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Chrysolepidomonas gen. Nov. is described for single celled monads with two flagella, a single chloroplast and distinctive canistrate and dendritic states. The Chrysolepidomonas dendrolepidota sp. Nov. is described for the first time. The canistrate scales bear eight "bumps" on the top surface, and the dendritic scales have a tapered base with a quantrifid tip. These organic scales are formed in the golgi apparatus and stored in a scale reservoir is bounded with two sides by the R[SUB1] and R[SUB2] microtubular roots of the basal apparatus. The cyst (= stomatocyst statospore) forms endogenenously by mean of a silica deposition vesicle. The outer cyst surface is, smooth and the pore region is unornamented. Two other organism bearing canistrate and dendritic scales, previously assigned to the genus Sphaleromantis are transferred to the genus Chrysolepidomonas. They are C. anglica sp. Nov. and C. marina (Pienaar) comb. Nov. The distinguishing feature of Chrysolepidomonas and Sphaleromantis are discussed. A new family, Chrysolepidomonadaceae fam. Nov. is described for flagellates covered with organic scales. [ABSTRACT FROM AUTHOR]

The flagellar apparatus of Chrysolepidomonas dendrolepidota Peters et enderson is similar to that of other members of the Ochromonadales, Chrysophyceae. There are four microtubular roots (R[SUB2-4])and a system H fiber(=rhizoplast) the R[SUB1] root consist of three microtubules. One compressed band of 10 or more cytoplasmic microtubules is directed back along the R[SUB1] root is an anti-parallel direction. The R[SUB2] root consist of one to two microtubules and it extends toward the distal end of the R[SUB3] root. The R[SUB3] root consist of six (?seven) microtubules near its proximal end. The "a" and "f" microtubules of the R[SUB3] roots are under the short flagglum, and the "f" microtubule loop back and under the basal body, extending down to the nucleus. The R[SUB4] root consist of one to two microtubules extending along the left side of the short flagellum and carving under the short flagellum where it terminates near the "a" microtubule of the R[SUB3] Both flagella have a transitional plate and a transitional helix with five gyres. There is a thin, second plate in the basal body at the level of the distal end of the "c" tubules of the basal body triplets. The triporlite flageller hairs have long leteral filaments. We compare the flagellar apparatus with that of other member of the Ochromonadales and members of the Hydrurales and Hibberdiales. [ABSTRACT FROM AUTHOR]

The Precision Interventions for Severe and/or Exacerbation-prone Asthma (PrecISE) study is an adaptive platform trial designed to investigate novel interventions to severe asthma. The study is conducted under a master protocol and utilizes a crossover design with each participant receiving up to five interventions and at least one placebo. Treatment assignments are based on the patients' biomarker profiles and precision health methods are incorporated into the interim and final analyses. We describe key elements of the PrecISE study including the multistage adaptive enrichment strategy, early stopping of an intervention for futility, power calculations, and the primary analysis strategy. [ABSTRACT FROM AUTHOR]

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 FcεR1‐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. [ABSTRACT FROM AUTHOR]

Asthma is a heterogeneous syndrome that has been subdivided into physiologic phenotypes and molecular endotypes. The most specific phenotypic manifestation of asthma is indirect airway hyperresponsiveness (AHR), and a prominent molecular endotype is the presence of type 2 inflammation. The underlying basis for type 2 inflammation and its relationship to AHR are incompletely understood. We assessed the expression of type 2 cytokines in the airways of subjects with and without asthma who were extensively characterized for AHR. Using quantitative morphometry of the airway wall, we identified a shift in mast cells from the submucosa to the airway epithelium specifically associated with both type 2 inflammation and indirect AHR. Using ex vivo modeling of primary airway epithelial cells in organotypic coculture with mast cells, we show that epithelial-derived IL-33 uniquely induced type 2 cytokines in mast cells, which regulated the expression of epithelial IL33 in a feed-forward loop. This feed-forward loop was accentuated in epithelial cells derived from subjects with asthma. These results demonstrate that type 2 inflammation and indirect AHR in asthma are related to a shift in mast cell infiltration to the airway epithelium, and that mast cells cooperate with epithelial cells through IL-33 signaling to regulate type 2 inflammation. [ABSTRACT FROM AUTHOR]

