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Sample records for activator inhibitor-1 drive

  1. Does plasminogen activator inhibitor-1 drive lymphangiogenesis?

    DEFF Research Database (Denmark)

    Bruyère, Françoise; Melen-Lamalle, Laurence; Blacher, Silvia

    2010-01-01

    The purpose of this study is to explore the function of plasminogen activator inhibitor-1 (PAI-1) during pathological lymphangiogenesis. PAI-1, the main physiological inhibitor of plasminogen activators is involved in pathological angiogenesis at least by controlling extracellular proteolysis...... by mammary carcinoma cell injection or spontaneously appearing in transgenic mice expressing the polyomavirus middle T antigen (PymT) under the control of a mouse mammary tumor virus long-terminal repeat promoter (MMTV-LTR). We also investigated inflammation-related lymphatic vessel recruitment by using two...... as a potential therapeutic target to counteract pathological lymphangiogenesis....

  2. The effects of residual platelets in plasma on plasminogen activator inhibitor-1 and plasminogen activator inhibitor-1-related assays.

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    Marlien Pieters

    Full Text Available Due to controversial evidence in the literature pertaining to the activity of plasminogen activator inhibitor-1 in platelets, we examined the effects of residual platelets present in plasma (a potential pre-analytical variable on various plasminogen activator inhibitor-1 and plasminogen activator inhibitor-1-related assays. Blood samples were collected from 151 individuals and centrifuged at 352 and 1500 g to obtain plasma with varying numbers of platelet. In a follow-up study, blood samples were collected from an additional 23 individuals, from whom platelet-poor (2000 g, platelet-containing (352 g and platelet-rich plasma (200 g were prepared and analysed as fresh-frozen and after five defrost-refreeze cycles (to determine the contribution of in vitro platelet degradation. Plasminogen activator inhibitor-1 activity, plasminogen activator inhibitor-1 antigen, tissue plasminogen activator/plasminogen activator inhibitor-1 complex, plasma clot lysis time, β-thromboglobulin and plasma platelet count were analysed. Platelet α-granule release (plasma β-thromboglobulin showed a significant association with plasminogen activator inhibitor-1 antigen levels but weak associations with plasminogen activator inhibitor-1 activity and a functional marker of fibrinolysis, clot lysis time. Upon dividing the study population into quartiles based on β-thromboglobulin levels, plasminogen activator inhibitor-1 antigen increased significantly across the quartiles while plasminogen activator inhibitor-1 activity and clot lysis time tended to increase in the 4th quartile only. In the follow-up study, plasma plasminogen activator inhibitor-1 antigen was also significantly influenced by platelet count in a concentration-dependent manner. Plasma plasminogen activator inhibitor-1 antigen levels increased further after complete platelet degradation. Residual platelets in plasma significantly influence plasma plasminogen activator inhibitor-1 antigen levels mainly

  3. Early Pregnancy Plasminogen Activator Inhibitor-1 Levels in ...

    African Journals Online (AJOL)

    2016-04-25

    Apr 25, 2016 ... inhibitor-1 (PAI-1) in normal pregnancy and preeclampsia and determined its relationship with disease ... its clinical utility. KEYWORDS: Disease severity, plasminogen activator inhibitor-1, preeclampsia, pregnancy ..... management of early-onset severe hypertensive disorders of pregnancy. Am J Obstet ...

  4. The Glycosylation of Plasminogen Activator Inhibitor-1

    DEFF Research Database (Denmark)

    Skottrup, Peter Durand; Pedersen, Katrine Egelund; Christensen, Anni

    Plasminogen activator inhibitor type-1 (PAI-1) has three potential sites for N-linked glycosylation, including Asn209Tyr210Thr211, Asn265Met266Thr267, and Asn329Glu330Ser331. Using a HEK293 expression system, we have made mutants with Asp or Gln substitutions of the Asn residue in each of these s...

  5. The Glycosylation of Plasminogen Activator Inhibitor-1

    DEFF Research Database (Denmark)

    Skottrup, Peter; Pedersen, Katrine Egelund; Christensen, Anni

    2002-01-01

    spectrometry and monosaccharide composition analysis and compared to that of natural and recombinant PAI-1 from other sources. These results contribute to a structural basis for previous observations of a different functional importance of the N-linked glycosylation at each of the 2 sequences.......Plasminogen activator inhibitor type-1 (PAI-1) has three potential sites for N-linked glycosylation, including Asn209Tyr210Thr211, Asn265Met266Thr267, and Asn329Glu330Ser331. Using a HEK293 expression system, we have made mutants with Asp or Gln substitutions of the Asn residue in each...... of these sequences. Analyses of these mutants for the content of N-acetyl glucosamine showed that Asn209 and Asn265, but not Asn329, are glycosylated, in agreement with previous suggestions made on the basis of X-ray crystal structure analysis of PAI-1 expressed in CHO cells (Xue et al. (1998) Structure 6, 627...

  6. The Glycosylation of Plasminogen Activator Inhibitor-1

    DEFF Research Database (Denmark)

    Skottrup, Peter; Pedersen, Katrine Egelund; Christensen, Anni

    spectrometry and monosaccharide composition analysis and compared to that of natural and recombinant PAI-1 from other sources. These results contribute to a structural basis for previous observations of a different functional importance of the N-linked glycosylation at each of the 2 sequences.......Plasminogen activator inhibitor type-1 (PAI-1) has three potential sites for N-linked glycosylation, including Asn209Tyr210Thr211, Asn265Met266Thr267, and Asn329Glu330Ser331. Using a HEK293 expression system, we have made mutants with Asp or Gln substitutions of the Asn residue in each...... of these sequences. Analyses of these mutants for the content of N-acetyl glucosamine showed that Asn209 and Asn265, but not Asn329, are glycosylated, in agreement with previous suggestions made on the basis of X-ray crystal structure analysis of PAI-1 expressed in CHO cells (Xue et al. (1998) Structure 6, 627...

  7. Biochemical Importance of Glycosylation of Plasminogen Activator Inhibitor-1

    DEFF Research Database (Denmark)

    Gils, Ann; Pedersen, Katrine Egelund; Skottrup, Peter

    2003-01-01

    The serpin plasminogen activator inhibitor-1 (PAI-1) is a potential target for anti-thrombotic and anti-cancer therapy. PAI-1 has 3 potential sites for N-linked glycosylation. We demonstrate here that PAI-1 expressed recombinantly or naturally by human cell lines display a heterogeneous...

  8. Biochemical Importance of Glycosylation of Plasminogen Activator Inhibitor-1

    DEFF Research Database (Denmark)

    Gils, Ann; Pedersen, Katrine Egelund; Skottrup, Peter Durand

    2003-01-01

    The serpin plasminogen activator inhibitor-1 (PAI-1) is a potential target for anti-thrombotic and anti-cancer therapy. PAI-1 has 3 potential sites for N-linked glycosylation. We demonstrate here that PAI-1 expressed recombinantly or naturally by human cell lines display a heterogeneous......-inactivating compounds of potential clinical importance....

  9. Role of plasminogen activator inhibitor-1 in senescence and aging.

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    Eren, Mesut; Boe, Amanda E; Klyachko, Ekaterina A; Vaughan, Douglas E

    2014-09-01

    The average age of the US population continues to increase. Age is the most important determinant of disease and disability in humans, but the fundamental mechanisms of aging remain largely unknown. Many age-related diseases are associated with an impaired fibrinolytic system. Elevated plasminogen activator inhibitor-1 (PAI-1) levels are reported in age-associated clinical conditions including cardiovascular diseases, type 2 diabetes, obesity and inflammation. PAI-1 levels are also elevated in animal models of aging. While the association of PAI-1 with physiological aging is well documented, it is only recently that its critical role in the regulation of aging and senescence has become evident. PAI-1 is synthesized and secreted in senescent cells and contributes directly to the development of senescence by acting downstream of p53 and upstream of insulin-like growth factor binding protein-3. Pharmacologic inhibition or genetic deficiency of PAI-1 was shown to be protective against senescence and the aging-like phenotypes in kl/kl and N(ω)-nitro-l-arginine methyl ester-treated wild-type mice. Further investigation into PAI-1's role in senescence and aging will likely contribute to the prevention and treatment of aging-related pathologies. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

  10. Transgenic overexpression of a stable Plasminogen Activator Inhibitor-1 variant.

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    Fahim, Abigail T; Wang, He; Feng, Jining; Ginsburg, David

    2009-03-01

    Plasminogen Activator Inhibitor-1 (PAI-1) is a member of the Serine Protease Inhibitor (SERPIN) gene family and a key regulator of fibrinolysis. PAI-1 is unique among SERPINs in its spontaneous transition to a latent, inactive state, with a half-life of approximately 2 hours under physiologic conditions. The biologic importance of the PAI-1 transition to latency is unknown. This study aimed to engineer transgenic overexpression of a stable murine PAI-1 variant to examine the physiologic effects in vivo from delayed transition of PAI-1 to latency. Ten independent transgenic lines were generated with expression of a stable PAI-1 variant driven by the hybrid CMV/chicken beta-actin promoter. Plasma PAI-1 levels in the transgenic founders ranged from 3.1+/-0.1 ng/mL to 1268.8+/-717.0 ng/mL. Quantitative PCR analysis in 3 transgenic lines demonstrated elevated PAI-1 mRNA in multiple tissues, with the highest increases observed in liver, brain, heart, and kidney. The fold-increase in PAI-1 mRNA over wild-type ranged from 2-fold to >2000-fold. Immunohistochemistry showed increased PAI-1 in liver, kidney, heart, spleen, and lung. Histologic examination of transgenic mice showed no evidence of thrombosis. The two founders with the highest plasma PAI-1 levels failed to produce any transgenic offspring that survived to weaning, although genotyping of expired pups revealed successful transmission of the transgene. These results suggest that high expression of a stable variant of PAI-1 may be lethal in mice, while more moderate expression is generally well tolerated and produces no apparent thrombosis.

  11. Plasminogen activator inhibitor-1 in the evolution of stroke

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    Jovanović Zagorka B.

    2004-01-01

    Full Text Available Fibrinolytic activity in the acute stroke was examined by monitoring the level of plasminogen activator inhibitor-1 (PAI-1, as one of the indicators of fibrinolytic activity. Given the role of PAI-1 in the processes of atherogenesis and thrombogenesis, plasma PAI-1 level was measured in 59 patients (up to 50 years of age with atherothrombotic stroke (verified by computed tomography scanning or magnetic resonance imaging of brain in the period from 12 to 24 hours (I analysis and 30 days after the onset of stroke (II analysis; then, it was correlated with plasma PAI-1 level in the control group (57 healthy subjects, which was 2.86±0.70 U/ml. It was found that PAI-1 level was significantly higher in the acute stroke (I analysis: PAI-1 =4.10±1.40 U/ml, p<0.001; II analysis: PAI-1 =3.64+0.90 U/ml, p<0.001, while fibrinolytic activity was lower, especially on the first day from the stroke that was not completely increased even after 30 days. There was no difference in PAI-1 levels between the subgroups of patients with infarction and lacunar cerebral ischemia (p>0.05, as well as between females and males (p>0.05. Along with significantly increased fibrinogen level (4.65±1 g/l, in the controls - 2.83±0.64 g/l, p<0.001, significantly higher triglycerides (2.04±0.76 mmol/l, in the controls - 1.38+0.54 mmol/l, p<0.001 and lipoproteins(a (0.405±0.29 g/l, in the controls -0.172±0.14 g/l, p<0.001 were found, correlating with higher plasma PAI-1 level in these patients. The increased plasma level of PAI-1 pointed to possibility of decreased fibrinolytic activity in pathogenesis of ischemie stroke, as well as, risk of reinsult, which had been the greatest after the onset of stroke and declined gradually within several weeks.

  12. Plasminogen activator inhibitor-1, free fatty acids, and insulin resistance in patients with myocardial infarction

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    Gruzdeva O

    2013-08-01

    Full Text Available Olga Gruzdeva, Evgenya Uchasova, Yulia Dyleva, Ekaterina Belik, Ekaterina Shurygina, Olga Barbarash Research Institute for Complex Issues of Cardiovascular Diseases under the Siberian Branch of the Russian Academy of Medical Sciences, Kemerovo, Russian Federation Background: Insulin resistance is known to be a common feature of type 2 diabetes mellitus and is regarded as an important mechanism in the pathogenesis of this disease. The key pathogenetic mechanisms of insulin resistance progression are free fatty acids metabolism impairment and enhanced activity of plasminogen activator inhibitor 1. Both free fatty acids and plasminogen activator inhibitor 1 are recognized as risk factors for coronary heart disease. Methods: The patients were divided into two groups: group 1 included 65 non-diabetic myocardial infarction patients and group 2 enrolled 60 diabetic myocardial infarction patients. The control group consisted of 30 sex- and age-matched volunteers. The concentration of serum free fatty acids, glucose, C-peptide, and insulin were measured on the 1st and 12th days of the study. All the patients had their postprandial glycemia, insulin, and C-peptide concentrations measured 2 hours after a standard carbohydrate breakfast containing 360 kcal (protein 20 g, carbohydrate 57 g, and fat 9 g. Results: Free fatty acids levels in group 1 and in group 2 exceeded the control group values by 7-fold and 11-fold, respectively. Plasminogen activator inhibitor 1 concentration was 2.5-fold higher in group 1 and 4.6-fold higher in group 2 compared to the control group on the 1st day from the myocardial infarction onset. In addition, plasminogen activator inhibitor 1 concentration was significantly reduced in both groups on the 12th day from the myocardial infarction onset; however, it did not achieve the control group values. Conclusion: Increased postprandial glucose level, insulinemia, and elevated levels of free fatty acids and plasminogen activator

  13. PAI-1 (Plasminogen Activator Inhibitor-1) Expression Renders Alternatively Activated Human Macrophages Proteolytically Quiescent.

