The Role of Platelet-Derived Growth Factor Signaling in Healing Myocardial Infarcts

ObjectivesThis study sought to examine the role of platelet-derived growth factor (PDGF) signaling in healing myocardial infarcts.BackgroundPlatelet-derived growth factor isoforms exert potent fibrogenic effects through interactions with PDGF receptor (PDGFR)-α and PDGFR-β. In addition, PDGFR-β signaling mediates coating of developing vessels with mural cells, leading to the formation of a mature vasculature. We hypothesized that PDGFR activation may regulate fibrosis and vascular maturation in healing myocardial infarcts.MethodsMice undergoing reperfused infarction protocols were injected daily with a neutralizing anti–PDGFR-β antibody (APB5), an anti-PDGFR-α antibody (APA5), or control immunoglobulin G, and were killed after 7 days of reperfusion.ResultsThe PDGF-B, PDGFR-α, and PDGFR-β mRNA expression was induced in reperfused mouse infarcts. Perivascular cells expressing phosphorylated PDGFR-β were identified in the infarct after 7 days of reperfusion, indicating activation of the PDGF-BB/PDGFR-β pathway. The PDGFR-β blockade resulted in impaired maturation of the infarct vasculature, enhanced capillary density, and formation of dilated uncoated vessels. Defective vascular maturation in antibody-treated mice was associated with increased and prolonged extravasation of red blood cells and monocyte/macrophages, suggesting increased permeability. These defects resulted in decreased collagen content in the healing infarct. In contrast, PDGFR-α inhibition did not affect vascular maturation, but significantly decreased collagen deposition in the infarct.ConclusionsPlatelet-derived growth factor signaling critically regulates postinfarction repair. Both PDGFR-β– and PDGFR-α–mediated pathways promote collagen deposition in the infarct. Activation of PDGF-B/PDGFR-β is also involved in recruitment of mural cells by neovessels, regulating maturation of the infarct vasculature. Acquisition of a mural coat and maturation of the vasculature promotes resolution of inflammation and stabilization of the scar

New Biochemical Insights into the Mechanisms of Pulmonary Arterial Hypertension in Humans

Diagnosis of pulmonary arterial hypertension (PAH) is difficult due to the lack of specific clinical symptoms and biomarkers, especially at early stages. We compared plasma metabolic fingerprints of PAH patients (n = 20) with matched healthy volunteers (n = 20) using, for the first time, untargeted multiplatform metabolomics approach consisting of high-performance liquid and gas chromatography coupled with mass spectrometry. Multivariate statistical analyses were performed to select metabolites that contribute most to groups' classification (21 from liquid in both ionization modes and 9 from gas chromatography-mass spectrometry). We found metabolites related to energy imbalance, such as glycolysis-derived metabolites, as well as metabolites involved in fatty acid, lipid and amino acid metabolism. We observed statistically significant changes in threitol and aminomalonic acid in PAH patients, which could provide new biochemical insights into the pathogenesis of the disease. The results were externally validated on independent case and control cohorts, confirming up to 16 metabolites as statistically significant in the validation study. Multiplatform metabolomics, followed by multivariate chemometric data analysis has a huge potential for explaining pathogenesis of PAH and for searching potential and new more specific and less invasive markers of the disease.This research was supported by the Polish National Science Center (2014/13/N/NZ7/04231), the Spanish Ministry of Economy and Competitiveness (MINECO) (SAF2014-58920R), by the Fondo de Investigacion Sanitaria del Instituto de Salud Carlos III and co-funding by Fondo Europeo de Desarrollo Regional (FEDER) (PI14-01427), and by the quality-promoting subsidy from the Ministry of Science and Higher Education of Poland, Leading National Research Centre (KNOW programme 2012-2017). The CNIC is supported by the Spanish Ministry of Economy and Competitiveness and the Pro-CNIC Foundation, and is a Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.S

