A Role of Myocardin Related Transcription Factor-A (MRTF-A) in Scleroderma Related Fibrosis.

In scleroderma (systemic sclerosis, SSc), persistent activation of myofibroblast leads to severe skin and organ fibrosis resistant to therapy. Increased mechanical stiffness in the involved fibrotic tissues is a hallmark clinical feature and a cause of disabling symptoms. Myocardin Related Transcription Factor-A (MRTF-A) is a transcriptional co-activator that is sequestered in the cytoplasm and translocates to the nucleus under mechanical stress or growth factor stimulation. Our objective was to determine if MRTF-A is activated in the disease microenvironment to produce more extracellular matrix in progressive SSc. Immunohistochemistry studies demonstrate that nuclear translocation of MRTF-A in scleroderma tissues occurs in keratinocytes, endothelial cells, infiltrating inflammatory cells, and dermal fibroblasts, consistent with enhanced signaling in multiple cell lineages exposed to the stiff extracellular matrix. Inhibition of MRTF-A nuclear translocation or knockdown of MRTF-A synthesis abolishes the SSc myofibroblast enhanced basal contractility and synthesis of type I collagen and inhibits the matricellular profibrotic protein, connective tissue growth factor (CCN2/CTGF). In MRTF-A null mice, basal skin and lung stiffness was abnormally reduced and associated with altered fibrillar collagen. MRTF-A has a role in SSc fibrosis acting as a central regulator linking mechanical cues to adverse remodeling of the extracellular matrix

Low field vortex matter in YBCO: an atomic beam magnetic resonance study

We report measurements of the low field structure of the magnetic vortex lattice in an untwinned YBCO single-crystal platelet. Measurements were carried out using a novel atomic beam magnetic resonance (ABMR) technique. For a 10.7 G field applied parallel to the c-axis of the sample, we find a triangular lattice with orientational order extending across the entire sample. We find the triangular lattice to be weakly distorted by the a-b anisotropy of the material and measure a distortion factor, f = 1.16. Model-experiment comparisons determine a penetration depth, lambda_ab = 140 (+-20) nm. The paper includes the first detailed description of the ABMR technique. We discuss both technical details of the experiment and the modeling used to interpret the measurements.Comment: 44 pages, 13 figures, submitted to Phys. Rev. B Revision includes Postscript wrapped figures + minor typo

Atomic Resonance and Scattering

Contains reports on eight research projects.National Science Foundation (Grant PHY83-06273)National Bureau of Standards (Grant NB83-NAHA-4058)National Science Foundation (Grant PHY84-11483)Joint Services Electronics Program (Contract DAAG29-83-K-0003)U.S. Navy - Office of Naval Research (Contract NO0014-79-C-0183)U.S. Navy - Office of Naval Research (Contract N00014-83-K-0695)National Science Foundation (Grant PHY83-07172-A01

miR-155 in the progression of lung fibrosis in systemic sclerosis

Background\ud MicroRNA (miRNA) control key elements of mRNA stability and likely contribute to the dysregulated lung gene expression observed in systemic sclerosis associated interstitial lung disease (SSc-ILD). We analyzed the miRNA gene expression of tissue and cells from patients with SSc-ILD. A chronic lung fibrotic murine model was used.\ud \ud Methods\ud RNA was isolated from lung tissue of 12 patients with SSc-ILD and 5 controls. High-resolution computed tomography (HRCT) was performed at baseline and 2–3 years after treatment. Lung fibroblasts and peripheral blood mononuclear cells (PBMC) were isolated from healthy controls and patients with SSc-ILD. miRNA and mRNA were analyzed by microarray, quantitative polymerase chain reaction, and/or Nanostring; pathway analysis was performed by DNA Intelligent Analysis (DIANA)-miRPath v2.0 software. Wild-type and miR-155 deficient (miR-155ko) mice were exposed to bleomycin.\ud \ud Results\ud Lung miRNA microarray data distinguished patients with SSc-ILD from healthy controls with 185 miRNA differentially expressed (q < 0.25). DIANA-miRPath revealed 57 Kyoto Encyclopedia of Genes and Genomes pathways related to the most dysregulated miRNA. miR-155 and miR-143 were strongly correlated with progression of the HRCT score. Lung fibroblasts only mildly expressed miR-155/miR-21 after several stimuli. miR-155 PBMC expression strongly correlated with lung function tests in SSc-ILD. miR-155ko mice developed milder lung fibrosis, survived longer, and weaker lung induction of several genes after bleomycin exposure compared to wild-type mice.\ud \ud Conclusions\ud miRNA are dysregulated in the lungs and PBMC of patients with SSc-ILD. Based on mRNA-miRNA interaction analysis and pathway tools, miRNA may play a role in the progression of the disease. Our findings suggest that targeting miR-155 might provide a novel therapeutic strategy for SSc-ILD