    Science.gov (United States)

    Hohensinner, Philipp J; Baumgartner, Johanna; Kral-Pointner, Julia B; Uhrin, Pavel; Ebenbauer, Benjamin; Thaler, Barbara; Doberer, Konstantin; Stojkovic, Stefan; Demyanets, Svitlana; Fischer, Michael B; Huber, Kurt; Schabbauer, Gernot; Speidl, Walter S; Wojta, Johann

    2017-10-01

    Macrophages are versatile immune cells capable of polarizing into functional subsets depending on environmental stimulation. In atherosclerotic lesions, proinflammatory polarized macrophages are associated with symptomatic plaques, whereas Th2 (T-helper cell type 2) cytokine-polarized macrophages are inversely related with disease progression. To establish a functional cause for these observations, we analyzed extracellular matrix degradation phenotypes in polarized macrophages. We provide evidence that proinflammatory polarized macrophages rely on membrane-bound proteases including MMP-14 (matrix metalloproteinase-14) and the serine protease uPA (urokinase plasminogen activator) together with its receptor uPAR for extracellular matrix degradation. In contrast, Th2 cytokine alternatively primed macrophages do not show different proteolytic activity in comparison to unpolarized macrophages and lack increased localization of MMP-14 and uPA receptor to the cell membrane. Nonetheless, they express the highest amount of the serine protease uPA. However, uPA activity is blocked by similarly increased expression of its inhibitor PAI-1 (plasminogen activator inhibitor 1). When inhibiting PAI-1 or when analyzing macrophages deficient in PAI-1, Th2 cytokine-polarized macrophages display the same matrix degradation capability as proinflammatory-primed macrophages. Within atherosclerotic lesions, macrophages positive for the alternative activation marker CD206 express high levels of PAI-1. In addition, to test changed tissue remodeling capacities of alternatively activated macrophages, we used a bleomycin lung injury model in mice reconstituted with PAI-1(-/-) bone marrow. These results supported an enhanced remodeling phenotype displayed by increased fibrosis and elevated MMP activity in the lung after PAI-1 loss. We were able to demonstrate matrix degradation dependent on membrane-bound proteases in proinflammatory stimulated macrophages and a forced proteolytical quiescence

  14. Structural insight into inactivation of plasminogen activator inhibitor-1 by a small-molecule antagonist

    DEFF Research Database (Denmark)

    Lin, Zhonghui; Jensen, Jan Kristian; Hong, Zebin

    2013-01-01

    Plasminogen activator inhibitor-1 (PAI-1), a serpin, is the physiological inhibitor of tissue-type and urokinase-type plasminogen activators and thus also an inhibitor of fibrinolysis and tissue remodeling. It is a potential therapeutic target in many pathological conditions, including thrombosis...... of PAI-1 into a substrate for its target proteases and the subsequent slow conversion of PAI-1 into an irreversibly inactivated form. Our work provides structural clues to an understanding of PAI-1 inactivation by small-molecule antagonists and an important step toward the design of drugs targeting PAI-1....

  15. Plasminogen Activator Inhibitor-1 in Cancer: Rationale and Insight for Future Therapeutic Testing.

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    Placencio, Veronica R; DeClerck, Yves A

    2015-08-01

    Despite its function as an inhibitor of urokinase and tissue-type plasminogen activator (PA), PA inhibitor-1 (PAI-1) has a paradoxical protumorigenic role in cancer, promoting angiogenesis and tumor cell survival. In this review, we summarize preclinical evidence in support of the protumorigenic function of PAI-1 that has led to the testing of small-molecule PAI-1 inhibitors, initially developed as antithrombotic agents, in animal models of cancer. The review discusses the challenges and the opportunities that lay ahead to the development of efficacious and nontoxic PAI-1 inhibitors as anticancer agents. ©2015 American Association for Cancer Research.

  16. Plasminogen activator inhibitor-1 polymers, induced by inactivating amphipathic organochemical ligands

    DEFF Research Database (Denmark)

    Pedersen, Katrine E; Einholm, Anja P; Christensen, Anni

    2003-01-01

    Negatively charged organochemical inactivators of the anti-proteolytic activity of plasminogen activator inhibitor-1 (PAI-1) convert it to inactive polymers. As investigated by native gel electrophoresis, the size of the PAI-1 polymers ranged from dimers to multimers of more than 20 units....... As compared with native PAI-1, the polymers exhibited an increased resistance to temperature-induced unfolding. Polymerization was associated with specific changes in patterns of digestion with non-target proteases. During incubation with urokinase-type plasminogen activator, the polymers were slowly...... converted to reactive centre-cleaved monomers, indicating substrate behaviour of the terminal PAI-1 molecules in the polymers. A quadruple mutant of PAI-1 with a retarded rate of latency transition also had a retarded rate of polymerization. Studying a number of serpins by native gel electrophoresis, ligand...

  17. Plasminogen activator inhibitor-1 activity and 4G/5G polymorphism in hemodialysis.

    Science.gov (United States)

    Trimarchi, H; Duboscq, C; Genoud, V; Lombi, F; Muryan, A; Young, P; Schwab, M; Castanon, M; Rodriguez-Reimundes, E; Forrester, M; Pereyra, H; Campolo-Girard, V; Seminario, O; Alonso, M; Kordich, L

    2008-01-01

    Chronic insufficiency alters homeostasis, in part due to endothelial inflammation. Plasminogen activator inhibitor-1 (PAI-1) is increased in renal disease, contributing to vascular damage. We assessed PAI-1 activity and PAI-1 4G/5G polymorphism in hemodialysis (HD) subjects and any association between thrombotic vascular access (VA) events and PAI-1 polymorphism. Prospective, observational study in 36 HD patients: mean age: 66.6 +/- 12.5 yr, males n=26 (72%), time on HD: 28.71 +/- 22.45 months. Vascular accesses: 10 polytetrafluoroethylene grafts (PTFEG), 22 arteriovenous fistulae (AVF), four dual lumen catheters (CAT). Control group (CG): 40 subjects; mean age: 60.0 +/- 15 yrs, males n=30 (75%). Group A (GA): thrombotic events (n=12), and group B (GB): No events (n=24). Groups were no different according to age (69.2 +/- 9.12 vs. 65.3 +/- 14.5 yrs), gender (males: 7; 58.3% vs. 18; 81.8%), time on HD (26.1 +/- 14.7 vs. 30.1 +/- 38.7 months), causes of renal failure. Time to follow-up for access thrombosis: 12 months. PAI-1 levels in HD: 7.21 +/- 2.13 vs. CG: 0.42 +/- 0.27 U/ml (p5G polymorphic variant distribution in HD: 5G/5G: 6 (17%), 4G/5G: 23 (64%); 4G/4G: 7 (19%) and in CG: 5G/5G: 14 (35%); 4G/5G: 18 (45%); 4G/4G: 8 (20%). C-reactive protein (CRP) in HD: 24.5 +/- 15.2 mg/L vs. in CG 2.3 +/- 0.2 mg/L (p5G variants: GA: 5G/5G: 3; 4G/5G: 8; 4G/4G: 1; GB: 5G/5G: 3; 4G/5G: 15; 4G/4G: 6. Thrombosis occurred in 8/10 patients (80%) with PTFEG, 3/22 (9%) in AVF, and 1/4 (25%) in CAT. Among the eight PTFEG patients with thrombosis, seven were PAI 4G/5G. PAI-1 levels were elevated in HD patients, independent of their polymorphic variants, 4G/5G being the most prevalent variant. Our data suggest that in patients with PTFEG the 4G/5G variant might be associated with an increased thrombosis risk.

  18. Plasma plasminogen activator inhibitor-1 predicts myocardial infarction in HIV-1-infected individuals

    DEFF Research Database (Denmark)

    Knudsen, Andreas; Katzenstein, Terese L; Benfield, Thomas

    2014-01-01

    of seven biomarkers with first-time myocardial infarction (MI) in an HIV-1-infected population. DESIGN: A matched case-control study of 54 cases and 54 controls. METHODS: We compared 54 HIV-1-infected patients with verified first-time MI and 54 HIV-1-infected controls matched for age, duration...... of antiretroviral therapy, sex, smoking and no known cardiovascular disease. Levels of high-sensitivity C-reactive protein, soluble endothelial selectin, soluble vascular cell adhesion molecule, soluble intercellular adhesion molecule, matrix metalloprotease 9, myeloperoxidase, and plasminogen activator inhibitor 1...... levels of PAI-1 were associated with risk of first-time MI in HIV-1-infected individuals independently of cardiovascular risk factors, HIV parameters and antiretroviral therapy. Therefore PAI-1 may be used for risk stratification and prediction of CHD, but further studies are needed....

  19. Plasminogen activator inhibitor-1 is elevated in patients with COPD independent of metabolic and cardiovascular function

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    Waschki B

    2017-03-01

    Full Text Available Benjamin Waschki,1–3 Henrik Watz,2,3 Olaf Holz,4,5 Helgo Magnussen,2,3 Beata Olejnicka,6 Tobias Welte,5,7 Klaus F Rabe,1,3 Sabina Janciauskiene5,7 1Pneumology, LungenClinic Grosshansdorf, Grosshansdorf, Germany; 2Pulmonary Research Institute at LungenClinic Grosshansdorf, Grosshansdorf, Germany; 3Airway Research Center North (ARCN, German Center for Lung Research (DZL, Grosshansdorf, Germany; 4Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany; 5Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH, German Center for Lung Research (DZL, Hannover, Germany; 6Department of Medicine, Trelleborg Hospital, Trelleborg, Sweden; 7Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany Introduction: Plasminogen activator inhibitor-1 (PAI-1, a major inhibitor of fibrinolysis, is associated with thrombosis, obesity, insulin resistance, dyslipidemia, and premature aging, which all are coexisting conditions of chronic obstructive pulmonary disease (COPD. The role of PAI-1 in COPD with respect to metabolic and cardiovascular functions is unclear. Methods: In this study, which was nested within a prospective cohort study, the serum levels of PAI-1 were cross-sectionally measured in 74 stable COPD patients (Global Initiative for Chronic Obstructive Lung Disease [GOLD] Stages I–IV and 18 controls without lung disease. In addition, triglycerides, high-density lipoprotein cholesterol, fasting plasma glucose, waist circumference, blood pressure, smoking status, high-sensitive C-reactive protein (hs-CRP, adiponectin, ankle–brachial index, N-terminal pro-B-type natriuretic peptide, and history of comorbidities were also determined. Results: The serum levels of PAI-1 were significantly higher in COPD patients than in controls, independent of a broad spectrum of possible confounders including metabolic and cardiovascular dysfunction. A multivariate regression analysis revealed

  20. Plasminogen Activator Inhibitor-1 Is Critical in Alcohol-Enhanced Acute Lung Injury in Mice.

    Science.gov (United States)

    Poole, Lauren G; Massey, Veronica L; Siow, Deanna L; Torres-Gonzáles, Edilson; Warner, Nikole L; Luyendyk, James P; Ritzenthaler, Jeffrey D; Roman, Jesse; Arteel, Gavin E

    2017-09-01

    Chronic alcohol exposure is a clinically important risk factor for the development of acute respiratory distress syndrome, the most severe form of acute lung injury (ALI). However, the mechanisms by which alcohol sensitizes the lung to development of this disease are poorly understood. We determined the role of the antifibrinolytic protein plasminogen activator inhibitor-1 (PAI-1) in alcohol enhancement of experimental endotoxin-induced ALI. Wild-type, PAI-1-/-, and integrin β3-/- mice were fed ethanol-containing Lieber-DeCarli liquid or a control diet for 6 weeks, followed by systemic LPS challenge. LPS administration triggered coagulation cascade activation as evidenced by increased plasma thrombin-antithrombin levels and pulmonary fibrin deposition. Ethanol-exposed animals showed enhanced PAI-1 expression and pulmonary fibrin deposition with coincident exaggeration of pulmonary inflammatory edematous injury. PAI-1 deficiency markedly reduced pulmonary fibrin deposition and greatly reduced inflammation and injury without impacting upstream coagulation. Interestingly, pulmonary platelet accumulation was effectively abolished by PAI-1 deficiency in ethanol/LPS-challenged mice. Moreover, mice lacking integrin αIIBβ3, the primary platelet receptor for fibrinogen, displayed a dramatic reduction in early inflammatory changes after ethanol/LPS challenge. These results indicate that the mechanism whereby alcohol exaggerates LPS-induced lung injury requires PAI-1-mediated pulmonary fibrin accumulation, and suggest a novel mechanism whereby alcohol contributes to inflammatory ALI by enhancing fibrinogen-platelet engagement.