Forward Neutron Production at the Fermilab Main Injector

We have measured cross sections for forward neutron production from a variety of targets using proton beams from the Fermilab Main Injector. Measurements were performed for proton beam momenta of 58 GeV/c, 84 GeV/c, and 120 GeV/c. The cross section dependence on the atomic weight (A) of the targets was found to vary as $A^(alpha)$ where $\alpha$ is $0.46\pm0.06$ for a beam momentum of 58 GeV/c and 0.54$\pm$0.05 for 120 GeV/c. The cross sections show reasonable agreement with FLUKA and DPMJET Monte Carlos. Comparisons have also been made with the LAQGSM Monte Carlo.Comment: Accepted for publication in Physical Review D. This version incorporates small changes suggested by referee and small corrections in the neutron production cross sections predicted by FLUK

Comparing large lecture mechanics curricula using the Force Concept Inventory: A five thousand student study

The performance of over 5000 students in introductory calculus-based mechanics courses at the Georgia Institute of Technology was assessed using the Force Concept Inventory (FCI). Results from two different curricula were compared: a traditional mechanics curriculum and the Matter & Interactions (M&I) curriculum. Post-instruction FCI averages were significantly higher for the traditional curriculum than for the M&I curriculum; the differences between curricula persist after accounting for factors such as pre-instruction FCI scores, grade point averages, and SAT scores. FCI performance on categories of items organized by concepts was also compared; traditional averages were significantly higher in each concept. We examined differences in student preparation between the curricula and found that the relative fraction of homework and lecture topics devoted to FCI force and motion concepts correlated with the observed performance differences. Limitations of concept inventories as instruments for evaluating curricular reforms are discussed.Comment: 21 pages, 4 figures, submitted to Am. J. Phys. arXiv admin note: substantial text overlap with arXiv:1112.559

Bactericidal activity of human eosinophilic granulocytes against Escherichia coli

Eosinophils participate in allergic inflammation and may have roles in the bodys defense against helminthic infestation. Even under noninflammatory conditions, eosinophils are present in the mucosa of the large intestine, where large numbers of gram-negative bacteria reside. Therefore, roles for eosinophils in host defenses against bacterial invasion are possible. In a system for bacterial viable counts, the bactericidal activity of eosinophils and the contribution of different cellular antibacterial systems against Escherichia coli were investigated. Eosinophils showed a rapid and efficient killing of E. coli under aerobic conditions, whereas under anaerobic conditions bacterial killing decreased dramatically. In addition, diphenylene iodonium chloride (DPI), an inhibitor of the NADPH oxidase and thereby of superoxide production, also significantly inhibited bacterial killing. The inhibitor of nitric oxide (NO) production L-N5-(1-iminoethyl)-ornithine dihydrochloride did not affect the killing efficiency, suggesting that NO or derivatives thereof are of minor importance under the experimental conditions used. To investigate the involvement of superoxide and eosinophil peroxidase (EPO) in bacterial killing, EPO was blocked by azide. The rate of E. coli killing decreased significantly in the presence of azide, whereas addition of DPI did not further decrease the killing, suggesting that superoxide acts in conjunction with EPO. Bactericidal activity was seen in eosinophil extracts containing granule proteins, indicating that oxygen-independent killing may be of importance as well. The findings suggest that eosinophils can participate in host defense against gram-negative bacterial invasion and that oxygen-dependent killing, i.e., superoxide acting in conjunction with EPO, may be the most important bactericidal effector function of these cells

Plasma Levels of Transforming Growth Factor-β1 Reflect Left Ventricular Remodeling in Aortic Stenosis

