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The use of high-quality simulated sky catalogs is essential for the success of cosmological surveys. The catalogs have diverse applications, such as investigating signatures of fundamental physics in cosmological observables, understanding the effect of systematic uncertainties on measured signals and testing mitigation strategies for reducing these uncertainties, aiding analysis pipeline development and testing, and survey strategy optimization. The list of applications is growing with improvements in the quality of the catalogs and the details that they can provide. Given the importance of simulated catalogs, it is critical to provide rigorous validation protocols that enable both catalog providers and users to assess the quality of the catalogs in a straightforward and comprehensive way. For this purpose, we have developed the DESCQA framework for the Large Synoptic Survey Telescope Dark Energy Science Collaboration as well as for the broader community. The goal of DESCQA is to enable the inspection, validation, and comparison of an inhomogeneous set of synthetic catalogs via the provision of a common interface within an automated framework. In this paper, we present the design concept and first implementation of DESCQA. In order to establish and demonstrate its full functionality we use a set of interim catalogs and validation tests. We highlight several important aspects, both technical and scientific, that require thoughtful consideration when designing a validation framework, including validation metrics and how these metrics impose requirements on the synthetic sky catalogs., La lista completa de autores se encuentra en el documento., Instituto de Astrofísica de La Plata, Facultad de Ciencias Astronómicas y Geofísicas

Eosinophilic esophagitis (EoE) is a chronic inflammatory disease characterized pathologically by eosinophil infiltration. In addition to loss of barrier integrity, a dominant T Helper 2-associated immune response and strong allergic connection, the esophagus tissue undergoes dramatic changes, with frequent presence of mucosal rings, strictures, linear furrows, and trachealization. Although the inflammatory mechanisms behind this disease are being increasingly well understood, the structural features remain unexplained. We examined the expression of key members of the Wnt-signaling pathway in biopsies from patients with EoE. This pathway has been shown to be critically important in regulating cellular homeostasis, growth, and differentiation and to be dysregulated in several disease conditions. Biopsies from adult EoE patients were collected by endoscopy and mRNA extracted. After cDNA synthesis, the relative gene expression from key upstream (secreted frizzled-related protein 1) and downstream (c-myc and Cyclin D1) molecules in the Wnt pathway, as well as several Wnt pathway members (Wnt1, Axin1, low-density lipoprotein receptor-related protein 6, glycogen synthase kinase 3 beta, and β-catenin), were determined. Biopsies from patients with EoE displayed significantly higher expression of secreted frizzed-related protein 1 than controls, as well as reductions in Cyclin D1 and c-myc. In contrast, there were no differences in the Wnt pathway molecules. The levels of expression of Cyclin D1 and c-myc, as well as β-catenin, in EoE patients showed strong correlations with the frequency of esophageal eosinophils. Our findings suggest that although there are no changes in the overall levels of key Wnt pathway genes in adult EoE, there is evidence for dysregulation of upstream and downstream regulators of Wnt signaling. Importantly, the associations with eosinophilia suggest that these may participate in the pathogenesis of this disease and be markers of disease severity.

Microalgae have been identified as a promising renewable feedstock for production of lipids for feeds and fuels. Current methods for identifying algae strains and growth conditions that support high lipid production require a variety of fluorescent chemical indicators, such as Nile Red and more recently, Bodipy. Despite notable successes using these approaches, chemical indicators exhibit several drawbacks, including non-uniform staining, low lipid specificity, cellular toxicity, and variable permeability based on cell-type, limiting their applicability for high-throughput bioprospecting. In this work, we used in vivo hyperspectral confocal fluorescence microscopy of a variety of potential microalgae production strains ( Nannochloropsis sp., Dunaliella salina , Neochloris oleoabundans , and Chlamydomonas reinhardtii ) to identify a label-free method for localizing lipid bodies and quantifying the lipid yield on a single-cell basis. By analyzing endogenous fluorescence from chlorophyll and resonance Raman emission from lipid-solubilized carotenoids we deconvolved pure component emission spectra and generated diffraction limited projections of the lipid bodies and chloroplast organelles, respectively. Applying this imaging method to nutrient depletion time-courses from lab-scale and outdoor cultivation systems revealed an additional autofluorescence spectral component that became more prominent over time, and varied inversely with the chlorophyll intensity, indicative of physiological compromise of the algal cell. This signal could result in false-positives for conventional measurements of lipid accumulation (via spectral overlap with Nile Red), however, the additional spectral feature was found to be useful for classification of lipid enrichment and culture crash conditions in the outdoor cultivation system. Under nutrient deprivation, increases in the lipid fraction of the cellular volume of ~ 500% were observed, as well as a correlated decrease in the chloroplast fraction of the total cellular volume. The results suggest that a membrane recycling mechanism dominates for nutrient deprivation-based lipid accumulation in the microalgae tested.