  1. Plasminogen activator inhibitor 1 and Antipain preserve acrosome integrity of bovine spermatozoa during cryopreservation

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    M.A. Castelo Branco

    Full Text Available ABSTRACT Seminal plasma contains serine proteases and serine protease inhibitor, which are involved in mammalian fertilization, and the inhibitors can be applied to prevent cold-induced sperm capacitation. The effects of different concentrations of two serine protease inhibitors were analyzed, Plasminogen activator inhibitor 1 - PAI-1 (70ƞg, 140ƞg and 210 ƞg and Antipain (10µg, 50µg and 100µg as supplementation to bovine semen cryopreservation extender. The effects of the inhibitors on the sperm parameters (sperm kinetics - CASA, acrosome integrity, plasma membrane integrity, mitochondrial membrane potential, sperm defects and acrosome reaction rate were evaluated in the post-thaw semen. Cryopreservation of sperm with Antipain decreased post-thaw kinetic parameters of MP, VSL, LIN, SRT and the percentage of hyper-activated sperm while PAI-1 (210 ƞg decreased VSL and LIN. Antipain and PAI-1 had no effect on the integrity parameters of the plasma membrane, mitochondrial membrane potential and sperm defects. Sperm cryopreserved in the presence of Antipain and PAI-1 (70 and 140 ƞg preserved acrosome integrity, as they were able to complete the in vitro acrosome reaction. In conclusion, the serine protease inhibitors, Antipain and PAI-1 (70 and 140ƞg are able to preserve the acrosome integrity of cryopreserved bovine sperm.

  2. A specific plasminogen activator inhibitor-1 antagonist derived from inactivated urokinase.

    Science.gov (United States)

    Gong, Lihu; Proulle, Valerie; Fang, Chao; Hong, Zebin; Lin, Zhonghui; Liu, Min; Xue, Guangpu; Yuan, Cai; Lin, Lin; Furie, Barbara; Flaumenhaft, Robert; Andreasen, Peter; Furie, Bruce; Huang, Mingdong

    2016-10-01

    Fibrinolysis is a process responsible for the dissolution of formed thrombi to re-establish blood flow after thrombus formation. Plasminogen activator inhibitor-1 (PAI-1) inhibits urokinase-type and tissue-type plasminogen activator (uPA and tPA) and is the major negative regulator of fibrinolysis. Inhibition of PAI-1 activity prevents thrombosis and accelerates fibrinolysis. However, a specific antagonist of PAI-1 is currently unavailable for therapeutic use. We screened a panel of uPA variants with mutations at and near the active site to maximize their binding to PAI-1 and identified a potent PAI-1 antagonist, PAItrap. PAItrap is the serine protease domain of urokinase containing active-site mutation (S195A) and four additional mutations (G37bR-R217L-C122A-N145Q). PAItrap inhibits human recombinant PAI-1 with high potency (Kd = 0.15 nM) and high specificity. In vitro using human plasma, PAItrap showed significant thrombolytic activity by inhibiting endogenous PAI-1. In addition, PAItrap inhibits both human and murine PAI-1, allowing the evaluation in murine models. In vivo, using a laser-induced thrombosis mouse model in which thrombus formation and fibrinolysis are monitored by intravital microscopy, PAItrap reduced fibrin generation and inhibited platelet accumulation following vascular injury. Therefore, this work demonstrates the feasibility to generate PAI-1 inhibitors using inactivated urokinase. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  3. Different induction of two plasminogen activator inhibitor 1 mRNA species by phorbol ester in human hepatoma cells

    NARCIS (Netherlands)

    Bosma, P.J.; Kooistra, T.

    1991-01-01

    In man, the plasminogen activator inhibitor 1 (PAI-1) gene codes for two mRNA species, one of 3.2 kilobases (kb) and the other of 2.4 kb. We report that the protein kinase C activating phorbol ester, phorbol 12-myristate-13-acetate (PMA), causes a different induction of the two PAI-1 mRNA species in

  4. Plasminogen activator inhibitor-1 and its cofactor vitronectin stabilize arterial thrombi after vascular injury in mice.

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    Konstantinides, S; Schäfer, K; Thinnes, T; Loskutoff, D J

    2001-01-30

    The origin and contribution of plasminogen activator inhibitor-1 (PAI-1) and its cofactor vitronectin (VN) to arterial thrombosis/thrombolysis in vivo is controversial. Ferric chloride was used to induce carotid artery injury in 97 wild-type (WT), 84 PAI-1-/-, and 84 VN-/- mice. Complete thrombotic occlusion was observed in 70% of PAI-1-/- mice versus 92% of WT (P:thrombi were unstable and frequently embolized. As a result, the patency rate of carotid vessels 30 minutes after injury was as high in VN-/- mice (36%) as in PAI-1-/- mice (which demonstrate progressive thrombolysis) and significantly higher than that of WT mice (12%; P:=0.013). Histochemical and reverse transcription-polymerase chain reaction studies revealed an early upregulation of PAI-1 mRNA and protein expression in the thrombus and the vessel wall, which persisted for >/=1 week. VN protein also accumulated after injury, but VN mRNA levels remained low at all times. PAI-1 and VN participate in the thrombotic response to arterial injury by preventing premature thrombus dissolution and embolization. The accumulation of PAI-1 in the thrombus/vessel wall after injury may result, at least in part, from local synthesis, whereas the VN protein appears to be derived from plasma.

  5. Plasminogen Activator Inhibitor-1 Controls Vascular Integrity by Regulating VE-Cadherin Trafficking.

    Directory of Open Access Journals (Sweden)

    Anna E Daniel

    Full Text Available Plasminogen activator inhibitor-1 (PAI-1, a serine protease inhibitor, is expressed and secreted by endothelial cells. Patients with PAI-1 deficiency show a mild to moderate bleeding diathesis, which has been exclusively ascribed to the function of PAI-1 in down-regulating fibrinolysis. We tested the hypothesis that PAI-1 function plays a direct role in controlling vascular integrity and permeability by keeping endothelial cell-cell junctions intact.We utilized PAI-039, a specific small molecule inhibitor of PAI-1, to investigate the role of PAI-1 in protecting endothelial integrity. In vivo inhibition of PAI-1 resulted in vascular leakage from intersegmental vessels and in the hindbrain of zebrafish embryos. In addition PAI-1 inhibition in human umbilical vein endothelial cell (HUVEC monolayers leads to a marked decrease of transendothelial resistance and disrupted endothelial junctions. The total level of the endothelial junction regulator VE-cadherin was reduced, whereas surface VE-cadherin expression was unaltered. Moreover, PAI-1 inhibition reduced the shedding of VE-cadherin. Finally, we detected an accumulation of VE-cadherin at the Golgi apparatus.Our findings indicate that PAI-1 function is important for the maintenance of endothelial monolayer and vascular integrity by controlling VE-cadherin trafficking to and from the plasma membrane. Our data further suggest that therapies using PAI-1 antagonists like PAI-039 ought to be used with caution to avoid disruption of the vessel wall.

  6. Plasminogen activator inhibitor-1 4G/5G polymorphism is associated with type 2 diabetes risk

    Science.gov (United States)

    Zhao, Luqian; Huang, Ping

    2013-01-01

    A number of studies were performed to assess the association between plasminogen activator inhibitor-1 (PAI-1) 4G/5G polymorphism and susceptibility to type 2 diabetes (T2DM). However, the results were inconsistent and inconclusive. In the present study, the possible association was investigated by a meta-analysis. Eligible articles were identified for the period up to June 2013. Pooled odds ratios (OR) with 95% confidence intervals (CI) were appropriately derived from random-effects models or fixed-effects models. Fourteen case-control studies with a total of 2487 cases and 3538 controls were eligible. In recessive model, PAI-1 4G/5G polymorphism was associated with T2DM risk (OR = 1.23; 95% CI 1.07-1.41; P = 0.004). In the subgroup analysis by ethnicity, a significant association was found among Asians (OR = 1.27; 95% CI 1.08-1.51; P = 0.005). This meta-analysis suggested that PAI-1 4G/5G polymorphism may be associated with T2DM development. PMID:24040470

  7. The Plasminogen Activator Inhibitor 1 4G/5G Polymorphism and the Risk of Alzheimer's Disease.

    Science.gov (United States)

    Fekih-Mrissa, Najiba; Mansour, Malek; Sayeh, Aicha; Bedoui, Ines; Mrad, Meriem; Riahi, Anis; Mrissa, Ridha; Nsiri, Brahim

    2017-09-01

    The aim of this study was to determine whether plasminogen activator inhibitor 1 (PAI-1) is associated with the risk of Alzheimer's disease (AD) in Tunisian patients. We analyzed the genotype and allele frequency distribution of the PAI-1 polymorphism in 60 Tunisian patients with AD and 120 healthy controls. The results show a significantly increased risk of AD in carriers of the 4G/4G and 4G/5G genotypes versus the wild-type 5G/5G genotype (4G/4G: 28.33% in patients vs 10.0% in controls; P 5G: 55.0% in patients vs 38.33% in controls; OR = 4.45; P < 10-3). The 4G allele was also more frequently found in patients compared with controls; P < 10-3; OR = 3.07. For all participants and by gender, homozygotic carriers (4G/4G) were at an increased risk of AD over heterozygotes and women were at an increased risk over their male genotype counterparts. The odds ratio for AD among 4G/4G carriers for any group was approximately twice that of heterozygotes in the same group. Women homozygotes ranked highest for AD risk (OR = 20.8) and, in fact, women heterozygotes (OR = 9.03) ranked higher for risk than male homozygotes (OR = 6.12). These preliminary exploratory results should be confirmed in a larger study.

  8. Tumor necrosis factor-alpha regulates plasminogen activator inhibitor-1 in rat testicular peritubular cells.

    Science.gov (United States)

    Le Magueresse-Battistoni, B; Pernod, G; Kolodié, L; Morera, A M; Benahmed, M

    1997-03-01

    We examined the regulation by tumor necrosis factor-alpha (TNF alpha) of plasminogen activator inhibitor-1 (PAI-1) in cultured peritubular cells recovered from 20-day-old rat testes. We demonstrated that TNF alpha in a nanomolar dose range stimulated PAI-1 messenger RNA (mRNA; Northern blots) as well as immunoreactive (Western blots) and bioactive (Stachrom) PAI-1 protein. Induction of PAI-1 mRNA started 4 h after the addition of TNF alpha (2.5-fold increase) and peaked (7-fold increase) after 24 h of treatment. Actinomycin D and cycloheximide inhibited the effects of TNF alpha on PAI-1 mRNA, suggesting that ongoing RNA and protein syntheses were required. The combined actions of transforming growth factor-alpha (TGF alpha), a potent inducer of PAI-1, and TNF alpha on PAI-1 were less than additive, suggesting the activation of some common pathway. TNF alpha action on PAI-1, like that of TGF alpha demonstrated previously, was masked by a preexposure to phorbol myristate acetate (a stimulator of protein kinase C) and strongly reduced by staurosporine (an inhibitor of the protein kinase C). Furthermore, using genistein to inhibit tyrosine kinase activity, we not only blocked the action of TGF alpha on PAI-1 [initiated upon binding to the tyrosine kinase epidermal growth factor/TGF alpha receptor (EGFR)], but also markedly reduced that of TNF alpha. Finally, TNF alpha, at a dose range that stimulated PAI-1, enhanced EGFR mRNA levels and EGF binding. Together, the present findings suggest that some of the biological effects of TNF alpha on PAI-1 might be secondary to de novo synthesis of EGFR. Because TNF alpha probably originates from testicular macrophages, such a regulation of PAI-1 by TNF alpha may occur in the context of physiological interactions between the testis and the immune system.

  9. Enhancing the function of CD34(+ cells by targeting plasminogen activator inhibitor-1.

    Directory of Open Access Journals (Sweden)

    Sugata Hazra

    Full Text Available Previously, we showed that transient inhibition of TGF- β1 resulted in correction of key aspects of diabetes-induced CD34(+ cell dysfunction. In this report, we examine the effect of transient inhibition of plasminogen activator inhibitor-1 (PAI-1, a major gene target of TGF-β1 activation. Using gene array studies, we examined CD34(+ cells isolated from a cohort of longstanding diabetic individuals, free of microvascular complications despite suboptimal glycemic control, and found that the cells exhibited reduced transcripts of both TGF-β1 and PAI-1 compared to age, sex, and degree of glycemic control-matched diabetic individuals with microvascular complications. CD34(+ cells from diabetic subjects with microvascular complications consistently exhibited higher PAI-1 mRNA than age-matched non-diabetic controls. TGF- β1 phosphorodiamidate morpholino oligo (PMO reduced PAI-1 mRNA in diabetic (p<0.01 and non-diabetic (p=0.05 CD34(+ cells. To reduce PAI-1 in human CD34(+ cells, we utilized PAI-1 siRNA, lentivirus expressing PAI-1 shRNA or PAI-1 PMO. We found that inhibition of PAI-1 promoted CD34(+ cell proliferation and migration in vitro, likely through increased PI3(K activity and increased cGMP production. Using a retinal ischemia reperfusion injury model in mice, we observed that recruitment of diabetic CD34(+ cells to injured acellular retinal capillaries was greater after PAI-1-PMO treatment compared with control PMO-treated cells. Targeting PAI-1 offers a promising therapeutic strategy for restoring vascular reparative function in defective diabetic progenitors.

