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Loss of SMAD3 Promotes Vascular Remodeling in Pulmonary Arterial Hypertension via MRTF Disinhibition.
RATIONALE: Vascular remodeling in pulmonary arterial hypertension (PAH) results from smooth muscle cell hypertrophy and proliferation of vascular cells. Loss of BMPR-II (bone morphogenetic protein receptor 2) signaling and increased signaling via TGF-β (transforming growth factor β) and its downstream mediators SMAD (small body size [a C. elegans protein] mothers against decapentaplegic [a Drosophila protein family])-2/3 has been proposed to drive lung vascular remodeling; yet, proteomic analyses indicate a loss of SMAD3 in PAH. OBJECTIVES: We proposed that SMAD3 may be dysregulated in PAH and that loss of SMAD3 may present a pathophysiological master switch by disinhibiting its interaction partner, MRTF (myocardin-related transcription factor), which drives muscle protein expression. METHODS: SMAD3 levels were measured in lungs from PAH patients, rats treated either with Sugen/hypoxia or monocrotaline (MCT), and in mice carrying a BMPR2 mutation. In vitro, effects of SMAD3 or BMPR2 silencing or SMAD3 overexpression on cell proliferation or smooth muscle hypertrophy were assessed. In vivo, the therapeutic and prophylactic potential of CCG1423, an inhibitor of MRTF, was investigated in Sugen/hypoxia rats. MEASUREMENTS AND MAIN RESULTS: SMAD3 was downregulated in lungs of patients with PAH and in pulmonary arteries of three independent PAH animal models. TGF-β treatment replicated the loss of SMAD3 in human pulmonary artery smooth muscle cells (huPASMCs) and human pulmonary artery endothelial cells. SMAD3 silencing increased proliferation and migration in huPASMCs and human pulmonary artery endothelial cells. Coimmunoprecipitation revealed reduced interaction of MRTF with SMAD3 in TGF-β-treated huPASMCs and pulmonary arteries of PAH animal models. In huPASMCs, loss of SMAD3 or BMPR-II increased smooth muscle actin expression, which was attenuated by MRTF inhibition. Conversely, SMAD3 overexpression prevented TGF-β-induced activation of an MRTF reporter and reduced actin stress fibers in BMPR2-silenced huPASMCs. MRTF inhibition attenuated PAH and lung vascular remodeling in Sugen/hypoxia rats. CONCLUSIONS: Loss of SMAD3 presents a novel pathomechanism in PAH that promotes vascular cell proliferation and-via MRTF disinhibition-hypertrophy of huPASMCs, thereby reconciling the parallel induction of a synthetic and contractile huPASMC phenotype
Improved X-ray detection and particle identification with avalanche photodiodes
Avalanche photodiodes are commonly used as detectors for low energy x-rays.
In this work we report on a fitting technique used to account for different
detector responses resulting from photo absorption in the various APD layers.
The use of this technique results in an improvement of the energy resolution at
8.2 keV by up to a factor of 2, and corrects the timing information by up to 25
ns to account for space dependent electron drift time. In addition, this
waveform analysis is used for particle identification, e.g. to distinguish
between x-rays and MeV electrons in our experiment.Comment: 6 pages, 6 figure
The proton radius puzzle
High-precision measurements of the proton radius from laser spectroscopy of
muonic hydrogen demonstrated up to six standard deviations smaller values than
obtained from electron-proton scattering and hydrogen spectroscopy. The status
of this discrepancy, which is known as the proton radius puzzle will be
discussed in this paper, complemented with the new insights obtained from
spectroscopy of muonic deuterium.Comment: Moriond 2017 conference, 8 pages, 4 figure
Bronchopulmonary dysplasia: clinical aspects and preventive and therapeutic strategies
Abstract Background Bronchopulmonary dysplasia (BPD) is the result of a complex process in which several prenatal and/or postnatal factors interfere with lower respiratory tract development, leading to a severe, lifelong disease. In this review, what is presently known regarding BPD pathogenesis, its impact on long-term pulmonary morbidity and mortality and the available preventive and therapeutic strategies are discussed. Main body Bronchopulmonary dysplasia is associated with persistent lung impairment later in life, significantly impacting health services because subjects with BPD have, in most cases, frequent respiratory diseases and reductions in quality of life and life expectancy. Prematurity per se is associated with an increased risk of long-term lung problems. However, in children with BPD, impairment of pulmonary structures and function is even greater, although the characterization of long-term outcomes of BPD is difficult because the adults presently available to study have received outdated treatment. Prenatal and postnatal preventive measures are extremely important to reduce the risk of BPD. Conclusion Bronchopulmonary dysplasia is a respiratory condition that presently occurs in preterm neonates and can lead to chronic respiratory problems. Although knowledge about BPD pathogenesis has significantly increased in recent years, not all of the mechanisms that lead to lung damage are completely understood, which explains why therapeutic approaches that are theoretically effective have been only partly satisfactory or useless and, in some cases, potentially negative. However, prevention of prematurity, systematic use of nonaggressive ventilator measures, avoiding supraphysiologic oxygen exposure and administration of surfactant, caffeine and vitamin A can significantly reduce the risk of BPD development. Cell therapy is the most fascinating new measure to address the lung damage due to BPD. It is desirable that ongoing studies yield positive results to definitively solve a major clinical, social and economic problem
Efficient Solution of Large-Scale Saddle Point Systems Arising in Riccati-Based Boundary Feedback Stabilization of Incompressible Stokes Flow
D1-3: Marshfield Dictionary of Clinical and Translational Science (MD-CTS): An Online Reference for Clinical and Translational Science Terminology
Der Inhalt der gesamtgesellschaftlichen Interessen bei der weiteren Gestaltung der entwickelten sozialistischen Gesellschaft ihre sozial-oekonomischen Grundlagen und Hauptformen ihrer Herausbildung
IFR-L 101 / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman