richness and relative abundance, which should not be overlooked. We suggest that, as for other fragmented rivers, acting on numerous small barriers might bring about greater benefits in fish species richness than focusing only on the largest dams

Actin: its cumbersome pilgrimage through cellular compartments

In this article, we follow the history of one of the most abundant, most intensely studied proteins of the eukaryotic cells: actin. We report on hallmarks of its discovery, its structural and functional characterization and localization over time, and point to present days’ knowledge on its position as a member of a large family. We focus on the rather puzzling number of diverse functions as proposed for actin as a dual compartment protein. Finally, we venture on some speculations as to its origin