  10. Distal hinge of plasminogen activator inhibitor-1 involves its latency transition and specificities toward serine proteases

    Directory of Open Access Journals (Sweden)

    Shaltiel Shmuel

    2003-07-01

    Full Text Available Abstract Background The plasminogen activator inhibitor-1 (PAI-1 spontaneously converts from an inhibitory into a latent form. Specificity of PAI-1 is mainly determined by its reactive site (Arg346-Met347, which interacts with serine residue of tissue-type plasminogen activator (tPA with concomitant formation of SDS-stable complex. Other sites may also play roles in determining the specificity of PAI-1 toward serine proteases. Results To understand more about the role of distal hinge for PAI-1 specificities towards serine proteases and for its conformational transition, wild type PAI-1 and its mutants were expressed in baculovirus system. WtPAI-1 was found to be about 12 fold more active than the fibrosarcoma PAI-1. Single site mutants within the Asp355-Arg356-Pro357 segment of PAI-1 yield guanidine activatable inhibitors (a that can still form SDS stable complexes with tPA and urokinase plasminogen activator (uPA, and (b that have inhibition rate constants towards plasminogen activators which resemble those of the fibrosarcoma inhibitor. More importantly, latency conversion rate of these mutants was found to be ~3–4 fold faster than that of wtPAI-1. We also tested if Glu351 is important for serine protease specificity. The functional stability of wtPAI-1, Glu351Ala, Glu351Arg was about 18 ± 5, 90 ± 8 and 14 ± 3 minutes, respectively, which correlated well with both their corresponding specific activities (84 ± 15 U/ug, 112 ± 18 U/ug and 68 ± 9 U/ug, respectively and amount of SDS-stable complex formed with tPA after denatured by Guanidine-HCl and dialyzed against 50 mM sodium acetate at 4°C. The second-order rate constants of inhibition for uPA, plasmin and thrombin by Glu351Ala and Glu351Arg were increased about 2–10 folds compared to wtPAI-1, but there was no change for tPA. Conclusion The Asp355-Pro357 segment and Glu351 in distal hinge are involved in maintaining the inhibitory conformation of PAI-1. Glu351 is a specificity

  11. Studies on the mechanism of fibrate-inhibited expression of plasminogen activator inhibitor-1 in cultured hepatocytes from cynomolgus monkey

    NARCIS (Netherlands)

    Arts, J.; Kooistra, T.

    1997-01-01

    Fibrates are widely used drugs in hyperlipidemic disorders. In addition to lowering serum triglyceride levels, fibrates have also been shown to reduce elevated plasma plasminogen activator inhibitor-1 (PAI-1) levels in vivo. We demonstrate that fibrates suppress PAI-1 synthesis in cultured

  12. High-fat diet enhances and plasminogen activator inhibitor-1 deficiency attenuates bone loss in mice with Lewis Lung carcinoma

    Science.gov (United States)

    This study determined the effects of a high-fat diet and plasminogen activator inhibitor-1 deficiency (PAI-1-/-) on bone structure in mice bearing Lewis lung carcinoma (LLC) in lungs. Reduction in bone volume fraction (BV/TV) by 22% and 21%, trabecular number (Tb.N) by 8% and 4% and bone mineral de...

  13. The suicide substrate reaction between plasminogen activator inhibitor 1 acid thrombin is regulated by the cofactors vitronectin and heparin

    NARCIS (Netherlands)

    van Meijer, M.; Smilde, A.; Tans, G.; Nesheim, M. E.; Pannekoek, H.; Horrevoets, A. J.

    1997-01-01

    The interaction of thrombin with plasminogen activator inhibitor 1 (PAI-1) is shown to result in the simultaneous formation of both cleaved PAI-1 and a sodium dodecyl sulfate-stable thrombin-PAI-1 complex. The kinetics of this reaction can be described by a ''suicide substrate'' mechanism that

  14. Plasminogen activator inhibitor-1 is elevated in patients with COPD independent of metabolic and cardiovascular function.

    Science.gov (United States)

    Waschki, Benjamin; Watz, Henrik; Holz, Olaf; Magnussen, Helgo; Olejnicka, Beata; Welte, Tobias; Rabe, Klaus F; Janciauskiene, Sabina

    2017-01-01

    Plasminogen activator inhibitor-1 (PAI-1), a major inhibitor of fibrinolysis, is associated with thrombosis, obesity, insulin resistance, dyslipidemia, and premature aging, which all are coexisting conditions of chronic obstructive pulmonary disease (COPD). The role of PAI-1 in COPD with respect to metabolic and cardiovascular functions is unclear. In this study, which was nested within a prospective cohort study, the serum levels of PAI-1 were cross-sectionally measured in 74 stable COPD patients (Global Initiative for Chronic Obstructive Lung Disease [GOLD] Stages I-IV) and 18 controls without lung disease. In addition, triglycerides, high-density lipoprotein cholesterol, fasting plasma glucose, waist circumference, blood pressure, smoking status, high-sensitive C-reactive protein (hs-CRP), adiponectin, ankle-brachial index, N-terminal pro-B-type natriuretic peptide, and history of comorbidities were also determined. The serum levels of PAI-1 were significantly higher in COPD patients than in controls, independent of a broad spectrum of possible confounders including metabolic and cardiovascular dysfunction. A multivariate regression analysis revealed triglyceride and hs-CRP levels to be the best predictors of PAI-1 within COPD. GOLD Stages II and III remained independently associated with higher PAI-1 levels in a final regression analysis. The data from the present study showed that the serum levels of PAI-1 are higher in patients with COPD and that moderate-to-severe airflow limitation, hypertriglyceridemia, and systemic inflammation are independent predictors of an elevated PAI-1 level. PAI-1 may be a potential biomarker candidate for COPD-specific and extra-pulmonary manifestations.

  15. Genetics of Plasminogen Activator Inhibitor-1 (PAI-1 in a Ghanaian Population.

    Directory of Open Access Journals (Sweden)

    Marquitta J White

    Full Text Available Plasminogen activator inhibitor 1 (PAI-1, a major modulator of the fibrinolytic system, is an important factor in cardiovascular disease (CVD susceptibility and severity. PAI-1 is highly heritable, but the few genes associated with it explain only a small portion of its variation. Studies of PAI-1 typically employ linear regression to estimate the effects of genetic variants on PAI-1 levels, but PAI-1 is not normally distributed, even after transformation. Therefore, alternative statistical methods may provide greater power to identify important genetic variants. Additionally, most genetic studies of PAI-1 have been performed on populations of European descent, limiting the generalizability of their results. We analyzed >30,000 variants for association with PAI-1 in a Ghanaian population, using median regression, a non-parametric alternative to linear regression. Three variants associated with median PAI-1, the most significant of which was in the gene arylsulfatase B (ARSB (p = 1.09 x 10(-7. We also analyzed the upper quartile of PAI-1, the most clinically relevant part of the distribution, and found 19 SNPs significantly associated in this quartile. Of note an association was found in period circadian clock 3 (PER3. Our results reveal novel associations with median and elevated PAI-1 in an understudied population. The lack of overlap between the two analyses indicates that the genetic effects on PAI-1 are not uniform across its distribution. They also provide evidence of the generalizability of the circadian pathway's effect on PAI-1, as a recent meta-analysis performed in Caucasian populations identified another circadian clock gene (ARNTL.

  16. Cilioretinal artery: Vasculogenesis might be promoted by plasminogen activator inhibitor-1 5G allele.

    Science.gov (United States)

    Yilmaz, Sarenur; Ardagil, Aylin; Akalin, Ibrahim; Altinel, Meltem Guzin; Dag, Yasar; Kurum, Esra; Koyun, Efe; Ari Yaylali, Sevil; Bayramlar, Huseyin

    2017-01-01

    Cilioretinal arteries (CAs) represent enlargements of microscopic and early established collaterals formed via vasculogenesis between choroidal and retinal circulations. We aimed to investigate whether genetic tendency to thrombosis due to well-known gene polymorphisms may induce CA vasculogenesis in embryonic life. We assessed plasminogen activator inhibitor-1 (PAI-1) 4G/5G, methylenetetrahydrofolatereductase (MTHFR), FACTOR V LEIDEN and PROTHROMBIN gene polymorphisms on 130 patients [82/48 females/males; Median age: 57 (18-84) with visible CAs and 100 (64/36: female/male; Median age: 55 (19-90)] without visible CAs. Using multiple logistic regression models, we found PAI-1 4G/5G; MTHFR (C677T and A1298C) polymorphisms to have significant effects on the probability of visible CAs, that having at least one 5G allele would increase the odds of having visible cilioretinal artery by 98.4% [Odds ratio: 1984 (95% CI: 1.320-3.000, p = 0.001)], and having at least one MTHFR C677T or A1298C allele would decrease the odds of having visible CAs by approximately 38% (OR = 0.618, 95% CI: 0.394-0.961, p = 0.035) or 44% (OR = 0.558, 95% CI: 0.354-0.871, p = 0.011), respectively. This is the first study to test the existence of significant association between presence of enlarged and visible CAs and genetic factors predisposing to thrombosis, according to the literature. Here we suggest that not only the lack of genetic predisposition to thrombosis by MTHFR gene polymorphisms, but also the PAI-1 5G allele might promote vasculogenesis of CAs.

  17. Is plasminogen activator inhibitor-1 a physiological bottleneck bridging major depressive disorder and cardiovascular disease?

    Science.gov (United States)

    Savoy, C; Van Lieshout, R J; Steiner, M

    2017-04-01

    Major depressive disorder (MDD) is estimated to affect one in twenty people worldwide. MDD is highly comorbid with cardiovascular disease (CVD), itself one of the single largest causes of mortality worldwide. A number of pathological changes observed in MDD are believed to contribute to the development of cardiovascular disease, although no single mechanism has been identified. There are also no biological markers capable of predicting the future risk of developing heart disease in depressed individuals. Plasminogen activator inhibitor-1 (PAI-1) is a prothrombotic plasma protein secreted by endothelial tissue and has long been implicated in CVD. An expanding body of literature has recently implicated it in the pathogenesis of major depressive disorder as well. In this study, we review candidate pathways implicating MDD in CVD and consider how PAI-1 might act as a mediator by which MDD induces CVD development: chiefly through sleep disruption, adiposity, brain-derived neurotrophic factor (BDNF) metabolism, systemic inflammation and hypothalamic-pituitary-adrenal (HPA)-axis dysregulation. As both MDD and CVD are more prevalent in women than in men, and incidence of either condition is dramatically increased during reproductive milestones, we also explore hormonal and sex-specific associations between MDD, PAI-1 and CVD. Of special interest is the role PAI-1 plays in perinatal depression and in cardiovascular complications of pregnancy. Finally, we propose a theoretical model whereby PAI-1 might serve as a useful biomarker for CVD risk in those with depression, and as a potential target for future treatments. © 2016 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.

  18. Expression of plasminogen activator inhibitor-1 in human adipose tissue: a role for TNF-alpha?

    Science.gov (United States)

    Cigolini, M; Tonoli, M; Borgato, L; Frigotto, L; Manzato, F; Zeminian, S; Cardinale, C; Camin, M; Chiaramonte, E; De Sandre, G; Lunardi, C

    1999-03-01

    Elevated plasminogen activator inhibitor-1 (PAI-1) plasma levels, responsible for reduced fibrinolysis, are associated with animal and human obesity and with increased cardiovascular disease. The expression of PAI-1 has been found recently in animal and human adipose tissue. Factors and mechanisms regulating such an expression remain to be elucidated. In omental and/or subcutaneous biopsies from obese non-diabetic patients, incubated in Medium 199, we have confirmed that human adipose tissue expresses PAI-1 protein and mRNA; furthermore we have demonstrated that such an expression is clearly evident also in collagenase isolated human adipocytes and that it is stimulated by incubation itself and enhanced by exogenous human tumor necrosis factor-alpha (h-TNF-alpha). Since human adipose tissue produces TNF-alpha, to further characterize the relationship of PAI-1 to TNF-alpha, human fat biopsies were also incubated with Pentoxifylline (PTX) or Genistein, both known to inhibit endogenous TNF-alpha through different mechanisms. PTX caused a dose-dependent decrease of basal PAI-1 protein release, reaching 80% maximal inhibitory effect at 10(-3)M, the same inhibitory effect caused by Genistein at 100 microg/ml. This was associated to a marked inhibition of PAI-1 mRNA and of endogenous TNF-alpha production. Furthermore, when human fat biopsies were incubated in the presence of polyclonal rabbit neutralizing anti-human TNF-alpha antibody (at a concentration able to inhibit 100 UI/ml human TNF-alpha activity), a modest but significant decrease of the incubation induced expression of PAI-1 mRNA was observed (19.8+/-19.0% decrease, P = 0.04, n = 7). In conclusion, the results of this study demonstrate that PAI-I expression is present in human isolated adipocytes and that it is enhanced in human adipose tissue in vitro by exogenous TNF-alpha. Furthermore our data support the possibility of a main role of endogenous TNF-alpha on human adipose tissue PAI-1 expression. This

  19. Plasminogen activator inhibitor-1 removal using dextran sulphate columns. Evidence of PAI-1 homeostasis.

    LENUS (Irish Health Repository)

    Maher, Vincent M G

    2009-08-01

    Patients with high plasma plasminogen activator inhibitor-1 (PAI-1) antigen levels are prone to develop thrombosis. Lowering PAI-1 levels may offer a therapeutic option and help to better understand PAI-1 metabolism. We examined the effect on plasma PAI-1 levels of LDL-apheresis using dextran sulphate (DS) columns in 12 patients (9 male, 3 female, 49 +\\/- 10 years) with heterozygous familial hypercholesterolaemia and coronary artery disease. One plasma volume equivalent (2.3-4.0 l) was treated during each procedure (at flow rates of 23 +\\/- 2 ml\\/min). Lipids and PAI-1 antigen levels were measured in plasma before and immediately after 19 aphereses (once in 7 patients, twice in 3 patients and three times in 2 patients) and also at 3 and 7 days post apheresis in five of these patients and in the column eluates from 8 of these patients. DS-apheresis reduced plasma cholesterol (50 +\\/- 8%), triglyceride (45 +\\/- 27%), apolipoprotein B (59 +\\/- 10%) and PAI-1 antigen levels from 10.2 +\\/- 5.2 to 6.0 +\\/- 3.1 ng\\/ml (P = 0.005). The PAI-I changes were independent of circadian variation. PAI-I bound to the DS-columns (3.51 +\\/- 1.03 ng\\/ml filtered plasma) and the percent of filtered PAI-1 that was bound correlated inversely (r = -0.81, P < 0.02) with basal PAI-1 levels indicating a high affinity saturable binding process. In four patients, plasma PAI-1 levels post-apheresis were higher than expected based on the amount of PAI-removed by the DS columns. The difference between the expected and actual PAI-1 level post apheresis, reflecting PAI-1 secretion or extracellular redistribution, correlated inversely with basal PAI-1 levels (r = -0.83, P = 0.01). PAI-1 levels returned to baseline pre-apheresis values 7 days post apheresis. PAI-1 antigen may be removed from plasma without adverse effect, resulting temporarily in its extracellular redistribution and restoration to baseline levels over one week. PAI-1 redistribution particularly when baseline pre

  20. Clinicopathological significance of plasminogen activator inhibitor-1 gene polymorphism in breast cancer patients from North West of Iran

    OpenAIRE

    M Younesi; MA Hosseinpour Feizi; N Pouladi

    2016-01-01

    Introduction: A common polymorphism 4G/5G in the promoter region of the Plasminogen activator inhibitor-1 (PAI-1) gene has been reported to influence the expression levels of PAI-1. According to the evidence, progression of breast cancer can be associated with elevated levels of PAI-1, it seems that evaluation of a possible correlation between the polymorphism and clinical status of breast cancer patients is reasonable. Methods: This descriptive-analytical study included 160 unrelated pat...