Background: TGF-b1 is involved in cardiac remodeling through an auto/paracrine mechanism. The contribution of TGF-b1 from plasmatic source to pressure overload myocardial remodeling has not been analyzed. We investigated, in patients with valvular aortic stenosis (AS), and in mice subjected to transverse aortic arch constriction (TAC), whether plasma TGF-b1 relates with myocardial remodeling, reflected by LV transcriptional adaptations of genes linked to myocardial hypertrophy and fibrosis, and by heart morphology and function. Methodology/Principal Findings: The subjects of the study were: 39 patients operated of AS; 27 healthy volunteers; 12 mice subjected to TAC; and 6 mice sham-operated. Myocardial samples were subjected to quantitative PCR. Plasma TGF-b1 was determined by ELISA. Under pressure overload, TGF-b1 plasma levels were significantly increased both in AS patients and TAC mice. In AS patients, plasma TGF-b1 correlated directly with aortic transvalvular gradients and LV mass surrogate variables, both preoperatively and 1 year after surgery. Plasma TGF-b1 correlated positively with the myocardial expression of genes encoding extracellular matrix (collagens I and III, fibronectin) and sarcomeric (myosin light chain-2, b-myosin heavy chain) remodelling targets of TGF-b1, in TAC mice and in AS patients. Conclusions/Significance: A circulating TGF-b1-mediated mechanism is involved, in both mice and humans, in the excessive deposition of ECM elements and hypertrophic growth of cardiomyocytes under pressure overload. The possible value of plasma TGF-b1 as a marker reflecting preoperative myocardial remodeling status in AS patients deserves further analysis in larger patient cohorts

The Cyst-Theca Relationship Of The Dinoflagellate Cyst Trinovantedinium Pallidifulvum, With Erection Of Protoperidinium Lousianensis Sp Nov And Their Phylogenetic Position Within The Conica Group

We establish the cyst-theca relationship of the dinoflagellate cyst species Trinovantedinium pallidifulvum Matsuoka 1987 based on germination experiments of specimens isolated from the Gulf of Mexico. We show that the motile stage is a new species, designated as Protoperidinium louisianensis. We also determine its phylogenetic position based on single-cell polymerase chain reaction (PCR) of a single cell germinated from the Gulf of Mexico cysts. To further refine the phylogeny, we determined the large subunit (LSU) sequence through single-cell PCR of the cyst Selenopemphix undulata isolated from Brentwood Bay (Saanich Inlet, BC, Canada). The phylogeny shows that P. louisianensis is closest to P. shanghaiense, the motile stage of T. applanatum, and is consistent with the monophyly of the genus Trinovantedinium. Selenopemphix undulata belongs to a different clade than Selenopemphix quanta (alleged cyst of P. conicum), suggesting that the genus Selenopemphix is polyphyletic. Trinovantedinium pallidifulvum is widely distributed with occurrences in the Gulf of Mexico, the North Atlantic, the northeast Pacific and southeast Asia. In addition, we illustrate the two other extant species, Trinovantedinium applanatum and Trinovantedinium variabile, and two morphotypes of Trinovantedinium. Geochemical analyses of the cyst wall of T. pallidifulvum indicate the presence of amide groups in agreement with other heterotrophic dinoflagellate species, although the cyst wall of T. pallidifulvum also includes some unique features

Transforming growth factor β receptor 1 is a new candidate prognostic biomarker after acute myocardial infarction