Background Mast cells play a critical role in inflammatory skin diseases through releasing proinflammatory mediators; however, few therapies directly target these cells. In 1878, the use of topical thymol, a now recognized potent agonist for transient receptor potential channels, was first described to treat eczema and psoriasis. Objective We sought to determine the mechanisms through which thymol can alter skin inflammation. Methods We examined the effect of topical thymol on IgE-dependent responses using a mast cell–dependent passive cutaneous anaphylaxis (PCA) model, as well as in vitro –cultured mast cells. Results Thymol dose-dependently inhibited PCA when administered topically 24 hours before antigen challenge but provoked an ear-swelling response directly on application. This direct effect was associated with local mast cell degranulation and was absent in histamine-deficient mice. However, unlike with PCA responses, there was no late-phase swelling. In vitro thymol directly triggered calcium flux in mast cells through transient receptor potential channel activation, along with degranulation and cytokine transcription. However, no cytokine protein was produced. Instead, thymol induced a significant increase in apoptotic cell death that was seen both in vitro and in vivo . Conclusions We propose that the efficacy of thymol in reducing IgE-dependent responses is through promotion of activation-induced apoptotic cell death of mast cells and that this likely explains the clinical benefits observed in early clinical reports.

Paralleling the overall trend in allergic diseases, Eosinophilic Esophagitis is rapidly increasing in incidence. It is associated with food antigen-triggered, eosinophil-predominant inflammation and the pathogenic mechanisms have many similarities to other chronic atopic diseases, such as eczema and allergic asthma. Studies in animal models and from patients over the last 15 years have suggested that allergic sensitization leads to food-specific IgE and T-helper lymphocyte type 2 cells, both of which appear to contribute to the pathogenesis along with basophils, mast cells, and antigen-presenting cells. This review will outline our current understandings of the allergic mechanisms that drive eosinophilic esophagitis, drawing from clinical and translational studies in humans as well as experimental animal models.

Food allergies represent an increasingly prevalent human health problem, and therapeutic options remain limited, with avoidance being mainstay, despite its adverse effects on quality of life. A better understanding of the key immunological mechanisms involved in such responses likely will be vital for development of new therapies. This review outlines the current understanding of how the immune system is thought to contribute to prevention or development of food allergies. Drawing from animal studies, as well as clinical data when available, the importance of oral tolerance in sustaining immunological nonresponsiveness to food Ags, our current understanding of why oral tolerance may fail and sensitization may occur, and the knowledge of pathways that may lead to anaphylaxis and food allergy–associated responses are addressed.

Eosinophilic esophagitis (EoE) is a chronic immune/antigen-mediated esophageal disease characterized by esophageal dysfunction and esophageal mucosal eosinophilia. Diet therapy is effective in the treatment of EoE in both children and adults. The role of food allergens is well established in the pathogenesis and treatment of eosinophilic esophagitis. Empiric elimination with a six-food elimination diet (avoiding milk, wheat, egg, soy, peanuts/tree nuts, and fish/shellfish) demonstrates remission in over 70% of adults with this disease. Dietary therapy in adult EoE is becoming more accepted by both patients and clinicians. Dietary therapy can be effectively implemented in clinical practice with appropriate dietary education, patient resources, and close communication with physician and clinical staff. The ability to identify specific food triggers to help tailor dietary therapy for long-term management allows for a return to consumption of most table foods. Furthermore, the diet approach avoids the need for chronic topical corticosteroid use and possible long-term side effects of these medications. The decision to proceed with dietary therapy should be decided by patient preference and available resources. A collaborative and multidisciplinary approach including gastroenterologists, allergists, nurses, and dietitians is essential in the success of this approach.

Food allergy is a rapidly growing public health concern because of its increasing prevalence and life-threatening potential. Animal models of food allergy have emerged as a tool for identifying mechanisms involved in the development of sensitization to normally harmless food allergens, as well as delineating the critical immune components of the effector phase of allergic reactions to food. However, the role animal models might play in understanding human diseases remains contentious. This review summarizes how animal models have provided insights into the etiology of human food allergy, experimental corroboration for epidemiologic findings that might facilitate prevention strategies, and validation for the utility of new therapies for food allergy. Improved understanding of food allergy from the study of animal models together with human studies is likely to contribute to the development of novel strategies to prevent and treat food allergy.