  1. Heparanase procoagulant activity, factor Xa, and plasminogen activator inhibitor 1 are increased in shift work female nurses.

    Science.gov (United States)

    Nadir, Yona; Saharov, Gleb; Hoffman, Ron; Keren-Politansky, Anat; Tzoran, Inna; Brenner, Benjamin; Shochat, Tamar

    2015-07-01

    Epidemiologic studies indicate on an increased risk of cardiovascular disease and cancer in shift workers, although the underlying mechanism is obscure. Heparanase directly enhances tissue factor (TF) activity leading to increased factor Xa production and subsequent activation of the coagulation system. In the present study, a comparison of coagulation markers among healthy shift working (SW) vs. healthy daytime working (DW) female nurses was performed. Thirty SW and 30 DW female nurses were enrolled. For each of the 60 participants, blood was drawn between 7:00 and 8:00 a.m. and at least 8 h after the last work shift. Plasma was studied for coagulation marker that included TF/heparanase procoagulant activity, TF activity, heparanase procoagulant activity, heparanase level, factor Xa level, plasminogen activator inhibitor 1 (PAI-1), plasminogen, α2-antiplasmin, fibrinogen, global protein C, von Willebrand factor, and D-dimer by chromogenic assays and enzyme-linked immunosorbent assays (ELISAs). Sleep quality was assessed by self-report according to the Pittsburgh Sleep Quality Index. The heparanase procoagulant activity increased by 2-fold and the TF/heparanase procoagulant activity increased by 1.5-fold in SW nurses compared to DW nurses (P cardiovascular and cancer morbidity.

  2. Effect of Plasminogen Activator Inhibitor-1 and Tissue Plasminogen Activator Polymorphisms on Susceptibility to Type 2 Diabetes in Malaysian Subjects

    Directory of Open Access Journals (Sweden)

    Zaid Al-Hamodi

    2012-01-01

    Full Text Available Elevated activity of plasminogen activator inhibitor-1 (PAI-1 and decreased tissue plasminogen activator (tPA activity are considered to be important risk factors for type 2 diabetes mellitus (T2DM and metabolic syndrome (MetS. The aim of this study was to investigate the association of the PAI-1 4G/5G and tPA Alu-repeat I/D polymorphisms with T2DM in Malaysian subjects. Serum insulin, coronary risk panel, plasma glucose, and PAI-1 4G/5G and tPA Alu-repeat I/D polymorphisms were studied in 303 T2DM subjects (227 with MetS and 76 without MetS and 131 normal subjects without diabetes and MetS. Statistical analysis showed that the dominant and additive models of PAI-1 4G/5G polymorphism showed a weak association with T2DM without MetS (OR=2.35, P=0.045; OR=1.67, P=0.058. On the other hand, the recessive model of the tPA Alu-repeat I/D polymorphism showed an association with T2DM with MetS (OR=3.32, P=0.013 whereas the dominant and additive models of the tPA Alu-repeat I/D polymorphism were not associated with T2DM either with or without MetS.

  3. Interactions of plasminogen activator inhibitor-1 with vitronectin involve an extensive binding surface and induce mutual conformational rearrangements

    DEFF Research Database (Denmark)

    Blouse, Grant E; Dupont, Daniel Miotto; Schar, Christine R

    2009-01-01

    that concomitant structural changes occur as well in native vitronectin. Furthermore, we have measured the effect of vitronectin on the rate of insertion of the reactive center loop into beta-sheet A of PAI-1 during reaction with target proteases. With a variety of PAI-1 variants, we observe that both full......-length vitronectin and the SMB domain have protease-specific effects on the rate of loop insertion but that the two exhibit clearly different effects. These results support a model for PAI-1 binding to vitronectin in which the interaction surface extends beyond the region of PAI-1 occupied by the SMB domain......In order to explore early events during the association of plasminogen activator inhibitor-1 (PAI-1) with its cofactor vitronectin, we have applied a robust strategy that combines protein engineering, fluorescence spectroscopy, and rapid reaction kinetics. Fluorescence stopped-flow experiments...

  4. Low-dose spironolactone ameliorates insulin resistance and suppresses elevated plasminogen activator inhibitor-1 during gestational testosterone exposure.

    Science.gov (United States)

    Olatunji, Lawrence A; Usman, Taofeek O; Akinade, Aminat I; Adeyanju, Oluwaseun A; Kim, InKyeom; Soladoye, Ayodele O

    2017-12-01

    Elevated gestational circulating testosterone has been associated with pathological pregnancies that increase the risk of development of cardiometabolic disorder in later life. We hypothesised that gestational testosterone exposure, in late pregnancy, causes glucose deregulation and atherogenic dyslipidaemia that would be accompanied by high plasminogen activator inhibitor-1 (PAI-1). The study also hypothesise that low-dose spironolactone treatment would ameliorate these effects. Pregnant Wistar rats received vehicle, testosterone (0.5 mg/kg; sc), spironolactone (0.5 mg/kg, po) or testosterone and spironolactone daily between gestational days 15 and 19. Gestational testosterone exposure led to increased HOMA-IR, circulating insulin, testosterone, 1-h post-load glucose, atherogenic dyslipidaemia, PLR, PAI-1 and MDA. However, all these effects, except that of circulating testosterone, were ameliorated by spironolactone. These results demonstrate that low-dose spironolactone ameliorates glucose deregulation and atherogenic dyslipidaemia during elevated gestational testosterone exposure, at least in part, by suppressing elevated PAI-1.

  5. Plasminogen activator inhibitor 1: Mechanisms of its synergistic regulation by growth factors

    Energy Technology Data Exchange (ETDEWEB)

    Song, Xiaoling [Iowa State Univ., Ames, IA (United States)

    2010-01-01

    My research is on the synergistic regulation of PAI-1 by EGF and TGF-β. The mechanism of synergistic regulation of PAI-1 by EGF and TGF-β are addressed. Methods are described for effective identification of RNA accessible sites for antisense oligodexoxynucleotides (ODNs) and siRNA. In this study effective AS-ODN sequences for both Lcn2 and Bcl2 were identified by in vitro tiled microarray studies. Our results suggest that hybridization of ODN arrays to a target mRNA under physiological conditions might be used as a rapid and reliable in vitro method to accurately identify targets on mRNA molecules for effective antisense and potential siRNA activity in vivo.

  6. Gastrin stimulates expression of plasminogen activator inhibitor-1 in gastric epithelial cells.

    Science.gov (United States)

    Nørsett, Kristin G; Steele, Islay; Duval, Cedric; Sammut, Stephen J; Murugesan, Senthil V M; Kenny, Susan; Rainbow, Lucille; Dimaline, Rod; Dockray, Graham J; Pritchard, D Mark; Varro, Andrea

    2011-09-01

    Plasminogen activator inhibitor (PAI)-1 is associated with cancer progression, fibrosis and thrombosis. It is expressed in the stomach but the mechanisms controlling its expression there, and its biological role, are uncertain. We sought to define the role of gastrin in regulating PAI-1 expression and to determine the relevance for gastrin-stimulated cell migration and invasion. In gastric biopsies from subjects with elevated plasma gastrin, the abundances of PAI-1, urokinase plasminogen activator (uPA), and uPA receptor (uPAR) mRNAs measured by quantitative PCR were increased compared with subjects with plasma concentrations in the reference range. In patients with hypergastrinemia due to autoimmune chronic atrophic gastritis, there was increased abundance of PAI-1, uPA, and uPAR mRNAs that was reduced by octreotide or antrectomy. Immunohistochemistry revealed localization of PAI-1 to parietal cells and enterochromaffin-like cells in micronodular neuroendocrine tumors in hypergastrinemic subjects. Transcriptional mechanisms were studied by using a PAI-1-luciferase promoter-reporter construct transfected into AGS-G(R) cells. There was time- and concentration-dependent increase of PAI-1-luciferase expression in response to gastrin that was reversed by inhibitors of the PKC and MAPK pathways. In Boyden chamber assays, recombinant PAI-1 inhibited gastrin-stimulated AGS-G(R) cell migration and invasion, and small interfering RNA treatment increased responses to gastrin. We conclude that elevated plasma gastrin concentrations are associated with increased expression of gastric PAI-1, which may act to restrain gastrin-stimulated cell migration and invasion.

  7. Hypoxic regulation of plasminogen activator inhibitor-1 expression in human buccal mucosa fibroblasts stimulated with arecoline.

    Science.gov (United States)

    Tsai, Chung-Hung; Lee, Shiuan-Shinn; Chang, Yu-Chao

    2015-10-01

    Oral submucous fibrosis (OSF) is regarded as a pre-cancerous condition with fibrosis in oral subepithelial connective tissue. Hypoxia-inducible factor (HIF)-1α regulates a wide variety of profibrogenic genes, which are closely associated with tissue fibrosis. The aim of this study was to compare HIF-1α expression in normal buccal mucosa tissues and OSF specimens and further explore the potential mechanisms that may lead to the induction of HIF-1α expression. Twenty-five OSF specimens and six normal buccal mucosa were examined by immunohistochemistry. The expression of HIF-1α from fibroblasts cultured from OSF and normal buccal mucosa was measured by Western blot. Arecoline, a major areca nut alkaloid, was challenged to normal buccal mucosa fibroblasts (BMFs) to elucidate whether HIF-1α expression could affect by arecoline. In addition, the effects of arecoline on plasminogen activator inhibitor (PAI)-1 expression were evaluated in environmental hypoxia. HIF-1α expression was significantly higher in OSF specimens and expressed mainly by fibroblasts, epithelial cells, and inflammatory cells. Fibroblasts derived from OSF were found to exhibit higher HIF-1α protein expression than BMFs (P oral submucosa leading to fibrosis. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  8. CLIF, a novel cycle-like factor, regulates the circadian oscillation of plasminogen activator inhibitor-1 gene expression.

    Science.gov (United States)

    Maemura, K; de la Monte, S M; Chin, M T; Layne, M D; Hsieh, C M; Yet, S F; Perrella, M A; Lee, M E

    2000-11-24

    The onset of myocardial infarction occurs frequently in the early morning, and it may partly result from circadian variation of fibrinolytic activity. Plasminogen activator inhibitor-1 activity shows a circadian oscillation and may account for the morning onset of myocardial infarction. However, the molecular mechanisms regulating this circadian oscillation remain unknown. Recent evidence indicates that basic helix-loop-helix (bHLH)/PAS domain transcription factors play a crucial role in controlling the biological clock that controls circadian rhythm. We isolated a novel bHLH/PAS protein, cycle-like factor (CLIF) from human umbilical vein endothelial cells. CLIF shares high homology with Drosophila CYCLE, one of the essential transcriptional regulators of circadian rhythm. CLIF is expressed in endothelial cells and neurons in the brain, including the suprachiasmatic nucleus, the center of the circadian clock. In endothelial cells, CLIF forms a heterodimer with CLOCK and up-regulates the PAI-1 gene through E-box sites. Furthermore, Period2 and Cryptochrome1, whose expression show a circadian oscillation in peripheral tissues, inhibit the PAI-1 promoter activation by the CLOCK:CLIF heterodimer. These results suggest that CLIF regulates the circadian oscillation of PAI-1 gene expression in endothelial cells. In addition, the results potentially provide a molecular basis for the morning onset of myocardial infarction.

  9. Beta8 integrin binds Rho GDP dissociation inhibitor-1 and activates Rac1 to inhibit mesangial cell myofibroblast differentiation.