<p>Abstract</p> <p>Background</p> <p>Prediction of left ventricular (LV) remodeling after acute myocardial infarction (MI) is clinically important and would benefit from the discovery of new biomarkers.</p> <p>Methods</p> <p>Blood samples were obtained upon admission in patients with acute ST-elevation MI who underwent primary percutaneous coronary intervention. Messenger RNA was extracted from whole blood cells. LV function was evaluated by echocardiography at 4-months.</p> <p>Results</p> <p>In a test cohort of 32 MI patients, integrated analysis of microarrays with a network of protein-protein interactions identified subgroups of genes which predicted LV dysfunction (ejection fraction ≤ 40%) with areas under the receiver operating characteristic curve (AUC) above 0.80. Candidate genes included transforming growth factor beta receptor 1 (TGFBR1). In a validation cohort of 115 MI patients, TGBFR1 was up-regulated in patients with LV dysfunction (P < 0.001) and was associated with LV function at 4-months (P = 0.003). TGFBR1 predicted LV function with an AUC of 0.72, while peak levels of troponin T (TnT) provided an AUC of 0.64. Adding TGFBR1 to the prediction of TnT resulted in a net reclassification index of 8.2%. When added to a mixed clinical model including age, gender and time to reperfusion, TGFBR1 reclassified 17.7% of misclassified patients. TGFB1, the ligand of TGFBR1, was also up-regulated in patients with LV dysfunction (P = 0.004), was associated with LV function (P = 0.006), and provided an AUC of 0.66. In the rat MI model induced by permanent coronary ligation, the TGFB1-TGFBR1 axis was activated in the heart and correlated with the extent of remodeling at 2 months.</p> <p>Conclusions</p> <p>We identified TGFBR1 as a new candidate prognostic biomarker after acute MI.</p

Regulation of endothelial cell plasticity by TGF-β

Recent evidence has demonstrated that endothelial cells can have a remarkable plasticity. By a process called Endothelial-to-Mesenchymal Transition (EndMT) endothelial cells convert to a more mesenchymal cell type that can give rise to cells such as fibroblasts, but also bone cells. EndMT is essential during embryonic development and tissue regeneration. Interestingly, it also plays a role in pathological conditions like fibrosis of organs such as the heart and kidney. In addition, EndMT contributes to the generation of cancer associated fibroblasts that are known to influence the tumor-microenvironment favorable for the tumor cells. EndMT is a form of the more widely known and studied Epithelial-to-Mesenchymal Transition (EMT). Like EMT, EndMT can be induced by transforming growth factor (TGF)-β. Indeed many studies have pointed to the important role of TGF-β receptor/Smad signaling and downstream targets, such as Snail transcriptional repressor in EndMT. By selective targeting of TGF-β receptor signaling pathological EndMT may be inhibited for the therapeutic benefit of patients with cancer and fibrosis

(Photo)physical properties of new molecular glasses end-capped with thiophene rings composed of diimide and imine units

New symmetrical arylene bisimide derivatives formed by using electron-donating-electron-accepting systems were synthesized. They consist of a phthalic diimide or naphthalenediimide core and imine linkages and are end-capped with thiophene, bithiophene, and (ethylenedioxy)thiophene units. Moreover, polymers were obtained from a new diamine, N,N′-bis(5- aminonaphthalenyl)naphthalene-1,4,5,8-dicarboximide and 2,5- thiophenedicarboxaldehyde or 2,2′-bithiophene-5,5′-dicarboxaldehyde. The prepared azomethine diimides exhibited glass-forming properties. The obtained compounds emitted blue light with the emission maximum at 470 nm. The value of the absorption coefficient was determined as a function of the photon energy using spectroscopic ellipsometry. All compounds are electrochemically active and undergo reversible electrochemical reduction and irreversible oxidation processes as was found in cyclic voltammetry and differential pulse voltammetry (DPV) studies. They exhibited a low electrochemically (DPV) calculated energy band gap (Eg) from 1.14 to 1.70 eV. The highest occupied molecular orbital and lowest unoccupied molecular orbital levels and Eg were additionally calculated theoretically by density functional theory at the B3LYP/6-31G(d,p) level. The photovoltaic properties of two model compounds as the active layer in organic solar cells in the configuration indium tin oxide/poly(3,4-(ethylenedioxy)thiophene):poly(styrenesulfonate)/active layer/Al under an illumination of 1.3 mW/cm2 were studied. The device comprising poly(3-hexylthiophene) with the compound end-capped with bithiophene rings showed the highest value of Voc (above 1 V). The conversion efficiency of the fabricated solar cell was in the range of 0.69-0.90%