Mast cells and basophils are developmentally related cells whose activation is a hallmark of allergy. Functionally, mast cells and basophils overlap in their ability to produce several mediators, including histamine and granule proteases, but studies have increasingly demonstrated nonredundant roles. To characterize the transcriptional heterogeneity of mast cells and basophils upon their activation, we performed large-scale comparative microarrays of murine bone marrow–derived mast cells and bone marrow–derived basophils (BMBs) at rest, upon an adaptive-type activation (IgE cross-linking), or upon an innate-type activation (IL-33 stimulation). Hierarchical clustering demonstrated that bone marrow–derived mast cells and BMBs shared specific activation-associated transcriptional signatures but differed in other signatures both between cell type and between activation mode. In bone marrow–derived mast cells, IgE cross-linking upregulated 785 genes, including Egr2, Ccl1, and Fxyd6, whereas IL-33 stimulation induced 823 genes, including Ccl1, Egr2, and Il1b. Focused bioinformatics pathway analysis demonstrated that IgE activation aligned with processes such as oxidative phosphorylation, angiogenesis, and the p53 pathway. The IL-33–activated transcriptome was enriched in genes commonly altered by NF-κB in response to TNF, by IL-6 via STAT3, and in response to IFN-γ. Furthermore, BMBs activated via IgE cross-linking selectively induced immune response genes Ccl1, Il3, and Il2 compared with IL-33–stimulated BMBs. Principal-component analysis revealed key cell- and activation-specific clustering. Overall, our data demonstrate that mast cells and basophils have cell- and activation-specific transcriptional responses and suggest that context-specific gene networks and pathways may shape how the immune system responds to allergens and innate cytokines.

Sensing of tissue injury through interleukin 33 (IL-33) release from damaged epithelial and endothelial cells directs effector function(s) of T helper and cytotoxic subsets, group 2 innate lymphocytes, and various myeloid cells. However, it is unclear whether noncanonical IL-33 production from conventional dendritic cells (cDC) shapes infection outcome. This study interrogated whether IL-33 from epithelial cells functioned differently from IL-33 derived from conventional dendritic cells (cDC) during helminth driven Type 2 inflammation. Data show mice temporally deleted of intestinal epithelial cell IL-33 (VillinCre-ERIL33flox/flox)failed to induce ILC2 expansion and host immunity against the hookworm parasite Nippostrongylus brasiliensis, whereas selective loss of cDC-derived IL-33 (CD11cCreIL33flox/flox) abrogated ST2+Foxp3+Treg responses, enhanced TH2 and ILC2 responses, and accelerated worm clearance. Lack of cDC intrinsic IL-33 impaired Foxp3+Treg expansion and anti-IL-2/IL-2 complex administration restored Treg numbers and suppressed worm clearance in CD11cCreIL-33flox/floxmice compared to CD11cCrecontrols. Collectively, this work emphasizes cellular source as a key determinant in the ability of IL-33 to direct pathogen-specific immunity.

Introduction Pathologic accumulation and over-activation of mast cells and eosinophils have been implicated in certain allergic and inflammatory diseases. Siglec-8 is an inhibitory receptor selectively expressed on human eosinophils, mast cells, and, to a significantly lesser extent, basophils. Antibodies to Siglec-8 have the potential to be broadly anti-inflammatory by inducing apoptosis of eosinophils and inhibiting mast cell activation. AK002 is a novel, humanized, non-fucosylated IgG1 monoclonal antibody to Siglec-8. This study examines the ex vivo activity of AK002 on blood and tissue eosinophils and in vivo activity against human mast cells. Methods The apoptosis and antibody-dependent cell-mediated cytotoxicity (ADCC) activity of AK002 or an isotype-matched control antibody was assessed using human blood and tissue eosinophils by flow cytometry. In addition, the activity of a mouse AK002 precursor (mAK002) was tested in a model of IgE-induced systemic and cutaneous anaphylaxis in humanized mice. Results In the presence of peripheral blood NK cells, AK002 demonstrated potent ADCC activity against blood eosinophils. AK002 also directly induced apoptosis of cytokine-activated blood eosinophils. In ex vivo human lung tissue, Siglec-8 expression was found on all tissue eosinophils and AK002 significantly reduced these cells compared to an isotype control. Lastly, mAK002 inhibited passive systemic and cutaneous anaphylaxis in humanized mice, consistent with mast cell inhibition (Figure 1). Conclusions AK002 selectively depletes blood and tissue eosinophils and inhibits IgE-mediated anaphylaxis. AK002 may represent a novel therapeutic agent for patients with eosinophil and mast cell driven inflammatory diseases.