    Science.gov (United States)

    Lakhe-Reddy, Sujata; Khan, Shenaz; Konieczkowski, Martha; Jarad, George; Wu, Karen L; Reichardt, Louis F; Takai, Yoshimi; Bruggeman, Leslie A; Wang, Bingcheng; Sedor, John R; Schelling, Jeffrey R

    2006-07-14

    Alpha(v)beta8 integrin expression is restricted primarily to kidney, brain, and placenta. Targeted alpha(v) or beta8 deletion is embryonic lethal due to defective placenta and brain angiogenesis, precluding investigation of kidney alpha(v)beta8 function. We find that kidney beta8 is localized to glomerular mesangial cells, and expression is decreased in mouse models of glomerulosclerosis, suggesting that beta8 regulates normal mesangial cell differentiation. To interrogate beta8 signaling pathways, yeast two-hybrid and co-precipitation studies demonstrated beta8 interaction with Rho guanine nucleotide dissociation inhibitor-1 (GDI). Selective beta8 stimulation enhanced beta8-GDI interaction as well as Rac1 (but not RhoA) activation and lamellipodia formation. Mesangial cells from itgb8-/- mice backcrossed to a genetic background that permitted survival, or gdi-/- mice, which develop glomerulosclerosis, demonstrated RhoA (but not Rac1) activity and alpha-smooth muscle actin assembly, which characterizes mesangial cell myofibroblast transformation in renal disease. To determine whether Rac1 directly modulates RhoA-associated myofibroblast differentiation, mesangial cells were transduced with inhibitory Rac peptide fused to human immunodeficiency virus-Tat, resulting in enhanced alpha-smooth muscle actin organization. We conclude that the beta8 cytosolic tail in mesangial cells organizes a signaling complex that culminates in Rac1 activation to mediate wild-type differentiation, whereas decreased beta8 activation shifts mesangial cells toward a RhoA-dependent myofibroblast phenotype.

  10. Two distinct expression patterns of urokinase, urokinase receptor and plasminogen activator inhibitor-1 in colon cancer liver metastases

    DEFF Research Database (Denmark)

    Illemann, Martin; Bird, Nigel; Majeed, Ali

    2009-01-01

    Metastatic growth and invasion by colon cancer cells in the liver requires the ability of the cancer cells to interact with the new tissue environment. Plasmin(ogen) is activated on cell surfaces by urokinase-type PA (uPA), and is regulated by uPAR and plasminogen activator inhibitor-1 (PAI-1......). To compare the expression patterns of uPA, uPAR and PAI-1 in colon cancer with that in their liver metastases, we analysed matched samples from 14 patients. In all 14 primary colon cancers, we found upregulation of uPAR, uPA mRNA and PAI-1 in primarily stromal cells at the invasive front. In 5 of the 14......, whereas 8 of the remaining 9 showed direct contact between the cancer cells and the liver parenchyma. We conclude that there are 2 distinct patterns of expression of uPAR, uPA and PAI-1 in colon cancer liver metastases and that these correlate closely with 2 morphological growth patterns. These findings...

  11. Impact of the 4G/5G polymorphism in the plasminogen activator inhibitor-1 gene on primary nephrotic syndrome.

    Science.gov (United States)

    Luo, Yuezhong; Wang, Chao; Tu, Haitao

    2014-03-01

    The aim of the present study was to investigate whether the four guanosines (4G)/five guanosines (5G) polymorphism in the gene coding for plasminogen activator inhibitor-1 (PAI-1) affects the clinical features of primary nephrotic syndrome (PNS). A cohort of 200 biopsy-diagnosed PNS patients was studied, with 40 healthy subjects as controls. The PAI-1 gene polymorphism was detected by polymerase chain reaction and DNA sequencing. Associations between the PAI-1 4G/5G polymorphism and clinical features and pathological types of PNS were analyzed. The results indicated that the PAI-1 genotype distribution is significantly different between patients with PNS and healthy controls, with significantly higher numbers of the 4G/4G genotype and lower numbers of the 5G5G genotype detected in PNS patients compared to controls (both P5G genotypes, as well as of the 4G allele. The increased 4G frequency was also detected in patients with minimal change disease (MCD). Significantly increased international normalized ratio (INR) and prolonged activated partial thromboplastin time (APTT) were observed in 4G/4G compared to 5G/5G PNS subjects. The response to steroids was not significantly different among the three genotypes. In conclusion, the 4G allele of the PAI-1 gene appears to be associated with PNS, especially in MN and IgAN patients. These findings suggest that specific targeting may be required for the treatment of PNS patients with the 4G/4G genotype.

  12. Evaluation of 12-Lipoxygenase (12-LOX and Plasminogen Activator Inhibitor 1 (PAI-1 as Prognostic Markers in Prostate Cancer

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    Tomasz Gondek

    2014-01-01

    Full Text Available In carcinoma of prostate, a causative role of platelet 12-lipoxygenase (12-LOX and plasminogen activator inhibitor 1 (PAI-1 for tumor progression has been firmly established in tumor and/or adjacent tissue. Our goal was to investigate if 12-LOX and/or PAI-1 in patient’s plasma could be used to predict outcome of the disease. The study comprised 149 patients (age 70±9 divided into two groups: a study group with carcinoma confirmed by positive biopsy of prostate (n=116 and a reference group (n=33 with benign prostatic hyperplasia (BPH. The following parameters were determined by the laboratory test in plasma or platelet-rich plasma: protein level of 12-LOX, PAI-1, thromboglobulin (TGB, prostate specific antigen (PSA, C-reactive protein (CRP, hemoglobin (HGB, and hematocrit (HCT, as well as red (RBC and white blood cells (WBC, number of platelets (PLT, international normalized ratio of blood clotting (INR, and activated partial thromboplastin time (APTT. The only difference of significance was noticed in the concentration of 12-LOX in platelet rich plasma, which was lower in cancer than in BPH group. Standardization to TGB and platelet count increases the sensitivity of the test that might be used as a biomarker to assess risk for prostate cancer in periodically monitored patients.

  13. Association of Plasminogen Activator Inhibitor-1 (PAI-1 Gene Polymorphisms with Osteoporotic Vertebral Compression Fractures (OVCFs in Postmenopausal Women

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    Jung Oh Kim

    2016-12-01

    Full Text Available Osteoporosis and osteoporotic fractures are strongly associated with mortality and morbidity, both in developing and developed countries. Menopause accelerates bone loss due to estrogen deficiency and age-related linear bone loss. We investigated plasminogen activator inhibitor-1 (PAI-1 gene polymorphisms in postmenopausal women with osteoporotic vertebral compression fractures (OVCFs. In this case-control study, 355 postmenopausal women were genotyped for the presence of PAI-1 gene polymorphisms −844A > G, −675 4G > 5G, 43G > A, 9785A > G, and 11053T > G. Genetic polymorphisms of PAI-1 were analyzed by the polymerization chain reaction restriction fragment length polymorphism assay, and their association with disease status and folate and homocysteine levels was determined in 158 OVCF patients and 197 control subjects. The PAI-1 −675 5G5G (adjusted odds ratio (AOR, 3.302; p = 0.017 and 43GA + AA (AOR, 2.087; p = 0.042 genotype frequencies showed significant association with the increased prevalence of OVCFs in postmenopausal women. In addition, we performed gene–environment interaction studies and demonstrated an association between PAI-1 gene polymorphisms and OVCF prevalence. Our novel finding is the identification of several PAI-1 genetic variants that increase susceptibility to OVCF. Our findings suggest that polymorphisms in PAI-1 may contribute to OVCF, and that they can be developed as biomarkers for evaluating OVCF risk.

  14. Metabolic factors, adipose tissue, and plasminogen activator inhibitor-1 levels in type 2 diabetes: findings from the look AHEAD study.

    Science.gov (United States)

    Belalcazar, L Maria; Ballantyne, Christie M; Lang, Wei; Haffner, Steven M; Rushing, Julia; Schwenke, Dawn C; Pi-Sunyer, F Xavier; Tracy, Russell P

    2011-07-01

    Plasminogen activator inhibitor-1 (PAI-1) production by adipose tissue is increased in obesity, and its circulating levels are high in type 2 diabetes. PAI-1 increases cardiovascular risk by favoring clot stability, interfering with vascular remodeling, or both. We investigated in obese diabetic persons whether an intensive lifestyle intervention for weight loss (ILI) would decrease PAI-1 levels independently of weight loss and whether PAI-1 reduction would be associated with changes in fibrinogen, an acute phase reactant, or fibrin fragment D-dimer (D-dimer), a marker of ambient coagulation balance. We examined 1-year changes in PAI-1, D-dimer, and fibrinogen levels; adiposity; fitness; glucose; and lipid control with ILI in 1817 participants from Look AHEAD, a randomized trial investigating the effects of ILI, compared with usual care, on cardiovascular events in overweight or obese diabetic persons. Median PAI-1 levels decreased 29% with ILI and 2.5% with usual care (P < 0.0001). Improvements in fitness, glucose control, and high-density lipoprotein cholesterol were associated with decreased PAI-1, independently of weight loss (P = 0.03 for fitness, P < 0.0001 for others). Fibrinogen and D-dimer remained unchanged. Reductions in PAI-1 levels with ILI in obese diabetic individuals may reflect an improvement in adipose tissue health that could affect cardiovascular risk without changing fibrinogen or d-dimer levels. Clinical Trial Registration- URL: http://clinicaltrials.gov/ct2/show/NCT00017953. Unique identifier: NCT00017953.

  15. Plasminogen Activator Inhibitor-1 (PAI-1) gene 4G/5G alleles frequency distribution in the Lebanese population.

    Science.gov (United States)

    Shammaa, Dina M R; Sabbagh, Amira S; Taher, Ali T; Zaatari, Ghazi S; Mahfouz, Rami A R

    2008-09-01

    Plasminogen activator inhibitor-1 (PAI-1) is an inhibitor of fibrinolysis. Increased plasma PAI-1 levels play an essential role in the pathogenesis of cardiovascular risk and other diseases associated with thrombosis. The 4G/5G polymorphism of the PAI-1 promoter region has been extensively studied in different populations. We studied 160 healthy unrelated Lebanese individuals using a reverse hybridization PCR assay to detect the 5G/5G, 4G/5G and, 4G/4G genotypes of the PAI-1 gene and the frequencies of the 4G and 5G alleles. We found that 4G/5G genotype was the most prevalent (45.6%) followed by 5G/5G (36.9%) and 4G/4G (17.5%). The frequencies of the 4G and 5G alleles were calculated to be 0.403 and 0.597, respectively. Compared to other ethnic communities, the Lebanese population was found to harbour a relatively high prevalence of the rare 4G allele. This, in turn, may predispose this population to develop cardiovascular diseases and other thrombotic clinical conditions. This study aids to enhance our understanding of the genetic features of the Lebanese population.

  16. Meta-analysis of the association between plasminogen activator inhibitor-1 4G/5G polymorphism and recurrent pregnancy loss.

    Science.gov (United States)

    Li, Xuejiao; Liu, Yukun; Zhang, Rui; Tan, Jianping; Chen, Libin; Liu, Yinglin

    2015-04-11

    The association between plasminogen activator inhibitor-1 (PAI-1) 4G/5G polymorphism and recurrent pregnancy loss (RPL) risk is still contradictory. We thus performed a meta-analysis. Relevant studies were searched for in PubMed, Web of Science, Embase, and Cochrane Library. An odds ratio (OR) with a 95% confidence interval (CI) was used to assess the association between PAI-1 4G/5G polymorphism and RPL risk. A total of 22 studies with 4306 cases and 3076 controls were included in this meta-analysis. We found that PAI-1 4G/5G polymorphism was significantly associated with an increased RPL risk (OR=1.89; 95% CI 1.34-2.67; P=0.0003). In the subgroup analysis by race, PAI-1 4G/5G polymorphism was significantly associated with an increased RPL risk in Caucasians (OR=2.23; 95% CI 1.44-3.46; P=0.0003). However, no significant association was observed in Asians (OR=1.47; 95% CI 0.84-2.59; P=0.18). In conclusion, this meta-analysis suggests that PAI-1 4G/5G polymorphism might be associated with RPL development in Caucasians.

  17. Clinicopathological significance of plasminogen activator inhibitor-1 gene polymorphism in breast cancer patients from North West of Iran

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    M Younesi

    2016-06-01

    Full Text Available Introduction: A common polymorphism 4G/5G in the promoter region of the Plasminogen activator inhibitor-1 (PAI-1 gene has been reported to influence the expression levels of PAI-1. According to the evidence, progression of breast cancer can be associated with elevated levels of PAI-1, it seems that evaluation of a possible correlation between the polymorphism and clinical status of breast cancer patients is reasonable. Methods: This descriptive-analytical study included 160 unrelated patients from North West of Iran. According to established clinical criteria, these paitients were diagnosed with breast cancer. Based on previous study, PAI-1 4G/5G had been determined. In order to investigate the association of this polymorphism with clinicopathological features Fisher’s exact tests and SPSS software was used with a significance level of 0.05. Results: All declared features of breast cancer regarding PAI-1 4G/5G polymorphism were investigated. Results indicated that PAI-1 4G/5G polymorphism positive correlation with several traditional prognostic factors, including tumor size, lymph node metastases and tumor stage. Conclusion: Data showed that the patients with 5G/5G genotype are more susceptible to the development of breast cancer, while the paitients with 4G/4G and 4G/5G genotypes show lower sensitivity to the breast cancer. Therefore, the 4G allele likely has a protective role against the development of breast cancer in this cohort.

