Macrophage-released ADAMTS1 promotes muscle stem cell activation.

Coordinated activation of muscle stem cells (known as satellite cells) is critical for postnatal muscle growth and regeneration. The muscle stem cell niche is central for regulating the activation state of satellite cells, but the specific extracellular signals that coordinate this regulation are poorly understood. Here we show that macrophages at sites of muscle injury induce activation of satellite cells via expression of Adamts1. Overexpression of Adamts1 in macrophages in vivo is sufficient to increase satellite cell activation and improve muscle regeneration in young mice. We demonstrate that NOTCH1 is a target of ADAMTS1 metalloproteinase activity, which reduces Notch signaling, leading to increased satellite cell activation. These results identify Adamts1 as a potent extracellular regulator of satellite cell activation and have significant implications for understanding the regulation of satellite cell activity and regeneration after muscle injury.Satellite cells are crucial for growth and regeneration of skeletal muscle. Here the authors show that in response to muscle injury, macrophages secrete Adamts1, which induces satellite cell activation by modulating Notch1 signaling

Classifying publications from the clinical and translational science award program along the translational research spectrum: a machine learning approach

BACKGROUND: Translational research is a key area of focus of the National Institutes of Health (NIH), as demonstrated by the substantial investment in the Clinical and Translational Science Award (CTSA) program. The goal of the CTSA program is to accelerate the translation of discoveries from the bench to the bedside and into communities. Different classification systems have been used to capture the spectrum of basic to clinical to population health research, with substantial differences in the number of categories and their definitions. Evaluation of the effectiveness of the CTSA program and of translational research in general is hampered by the lack of rigor in these definitions and their application. This study adds rigor to the classification process by creating a checklist to evaluate publications across the translational spectrum and operationalizes these classifications by building machine learning-based text classifiers to categorize these publications. METHODS: Based on collaboratively developed definitions, we created a detailed checklist for categories along the translational spectrum from T0 to T4. We applied the checklist to CTSA-linked publications to construct a set of coded publications for use in training machine learning-based text classifiers to classify publications within these categories. The training sets combined T1/T2 and T3/T4 categories due to low frequency of these publication types compared to the frequency of T0 publications. We then compared classifier performance across different algorithms and feature sets and applied the classifiers to all publications in PubMed indexed to CTSA grants. To validate the algorithm, we manually classified the articles with the top 100 scores from each classifier. RESULTS: The definitions and checklist facilitated classification and resulted in good inter-rater reliability for coding publications for the training set. Very good performance was achieved for the classifiers as represented by the area under the receiver operating curves (AUC), with an AUC of 0.94 for the T0 classifier, 0.84 for T1/T2, and 0.92 for T3/T4. CONCLUSIONS: The combination of definitions agreed upon by five CTSA hubs, a checklist that facilitates more uniform definition interpretation, and algorithms that perform well in classifying publications along the translational spectrum provide a basis for establishing and applying uniform definitions of translational research categories. The classification algorithms allow publication analyses that would not be feasible with manual classification, such as assessing the distribution and trends of publications across the CTSA network and comparing the categories of publications and their citations to assess knowledge transfer across the translational research spectrum

Dynamic Maize Responses to Aphid Feeding Are Revealed by a Time Series of Transcriptomic and Metabolomic Assays

As a response to insect attack, maize (Zea mays) has inducible defenses that involve large changes in gene expression and metabolism. Piercing/sucking insects such as corn leaf aphid (Rhopalosiphum maidis) cause direct damage by acquiring phloem nutrients as well as indirect damage through the transmission of plant viruses. To elucidate the metabolic processes and gene expression changes involved in maize responses to aphid attack, leaves of inbred line B73 were infested with corn leaf aphids for 2 to 96 h. Analysis of infested maize leaves showed two distinct response phases, with the most significant transcriptional and metabolic changes occurring in the first few hours after the initiation of aphid feeding. After 4 d, both gene expression and metabolite profiles of aphid-infested maize reverted to being more similar to those of control plants. Although there was a predominant effect of salicylic acid regulation, gene expression changes also indicated prolonged induction of oxylipins, although not necessarily jasmonic acid, in aphid-infested maize. The role of specific metabolic pathways was confirmed using Dissociator transposon insertions in maize inbred line W22. Mutations in three benzoxazinoid biosynthesis genes, Bx1, Bx2, and Bx6, increased aphid reproduction. In contrast, progeny production was greatly decreased by a transposon insertion in the single W22 homolog of the previously uncharacterized B73 terpene synthases TPS2 and TPS3. Together, these results show that maize leaves shift to implementation of physical and chemical defenses within hours after the initiation of aphid feeding and that the production of specific metabolites can have major effects in maize-aphid interactions.Peer reviewe

Macrophage-released ADAMTS1 promotes muscle stem cell activation.

Coordinated activation of muscle stem cells (known as satellite cells) is critical for postnatal muscle growth and regeneration. The muscle stem cell niche is central for regulating the activation state of satellite cells, but the specific extracellular signals that coordinate this regulation are poorly understood. Here we show that macrophages at sites of muscle injury induce activation of satellite cells via expression of Adamts1. Overexpression of Adamts1 in macrophages in vivo is sufficient to increase satellite cell activation and improve muscle regeneration in young mice. We demonstrate that NOTCH1 is a target of ADAMTS1 metalloproteinase activity, which reduces Notch signaling, leading to increased satellite cell activation. These results identify Adamts1 as a potent extracellular regulator of satellite cell activation and have significant implications for understanding the regulation of satellite cell activity and regeneration after muscle injury.Satellite cells are crucial for growth and regeneration of skeletal muscle. Here the authors show that in response to muscle injury, macrophages secrete Adamts1, which induces satellite cell activation by modulating Notch1 signaling

Hydrogen exchange nuclear magnetic resonance spectroscopy mapping of antibody epitopes on the house dust mite allergen Der p 2.