Background: We designed an Internet-Based Monitoring Systems (IBS) survey to facilitate monitoring of asthma symptoms and asthma exacerbations in the Severe Asthma Research Program (SARP). Our objective was to evaluate compliance with the IBS survey tool and to explore how data from an IBS tool can inform understanding of asthma phenotypes.Methods: We invited adult subjects in the SARP III cohort (N = 528) to complete a monthly IBS asthma control survey. We compared the characteristics of subjects who did and those who did not participate in the IBS survey tool. Among subjects who participated in the IBS (IBS+), we identified participants with low, medium, and high Asthma Control Test (ACT) score variability, and we explored asthma morbidity in these three participant subgroups.Results: Two hundred fifty-nine subjects participated in the IBS (IBS+) survey. Compared with subjects who did not engage with the IBS (IBS-) survey, IBS+ subjects were older and more likely to be white, college educated, and have an annual household income > $25,000, and have controlled asthma. Among IBS+ participants, the subgroup with the highest ACT score variability was more likely to have severe asthma, with a lower ACT score at baseline and increased asthma-related health-care use (often precipitated by cold and flulike illnesses). Participants with high ACT variability were also characterized by metabolic dysfunction, as evidenced by obesity and hypertension.Conclusions: Active participation with an Internet-based symptom survey tool in patients with severe asthma is influenced by race, socioeconomic status, and asthma control. Among survey participants, a group with highly variable (labile) asthma control is identifiable as a specific subgroup with unmet treatment needs. The association of asthma lability, increased susceptibility to adverse asthma effects of cold and flulike illnesses, and metabolic dysfunction provides clues for potentially effective intervention strategies. [ABSTRACT FROM AUTHOR]

Type 2 inflammation occurs in a large subgroup of asthmatics, and novel cytokine-directed therapies are being developed to treat this population. In mouse models, interleukin-33 (IL-33) activates lung resident innate lymphoid type 2 cells (ILC2s) to initiate airway type 2 inflammation. In human asthma, which is chronic and difficult to model, the role of IL-33 and the target cells responsible for persistent type 2 inflammation remain undefined. Full-length IL-33 is a nuclear protein and may function as an "alarmin" during cell death, a process that is uncommon in chronic stable asthma. We demonstrate a previously unidentified mechanism of IL-33 activity that involves alternative transcript splicing, whichmay operate in stable asthma. In human airway epithelial cells, alternative splicing of the IL-33 transcript is consistently present, and the deletion of exons 3 and 4 (Δ exon 3,4) confers cytoplasmic localization and facilitates extracellular secretion, while retaining signaling capacity. In nonexacerbating asthmatics, the expression of Δ exon 3,4 is strongly associated with airway type 2 inflammation, whereas full-length IL-33 is not. To further define the extracellular role of IL-33 in stable asthma, we sought to determine the cellular targets of its activity. Comprehensive flow cytometry and RNA sequencing of sputum cells suggest basophils and mast cells, not ILC2s, are the cellular sources of type 2 cytokines in chronic asthma. We conclude that IL-33 isoforms activate basophils and mast cells to drive type 2 inflammation in chronic stable asthma, and novel IL-33 inhibitors will need to block all biologically active isoforms. [ABSTRACT FROM AUTHOR]

Some chronic pain syndromes are characterized by episodes of intense burning and hyperalgesia in localized areas of skin. These sensations are thought to be mediated, at least in part, by the activity of damaged, unmyelinated C nociceptors. These phenomena were modeled by assaying responses of macaques to thermal and chemical stimuli that produced periodic activation and sensitization of C nociceptors. Upon validation of this method, a recombinant herpes simplex vector encoding human preproenkephalin was topically applied to the dorsal surface of the feet of the monkeys. Immunohistochemistry and radioimmunoassay revealed that enkephalin peptides were being produced in releasable pools in sensory neurons innervating the treated skin area. Behavioral responses evoked by periodic sensitization and activation of C nociceptors innervating the vector-treated skin area revealed a substantial and long-lasting (at least 20 weeks) antihyperalgesic and analgesic effect limited to the areas to which the virus was applied. This approach may be a viable means of treating localized cutaneous burning pain and hyperalgesia.Molecular Therapy (2006) 13, 589–597; doi: 10.1016/j.ymthe.2005.08.023 [ABSTRACT FROM AUTHOR]