  18. Myocardial Production of Plasminogen Activator Inhibitor-1 is Associated with Coronary Endothelial and Ventricular Dysfunction after Acute Myocardial Infarction.

    Science.gov (United States)

    Shimizu, Takuya; Uematsu, Manabu; Yoshizaki, Toru; Obata, Jun-Ei; Nakamura, Takamitsu; Fujioka, Daisuke; Watanabe, Kazuhiro; Watanabe, Yosuke; Kugiyama, Kiyotaka

    2016-05-02

    Although plasminogen activator inhibitor-1 (PAI-1) is abundantly expressed in infarcted myocardium, the pathogenic role of myocardial PAI-1 remains unknown. This study examined whether PAI-1 in the infarcted lesion contributes to coronary endothelial dysfunction and left ventricular (LV) dysfunction in patients with acute myocardial infarction (AMI). Plasma levels of PAI-1 activity and tissue-plasminogen activator (tPA) antigen were measured 2 weeks and 6 months after MI by ELISA in plasma obtained from the aortic root (AO) and anterior interventricular vein (AIV) in 28 patients with a first AMI due to occlusion of the left anterior descending coronary artery (LAD). Coronary blood flow responses in LAD to intracoronary infusion of acetylcholine (ACh) and left ventriculography were measured at the same time points: 2 weeks and 6 months after MI. The trans-myocardial gradient of PAI-1 from AO to AIV, reflecting production/release of PAI-1 in the infarcted lesion, was inversely correlated with the coronary blood flow response to ACh 6 months after MI (r=-0.43, p=0.02) and with the percentage change in LV regional motion in the LAD territory from 2 weeks to 6 months after MI (r=-0.38, p=0.04). The trans-myocardial gradient of tPA level showed no significant correlations. PAI-1 produced in the infarcted myocardium and released into the coronary circulation is associated with endothelial dysfunction in resistance vessels of the infarct-related coronary arteries and with progressive dysfunction of the infarcted region of the left ventricle in AMI survivors.

  19. Truncated Plasminogen Activator Inhibitor-1 Protein Protects From Pulmonary Fibrosis Mediated by Irradiation in a Murine Model

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    Chung, Eun Joo; McKay-Corkum, Grace; Chung, Su; White, Ayla; Scroggins, Bradley T. [Radiation Oncology, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland (United States); Mitchell, James B. [Radiation Biology Branches, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland (United States); Mulligan-Kehoe, Mary Jo [Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire (United States); Citrin, Deborah, E-mail: citrind@mail.nih.gov [Radiation Oncology, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland (United States)

    2016-04-01

    Purpose: To determine whether the delivery of recombinant truncated plasminogen activator inhibitor-1 (PAI-1) protein (rPAI-1{sub 23}) would protect from the development of radiation-induced lung injury. Methods and Materials: C57Bl/6 mice received intraperitoneal injections of rPAI-1{sub 23} (5.4 μg/kg/d) or vehicle for 18 weeks, beginning 2 days before irradiation (IR) (5 daily fractions of 6 Gy). Cohorts of mice were followed for survival (n=8 per treatment) and tissue collection (n=3 per treatment and time point). Fibrosis in lung was assessed with Masson-Trichrome staining and measurement of hydroxyproline content. Senescence was assessed with staining for β-galactosidase activity in lung and primary pneumocytes. Results: Hydroxyproline content in irradiated lung was significantly reduced in mice that received rPAI-1{sub 23} compared with mice that received vehicle (IR+vehicle: 84.97 μg/lung; IR+rPAI-1{sub 23}: 56.2 μg/lung, P=.001). C57Bl/6 mice exposed to IR+vehicle had dense foci of subpleural fibrosis at 19 weeks, whereas the lungs of mice exposed to IR+rPAI-1{sub 23} were largely devoid of fibrotic foci. Cellular senescence was significantly decreased by rPAI-1{sub 23} treatment in primary pneumocyte cultures and in lung at multiple time points after IR. Conclusions: These studies identify that rPAI-1{sub 23} is capable of preventing radiation-induced fibrosis in murine lungs. These antifibrotic effects are associated with increased fibrin metabolism, enhanced matrix metalloproteinase-3 expression, and reduced senescence in type 2 pneumocytes. Thus, rPAI-1{sub 23} is a novel therapeutic option for radiation-induced fibrosis.

  20. Effects of a high-fat diet on spontaneous metastasis of Lewis lung carcinoma in plasminogen activator inhibitor-1 deficient and wild-type mice

    Science.gov (United States)

    We investigated the effects of plasminogen activator inhibitor-1 (PAI-1) deficiency on spontaneous metastasis of Lewis lung carcinoma (LLC) in PAI-1 deficient (PAI-1-/-) and wildtype mice (C57BL/6J background) fed the AIN93G diet or that diet modified with 45% calories from fat. The high-fat diet i...

  1. High-fat Diet Enhances and Plasminogen Activator Inhibitor-1 Deficiency Attenuates Bone Loss in Mice with Lewis Lung Carcinoma.

    Science.gov (United States)

    Yan, Lin; Nielsen, Forrest H; Sundaram, Sneha; Cao, Jay

    2015-07-01

    This study determined the effects of a high-fat diet and plasminogen activator inhibitor-1 deficiency (Pai1(-/-)) on the bone structure in male C57BL/6 mice bearing Lewis lung carcinoma (LLC) in lungs. Significant reduction in bone volume fraction (BV/TV), trabecular number (Tb.N) and bone mineral density (BMD) in femurs and vertebrae were found in LLC-bearing mice compared to non-tumor-bearing mice. In LLC-bearing mice, the high-fat diet compared to the AIN93G control diet significantly reduced BV/TV, Tb.N and BMD in femurs and BV/TV in vertebrae. The high-fat diet significantly reduced BMD in vertebrae in wild-type mice but not in Pai1(-/-) mice. Compared to wild-type mice, PAI1 deficiency significantly increased BV/TV and Tb.N in femurs. The plasma concentration of osteocalcin was significantly lower and that of tartrate-resistant acid phosphatase 5b (TRAP5b) was significantly higher in LLC-bearing mice. The high-fat diet significantly reduced plasma osteocalcin and increased TRAP5b. Deficiency in PAI1 prevented the high-fat diet-induced increases in plasma TRAP5b. These findings demonstrate that a high-fat diet enhances, whereas PAI1 deficiency, attenuates metastasis-associated bone loss, indicating that a high-fat diet and PAI1 contribute to metastasis-associated bone deterioration. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  2. Plasminogen Activator Inhibitor-1 Antagonist TM5484 Attenuates Demyelination and Axonal Degeneration in a Mice Model of Multiple Sclerosis.

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    Nicolas Pelisch

    Full Text Available Multiple sclerosis (MS is characterized by inflammatory demyelination and deposition of fibrinogen in the central nervous system (CNS. Elevated levels of a critical inhibitor of the mammalian fibrinolitic system, plasminogen activator inhibitor 1 (PAI-1 have been demonstrated in human and animal models of MS. In experimental studies that resemble neuroinflammatory disease, PAI-1 deficient mice display preserved neurological structure and function compared to wild type mice, suggesting a link between the fibrinolytic pathway and MS. We previously identified a series of PAI-1 inhibitors on the basis of the 3-dimensional structure of PAI-1 and on virtual screening. These compounds have been reported to provide a number of in vitro and in vivo benefits but none was tested in CNS disease models because of their limited capacity to penetrate the blood-brain barrier (BBB. The existing candidates were therefore optimized to obtain CNS-penetrant compounds. We performed an in vitro screening using a model of BBB and were able to identify a novel, low molecular PAI-1 inhibitor, TM5484, with the highest penetration ratio among all other candidates. Next, we tested the effects on inflammation and demyelination in an experimental allergic encephalomyelitis mice model. Results were compared to either fingolimod or 6α-methylprednisolone. Oral administration of TM5484 from the onset of signs, ameliorates paralysis, attenuated demyelination, and axonal degeneration in the spinal cord of mice. Furthermore, it modulated the expression of brain-derived neurotrophic factor, which plays a protective role in neurons against various pathological insults, and choline acetyltransferase, a marker of neuronal density. Taken together, these results demonstrate the potential benefits of a novel PAI-1 inhibitor, TM5484, in the treatment of MS.

  3. On the role of plasminogen activator inhibitor-1 in adipose tissue development and insulin resistance in mice.

    Science.gov (United States)

    Lijnen, H R; Alessi, M-C; Van Hoef, B; Collen, D; Juhan-Vague, I

    2005-06-01

    To investigate the role of plasminogen activator inhibitor-1 (PAI-1) in adipose tissue development and insulin metabolism. Aged male wild-type (WT) or transgenic mice with adipose tissue overexpression of PAI-1 (45-55 weeks) in 50% C57Bl/6: 50% Friend Virus B-strain (FVB) genetic background, kept on normal chow, were used without or with administration of a synthetic low molecular weight PAI-1 inhibitor (PAI-039) to the food (1 mg g(-1)) for 4 weeks. The PAI-1 transgenic mice showed somewhat lower body weight and adipose tissue mass than WT mice, whereas fasting insulin levels were higher. Glucose and insulin tolerance tests did not reveal significant differences between both genotypes. Addition of PAI-039 to the food did not significantly affect total body fat, weight of the isolated s.c. and gonadal fat territories or their adipocyte size and blood vessel composition in either genotype. Fasting glucose levels and glucose tolerance tests were, for both genotypes, comparable with those without inhibitor treatment. Insulin levels and insulin tolerance tests in WT, but not in PAI-1 transgenic mice, suggested a higher insulin sensitivity after inhibitor treatment (insulin level 30 min after glucose injection of 2.0 +/- 0.17 ng mL(-1) vs. 3.2 +/- 0.48 ng mL(-1) without inhibitor treatment; P = 0.028). In this model, overexpression of PAI-1 moderately impaired adipose tissue formation without affecting glucose or insulin tolerance. Administration of a synthetic PAI-1 inhibitor for 4 weeks did not affect adipose tissue development in WT or PAI-1 transgenic mice, but induced a higher insulin sensitivity in WT mice.

  4. Plasminogen activator inhibitor-1 5G/5G genotype is a protecting factor preventing posttransplant diabetes mellitus.

    Science.gov (United States)

    Chang, Horng-Rong; Yang, Shun-Fa; Tsai, Jen-Pi; Hsieh, Ming-Chia; Wu, Sheng-Wen; Tsai, Hui-Ching; Hung, Tung-Wei; Huang, Jun-Huang; Lian, Jong-Da

    2011-01-30

    Plasminogen activator inhibitor 1 (PAI-1) is thought to play a role in the pathogenesis of obesity and insulin resistance. A connection between gestational diabetes mellitus and the functional -675 PAI-1 genotype has been reported. Therefore, we examined the role of the PAI-1 gene polymorphism in kidney transplant recipients. A total of 376 kidney transplant recipients were prospectively screened for posttransplant diabetes mellitus (PTDM). Eighty-one (21.5%) patients were diagnosed with PTDM and the other 295 patients were non-diabetic following kidney transplantation. DNA samples were isolated from the sera and analyzed for the functional -675 4G/5G promoter polymorphisms of the PAI-1 gene. Kidney transplant recipients with PTDM were significantly associated with tacrolimus use (p=0.03), older age (p=0.036), and higher body mass index (p=0.001). The genotype distribution was significantly different between the patients with PTDM (genotype 4G/4G:4G/5G:5G/5G=33.3%:60.5%:6.2%) and those without PTDM (genotype 4G/4G:4G/5G:5G/5G=36.9%:44.1%:19.0%) (p=0.018). Patients with homozygosity for 5G had a significantly lower rate of PTDM (aOR, 0.286, p=0.022) and higher cumulative event-free probability of time to PTDM (log rank test, p=0.0058). Homozygosity for the 5G allele of the PAI-1 gene constitutes a protecting factor for the development of PTDM. Our findings are similar to a previous study on gestational diabetes mellitus, and strongly support a possible genetic role of PAI-1 in the development of PTDM. Copyright © 2010 Elsevier B.V. All rights reserved.

  5. Plasminogen activator inhibitor-1 4G/5G polymorphism and ischemic stroke risk: a meta-analysis in Chinese population.

    Science.gov (United States)

    Cao, Yuezhou; Chen, Weixian; Qian, Yun; Zeng, Yanying; Liu, Wenhua

    2014-12-01

    The guanosine insertion/deletion polymorphism (4G/5G) of plasminogen activator inhibitor-1 (PAI-1) gene has been suggested as a risk factor for ischemic stroke (IS), but direct evidence from genetic association studies remains inconclusive even in Chinese population. Therefore, we performed a meta-analysis to evaluate this association. All of the relevant studies were identified from PubMed, Embase, Chinese National Knowledge Infrastructure database and Chinese Wanfang database up to September 2013. Statistical analyses were conducted with Revman 5.2 and STATA 12.0 software. Odds ratio (OR) with 95% confidence interval (CI) values were applied to evaluate the strength of the association. Heterogeneity was evaluated by Q-test and the I² statistic. The Begg's test and Egger's test were used to assess the publication bias. A significant association and a borderline association between the PAI-1 4G/5G polymorphism and IS were found under the recessive model (OR = 1.639, 95% CI = 1.136-2.364) and allelic model (OR = 1.256, 95% CI = 1.000-1.578), respectively. However, no significant association was observed under homogeneous comparison model (OR = 1.428, 95% CI = 0.914-2.233), heterogeneous comparison model (OR = 0.856, 95% CI = 0.689-1.063) and dominant model (OR = 1.036, 95% CI = 0.846-1.270). This meta-analysis suggested that 4G4G genotype of PAI-1 4G/5G polymorphism might be a risk factor for IS in the Chinese population.