miR-155 in the progression of lung fibrosis in systemic sclerosis

Background: MicroRNA (miRNA) control key elements of mRNA stability and likely contribute to the dysregulated lung gene expression observed in systemic sclerosis associated interstitial lung disease (SSc-ILD). We analyzed the miRNA gene expression of tissue and cells from patients with SSc-ILD. A chronic lung fibrotic murine model was used. Methods: RNA was isolated from lung tissue of 12 patients with SSc-ILD and 5 controls. High-resolution computed tomography (HRCT) was performed at baseline and 2-3 years after treatment. Lung fibroblasts and peripheral blood mononuclear cells (PBMC) were isolated from healthy controls and patients with SSc-ILD. miRNA and mRNA were analyzed by microarray, quantitative polymerase chain reaction, and/or Nanostring; pathway analysis was performed by DNA Intelligent Analysis (DIANA)-miRPath v2.0 software. Wild-type and miR-155 deficient (miR-155ko) mice were exposed to bleomycin. Results: Lung miRNA microarray data distinguished patients with SSc-ILD from healthy controls with 185 miRNA differentially expressed (q < 0.25). DIANA-miRPath revealed 57 Kyoto Encyclopedia of Genes and Genomes pathways related to the most dysregulated miRNA. miR-155 and miR-143 were strongly correlated with progression of the HRCT score. Lung fibroblasts only mildly expressed miR-155/miR-21 after several stimuli. miR-155 PBMC expression strongly correlated with lung function tests in SSc-ILD. miR-155ko mice developed milder lung fibrosis, survived longer, and weaker lung induction of several genes after bleomycin exposure compared to wild-type mice. Conclusions: miRNA are dysregulated in the lungs and PBMC of patients with SSc-ILD. Based on mRNA-miRNA interaction analysis and pathway tools, miRNA may play a role in the progression of the disease. Our findings suggest that targeting miR-155 might provide a novel therapeutic strategy for SSc-ILD

Atomic Resonance and Scattering

Contains reports on two research projects.National Science Foundation (Grant PHY 87-06560)Joint Services Electronics Program (Contract DAAL03-86-K-O002)U.S. Navy - Office of Naval Research (Contract N00014-83-K-0695)National Science Foundation (Grant PHY 86-05893

Atomic Resonance and Scattering

Contains reports on six research projects.National Science Foundation (Grant PHY 83-06273)U.S. Navy - Office of Naval Research (Contract N00014-79-C-0183)Joint Services Electronics Program (Contract DAALO03-86-K-0002)National Science Foundation (Grant PHY 84-11483)National Science Foundation (Grant PHY 86-05893)National Science Foundation (Grant ECS 84-21392)U.S. Navy - Office of Naval Research (Contract N00014-83-K-0695)National Science Foundation (Grant CHE 84-21392

Atomic Resonance and Scattering

Contains reports on six research projects.National Science Foundation (PHY83-06273)Joint Services Electronics Program (DAAL03-86-K-0002)National Science Foundation (PHY84-11483)U.S. Navy-Office of Naval Research (Grant N00014-79-C-0183)Joint Services Electronics Program (Contract DAAG29-83-K-0003)National Science Foundation (Grant PHY83-07172-A01)U.S. Navy - Office of Naval Research (Grant N00014-83-K-0695)National Science Foundation (Grant CHE84-21392