New strategies for allergen-specific immunotherapy have focused on reducing IgE reactivity of purified recombinant allergens while maintaining T-cell epitopes. Previously, we showed that disrupting the disulfide bonds of the major house dust mite allergen Der p 2 resulted in 10-100-fold less skin test reactivity in mite-allergic subjects but did not change in vitro T-cell proliferative responses. To provide a more complete picture of the antigenic surface of Der p 2, we report here the identification of three epitopes using hydrogen protection nuclear magnetic resonance spectroscopy. The epitopes are defined by monoclonal antibodies that are able to inhibit IgE antibody binding to the allergen. Each monoclonal antibody affected the amide exchange rate of 2-3 continuous residues in different regions of Der p 2. Based on these data, a number of other residues were predicted to belong to each epitope, and this prediction was tested for monoclonal antibody 7A1 by generating alanine point mutants. The results indicate that only a small number of residues within the predicted epitope are functionally important for antibody binding. The molecular definition of these three epitopes will enable us to target limited positions for mutagenesis and to expand our studies of hypoallergenic variants for immunotherapy.</p

Macrophage-released ADAMTS1 promotes muscle stem cell activation

Coordinated activation of muscle stem cells (known as satellite cells) is critical for postnatal muscle growth and regeneration. The muscle stem cell niche is central for regulating the activation state of satellite cells, but the specific extracellular signals that coordinate this regulation are poorly understood. Here we show that macrophages at sites of muscle injury induce activation of satellite cells via expression of Adamts1. Overexpression of Adamts1 in macrophages in vivo is sufficient to increase satellite cell activation and improve muscle regeneration in young mice. We demonstrate that NOTCH1 is a target of ADAMTS1 metalloproteinase activity, which reduces Notch signaling, leading to increased satellite cell activation. These results identify Adamts1 as a potent extracellular regulator of satellite cell activation and have significant implications for understanding the regulation of satellite cell activity and regeneration after muscle injury.Satellite cells are crucial for growth and regeneration of skeletal muscle. Here the authors show that in response to muscle injury, macrophages secrete Adamts1, which induces satellite cell activation by modulating Notch1 signaling

Type 2 Innate Signals Stimulate Fibro/Adipogenic Progenitors to Facilitate Muscle Regeneration

In vertebrates, activation of innate immunity is an early response to injury, implicating it in the regenerative process. However, the mechanisms by which innate signals might regulate stem cell functionality are unknown. Here, we demonstrate that type 2 innate immunity is required for regeneration of skeletal muscle after injury. Muscle damage results in rapid recruitment of eosinophils, which secrete IL-4 to activate the regenerative actions of muscle resident fibro/adipocyte progenitors (FAPs). In FAPs, IL-4/IL-13 signaling serves as a key switch to control their fate and functions. Activation of IL-4/IL-13 signaling promotes proliferation of FAPs to support myogenesis while inhibiting their differentiation into adipocytes. Surprisingly, type 2 cytokine signaling is also required in FAPs, but not in myeloid cells, for rapid clearance of necrotic debris, a process that is necessary for timely and complete regeneration of tissues

A PD‐1highCD4+ T Cell Population With a Cytotoxic Phenotype is Associated With Interstitial Lung Disease in Systemic Sclerosis

Objective T cells contribute to tissue injury in systemic sclerosis (SSc), yet the specific T cell subsets expanded in patients with SSc remain incompletely defined. Here we evaluated specific phenotypes and functions of peripheral helper T (Tph) and follicular helper T (Tfh) cells, which have been implicated in autoantibody production, and assessed their associations with clinical features in a well‐characterized cohort of patients with SSc. Methods Mass cytometry of T cells from peripheral blood mononuclear cells of patients with SSc and controls were evaluated using t‐distributed stochastic neighbor embedding visualization, biaxial gating, and marker expression levels. Findings were validated with flow cytometry and in vitro assays. Results The frequencies of PD‐1highCXCR5+ Tfh cells and PD‐1highCXCR5− Tph cells were similar in patients with SSc and controls. t‐distributed stochastic neighbor embedding visualization (tSNE) revealed distinct populations within the PD‐1highCXCR5− cells distinguished by expression of HLA–DR and inducible costimulator (ICOS). Among PD‐1highCXCR5− cells, only the HLA–DR+ICOS− cell population was expanded in patients with SSc. Cytometric and RNA sequencing analyses indicated that these cells expressed cytotoxic rather than B cell helper features. HLA–DR+ICOS− PD‐1highCXCR5− cells were less potent in inducing B cell plasmablast differentiation and antibody production than comparator T helper cell populations. HLA–DR+ICOS−PD‐1highCXCR5− cells were significantly associated with the presence and severity of interstitial lung disease among patients with SSc. Conclusion Among PD‐1highCXCR5− T cells, a subset of HLA–DR+ICOS− cells with cytotoxic features is specifically expanded in patients with SSc and is significantly associated with interstitial lung disease severity. This potential cytotoxicity appearing in the CD4 T cell population can be evaluated as a prognostic disease biomarker in patients with SSc