Increased Hematopoietic Extracellular RNAs and Vesicles in the Lung during Allergic Airway Responses.

Extracellular RNAs (exRNAs) can be released by numerous cell types in vitro, are often protected within vesicles, and can modify recipient cell function. To determine how the composition and cellular sources of exRNAs and the extracellular vesicles (EVs) that carry them change in vivo during tissue inflammation, we analyzed bronchoalveolar lavage fluid (BALF) from mice before and after lung allergen challenge. In the lung, extracellular microRNAs (ex-miRNAs) had a composition that was highly correlated with airway-lining epithelium. Using cell type-specific membrane tagging and single vesicle flow, we also found that 80% of detected vesicles were of epithelial origin. After the induction of allergic airway inflammation, miRNAs selectively expressed by immune cells, including miR-223 and miR-142a, increased and hematopoietic-cell-derived EVs also increased >2-fold. These data demonstrate that infiltrating immune cells release ex-miRNAs and EVs in inflamed tissues to alter the local extracellular environment

MicroRNA regulation of type 2 innate lymphoid cell homeostasis and function in allergic inflammation.

MicroRNAs (miRNAs) exert powerful effects on immunity through coordinate regulation of multiple target genes in a wide variety of cells. Type 2 innate lymphoid cells (ILC2s) are tissue sentinel mediators of allergic inflammation. We established the physiological requirements for miRNAs in ILC2 homeostasis and immune function and compared the global miRNA repertoire of resting and activated ILC2s and T helper type 2 (TH2) cells. After exposure to the natural allergen papain, mice selectively lacking the miR-17∼92 cluster in ILC2s displayed reduced lung inflammation. Moreover, miR-17∼92-deficient ILC2s exhibited defective growth and cytokine expression in response to IL-33 and thymic stromal lymphopoietin in vitro. The miR-17∼92 cluster member miR-19a promoted IL-13 and IL-5 production and inhibited expression of several targets, including SOCS1 and A20, signaling inhibitors that limit IL-13 and IL-5 production. These findings establish miRNAs as important regulators of ILC2 biology, reveal overlapping but nonidentical miRNA-regulated gene expression networks in ILC2s and TH2 cells, and reinforce the therapeutic potential of targeting miR-19 to alleviate pathogenic allergic responses

Autotuning Algorithmic Choice for Input Sensitivity

Empirical autotuning is increasingly being used in many domains to achieve optimized performance in a variety of different execution environments. A daunting challenge faced by such autotuners is input sensitivity, where the best autotuned configuration may vary with different input sets. In this paper, we propose a two level solution that: first, clusters to find input sets that are similar in input feature space; then, uses an evolutionary autotuner to build an optimized program for each of these clusters; and, finally, builds an adaptive overhead aware classifier which assigns each input to a specific input optimized program. Our approach addresses the complex trade-off between using expensive features, to accurately characterize an input, and cheaper features, which can be computed with less overhead. Experimental results show that by adapting to different inputs one can obtain up to a 3x speedup over using a single configuration for all inputs

Method of providing a lunar habitat from an external tank

A lunar habitat is provided by placing an external tank of an orbiter in a low Earth orbit where the hydrogen tank is separated from the intertank and oxygen tank which form a base structure. The base structure is then outfitted with an air lock, living quarters, a thermal control system, an environmental control and life support system, and a propulsion system. After the mounting of an outer sheath about the base structure to act as a micrometeoroid shield, the base structure is propelled to a soft landing on the moon. The sheath is mounted at a distance from the base structure to provide a space therebetween which is filled with regolith after landing. Conveniently, a space station is used to outfit the base structure. Various elements of the oxygen tank and intertank are used in outfitting

Human Normal Keratinocytes Express Biologically Functional CD14 and Toll-Like Receptors

Digitalitzat per Artypla

An anti-siglec-8 antibody depletes sputum eosinophils from asthmatic subjects and inhibits lung mast cells

Background Sialic acid-binding immunoglobulin-like lectin (Siglec)-8 is expressed on mast cells and eosinophils, but information about Siglec-8 expression and function in the lung is limited. A humanized antibody, AK002, targeting Siglec-8 is undergoing development for treatment of diseases associated with mast cell and eosinophil-driven inflammation. Objective To characterize Siglec-8 expression in the airway in asthma and determine whether antibodies that target Siglec-8 (S8mAbs) can decrease airway eosinophils in asthma or inhibit lung mast cell activation. Methods Gene expression profiling and flow cytometry were used to characterize Siglec-8 expression in sputum cells from stable asthma. An antibody-dependent cellular cytotoxicity (ADCC) assay was used to determine whether an S8mAb can decrease eosinophils in sputum from asthma patients ex vivo. A mast cell activation assay was used to determine whether an S8mAb can inhibit mast cell activation in human lung tissue ex vivo. Results Gene expression for Siglec-8 is increased in sputum cells in asthma and correlates with gene expression for eosinophils and mast cells. Gene expression for Siglec-8 is inversely and significantly correlated with measures of airflow obstruction in asthma patients. Siglec-8 is prominently expressed on the surface of eosinophils and mast cells in sputum. S8mAbs decrease eosinophils in sputum from patients with asthma and inhibit Fc epsilon R1-activated mast cells in lung tissues. Conclusions and Clinical Relevance Siglec-8 is highly expressed on eosinophils and mast cells in asthmatic sputum and targeting Siglec-8 with an antibody is a plausible strategy to decrease sputum eosinophils and inhibit lung mast cells in asthma