  6. Association of plasminogen activator inhibitor-1 and angiotensin converting enzyme polymorphisms with recurrent pregnancy loss in Iranian women

    Directory of Open Access Journals (Sweden)

    Fatemeh Shakarami

    2015-10-01

    Full Text Available Background: Recurrent pregnancy loss (RPL defined by two or more failed pregnancies before 20 weeks of gestation. Several factors play a role in RPL including thrombophilic conditions which can be influenced by gene polymorphisms. Plasminogen activator inhibitor-1 (PAI-1 and angiotensin converting enzyme (ACE genes are closely related to fibrinolytic process, embryonic development and pregnancy success. Objective: The aim of this study was to investigate the relationship between RPL and common polymorphisms in ACE and PAI-1 genes. Materials and Methods: In this case control study, 100 women with recurrent abortions (at least two were selected as cases and 100 healthy women with two or more normal term deliveries without a history of abortion as controls. Total genomic DNA was isolated from blood leukocytes. The status of the PAI-1 4G/5G and ACE (D/I polymorphism was determined by PCR-RFLP. Results: Homozygosity for PAI-1 4G polymorphism was seen in 17 cases (17%, and 5 controls (5% (p=0.006 so patients with homozygote 4G mutation were significantly more prone to RPL in contrast to control group (OR: 4.63, % 95 CI: 1.55-13.84. In addition, 7 patients (7 %, and no one from the control group, were homozygote (I/I for ACE polymorphism (p=0.034, suggesting no significant associations between ACE D allele or DD genotype and RPL. Conclusion: Considering these results, because 4G/4G polymorphism for PAI-1 gene could be a thrombophilic variant leading to abortion, analysis of this mutation and other susceptibility factors are recommended in patients with RPL.

  7. Overexpression of SERBP1 (Plasminogen activator inhibitor 1 RNA binding protein in human breast cancer is correlated with favourable prognosis

    Directory of Open Access Journals (Sweden)

    Serce Nuran Bektas

    2012-12-01

    Full Text Available Abstract Background Plasminogen activator inhibitor 1 (PAI-1 overexpression is an important prognostic and predictive biomarker in human breast cancer. SERBP1, a protein that is supposed to regulate the stability of PAI-1 mRNA, may play a role in gynaecological cancers as well, since upregulation of SERBP1 was described in ovarian cancer recently. This is the first study to present a systematic characterisation of SERBP1 expression in human breast cancer and normal breast tissue at both the mRNA and the protein level. Methods Using semiquantitative realtime PCR we analysed SERBP1 expression in different normal human tissues (n = 25, and in matched pairs of normal (n = 7 and cancerous breast tissues (n = 7. SERBP1 protein expression was analysed in two independent cohorts on tissue microarrays (TMAs, an initial evaluation set, consisting of 193 breast carcinomas and 48 normal breast tissues, and a second large validation set, consisting of 605 breast carcinomas. In addition, a collection of benign (n = 2 and malignant (n = 6 mammary cell lines as well as breast carcinoma lysates (n = 16 were investigated for SERBP1 expression by Western blot analysis. Furthermore, applying non-radioisotopic in situ hybridisation a subset of normal (n = 10 and cancerous (n = 10 breast tissue specimens from the initial TMA were analysed for SERBP1 mRNA expression. Results SERBP1 is not differentially expressed in breast carcinoma compared to normal breast tissue, both at the RNA and protein level. However, recurrence-free survival analysis showed a significant correlation (P = 0.008 between abundant SERBP1 expression in breast carcinoma and favourable prognosis. Interestingly, overall survival analysis also displayed a tendency (P = 0.09 towards favourable prognosis when SERBP1 was overexpressed in breast cancer. Conclusions The RNA-binding protein SERBP1 is abundantly expressed in human breast cancer and may represent a

  8. A regulatory hydrophobic area in the flexible joint region of plasminogen activator inhibitor-1, defined with fluorescent activity-neutralizing ligands. Ligand-induced serpin polymerization

    DEFF Research Database (Denmark)

    Egelund, R; Einholm, A P; Pedersen, K E

    2001-01-01

    We have characterized the neutralization of the inhibitory activity of the serpin plasminogen activator inhibitor-1 (PAI-1) by a number of structurally distinct organochemicals, including compounds with environment-sensitive spectroscopic properties. In contrast to latent and reactive center...... by all tested nonfluorescent neutralizers, indicating that all neutralizers bind to a common hydrophobic area preferentially accessible in active PAI-1. Activity neutralization proceeded through two consecutive steps as follows: first step is conversion to forms displaying substrate behavior toward u......-cleaved PAI-1 and PAI-1 in complex with urokinase-type plasminogen activator (uPA), active PAI-1 strongly increased the fluorescence of the PAI-1-neutralizing compounds 1-anilinonaphthalene-8-sulfonic acid and 4,4'-dianilino-1,1'-bisnaphthyl-5,5'-disulfonic acid. The fluorescence increase could be competed...

  9. Plasminogen activator inhibitor-1 4G/5G polymorphism and retinopathy risk in type 2 diabetes: a meta-analysis.

    Science.gov (United States)

    Zhang, Tengyue; Pang, Chong; Li, Ningdong; Zhou, Elaine; Zhao, Kanxing

    2013-01-02

    Mounting evidence has suggested that plasminogen activator inhibitor-1 (PAI-1) is a candidate for increased risk of diabetic retinopathy. Studies have reported that insertion/deletion polymorphism in the PAI-1 gene may influence the risk of this disease. To comprehensively address this issue, we performed a meta-analysis to evaluate the association of PAI-1 4G/5G polymorphism with diabetic retinopathy in type 2 diabetes. Data were retrieved in a systematic manner and analyzed using Review Manager and STATA Statistical Software. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of associations. Nine studies with 1, 217 cases and 1, 459 controls were included. Allelic and genotypic comparisons between cases and controls were evaluated. Overall analysis suggests a marginal association of the 4G/5G polymorphism with diabetic retinopathy (for 4G versus 5G: OR 1.13, 95%CI 1.01 to 1.26; for 4G/4G versus 5G/5G: OR 1.30, 95%CI 1.04 to 1.64; for 4G/4G versus 5G/5G + 4G/5G: OR 1.26, 95%CI 1.05 to 1.52). In subgroup analysis by ethnicity, we found an association among the Caucasian population (for 4G versus 5G: OR 1.14, 95% CI 1.00 to 1.30; for 4G/4G versus 5G/5G: OR 1.33, 95%CI 1.02 to 1.74; for 4G/4G versus 5G/5G + 4G/5G: OR 1.41, 95%CI 1.13 to 1.77). When stratified by the average duration of diabetes, patients with diabetes histories longer than 10 years have an elevated susceptibility to diabetic retinopathy than those with shorter histories (for 4G/4G versus 5G/5G: OR 1.47, 95%CI 1.08 to 2.00). We also detected a higher risk in hospital-based studies (for 4G/4G versus 5G/5G+4G/5G: OR 1.27, 95%CI 1.02 to 1.57). The present meta-analysis suggested that 4G/5G polymorphism in the PAI-1 gene potentially increased the risk of diabetic retinopathy in type 2 diabetes and showed a discrepancy in different ethnicities. A higher susceptibility in patients with longer duration of diabetes (more than 10 years) indicated a gene

  10. Plasminogen activator inhibitor-1 (PAI-1 and urokinase plasminogen activator (uPA in sputum of allergic asthma patients.

    Directory of Open Access Journals (Sweden)

    Sebastian Zukowski

    2008-06-01

    Full Text Available Urokinase plasminogen activator (uPA and its inhibitor (PAI-1 have been associated with asthma. The aim of this study was to evaluate concentration of uPA and PAI-1 in induced sputum of house dust mite allergic asthmatics (HDM-AAs. The study was performed on 19 HDM-AAs and 8 healthy nonatopic controls (HCs. Concentration of uPA and PAI-1 was evaluated in induced sputum supernatants using ELISA method. In HDM-AAs the median sputum concentration of uPA (128 pg/ml; 95% CI 99 to 183 pg/ml and PAI-1 (4063 pg/ml; 95%CI 3319 to 4784 pg/ml were significantly greater than in HCs (17 pg/ml; 95%CI 12 to 32 pg/ml; p<0.001 and 626 pg/ml; 95%CI 357 to 961 pg/ml; p<0.001 for uPA and PAI-1 respectively. The sputum concentration of uPA correlated with sputum total cell count (r=0.781; p=0.0001 and with logarithmically transformed exhaled nitric oxide concentration (eNO (r=0.486; p=0.035 but not with FEV1 or bronchial reactivity to histamine. On the contrary, the sputum PAI-1 concentration correlated with FEV1 (r=-0,718; p=0.0005 and bronchial reactivity to histamine expressed as log(PC20 (r=-0.824; p<0.0001 but did not correlate with sputum total cell count or eNO. The results of this study support previous observations linking PAI-1 with airway remodeling and uPA with cellular inflammation. Moreover, the observed effect of uPA seems to be independent of its fibrynolytic activity.

  11. Hydrogen/Deuterium Exchange Mass Spectrometry Reveals Specific Changes in the Local Flexibility of Plasminogen Activator Inhibitor 1 upon Binding to the Somatomedin B Domain of Vitronectin

    DEFF Research Database (Denmark)

    Trelle, Morten Beck; Hirschberg, Daniel; Jansson, Anna

    2012-01-01

    The native fold of plasminogen activator inhibitor 1 (PAI-1) represents an active metastable conformation that spontaneously converts to an inactive latent form. Binding of the somatomedin B domain (SMB) of the endogenous cofactor vitronectin to PAI-1 delays the transition to the latent state...... and increases the thermal stability of the protein dramatically. We have used hydrogen/deuterium exchange mass spectrometry to assess the inherent structural flexibility of PAI-1 and to monitor the changes induced by SMB binding. Our data show that the PAI-1 core consisting of β-sheet B is rather protected...

  12. The association between the 4G/5G polymorphism in the promoter of the plasminogen activator inhibitor-1 gene and extension of postsurgical calf vein thrombosis.

    Science.gov (United States)

    Ferrara, Filippo; Meli, Francesco; Raimondi, Francesco; Montalto, Salvatore; Cospite, Valentina; Novo, Giuseppina; Novo, Salvatore

    2013-04-01

    The objective of this study was to evaluate whether the presence of a plasminogen activator inhibitor type 1 (PAI-1) promoter polymorphism 4G/5G could significantly influence the proximal extension of vein thrombosis in spite of anticoagulant treatment in patients with calf vein thrombosis (CVT) following orthopaedic, urological and abdominal surgery. We studied 168 patients with CVT, who had undergone orthopaedic, urological and abdominal surgery, subdivided as follows: first, 50 patients with thrombosis progression; second, 118 patients without thrombosis progression. The 4G/5G polymorphism of the plasminogen activator inhibitor 1 was evaluated in all patients and in 70 healthy matched controls. We also studied PAI-1 activity in plasma. The presence of 4G/5G genotype was significantly increased in the group of patients with the extension of thrombotic lesions and was associated with an increase in CVT extension risk (odds ratio adjusted for sex 2.692; 95% confidence interval 1.302-4.702). Moreover, we observed a significant increase of PAI-1 plasma activity in patients with extension of thrombotic lesion vs. patients without extension (P=0.0001). Patients with 4G/5G genotype in the promoter of the plasminogen activator inhibitor - 1 gene present a higher risk of extension of thrombotic lesions.

  13. Inhibition of plasminogen activator inhibitor-1 binding to endocytosis receptors of the low density lipoprotein receptor family by a peptide isolated from a phage displayed library

    DEFF Research Database (Denmark)

    Jensen, Jan K.; Malmendal, Anders; Schiøtt, Birgit

    2006-01-01

    The functions of the serpin plasminogen activator inhibitor-1 (PAI-1) are based on molecular interactions with its target proteases urokinase-type and tissue-type plasminogen activator (uPA and tPA), with vitronectin, and with endocytosis receptors of the low density lipoprotein family. Understan......The functions of the serpin plasminogen activator inhibitor-1 (PAI-1) are based on molecular interactions with its target proteases urokinase-type and tissue-type plasminogen activator (uPA and tPA), with vitronectin, and with endocytosis receptors of the low density lipoprotein family...... (DVPCFGWCQDA) was determined by NMR. A binding site in the so-called flexible joint region of PAI-1 was suggested by molecular modelling and validated through binding studies with various competitors and site-directed mutagenesis of PAI-1. The peptide with an N-terminal biotin inhibited the binding of the u......PA-PAI-1 complex to the endocytosis receptors low density lipoprotein receptor-related protein (LRP-1A) and very low density lipoprotein receptor (VLDLR) in vitro and inhibited endocytosis of the uPA-PAI-1 complex in U937 cells. We conclude that the isolated peptide represents a novel approach...

  14. Plasminogen Activator Inhibitor 1 Protects Fibrosarcoma Cells from Etoposide-Induced Apoptosis through Activation of the PI3K/Akt Cell Survival Pathway1

    Science.gov (United States)

    Rømer, Maria U; Larsen, Lise; Offenberg, Hanne; Brünner, Nils; Lademann, Ulrik A

    2008-01-01

    High levels of plasminogen activator inhibitor (PAI-1) in tumors are associated with poor prognosis in several cancer types, and the reason for this association is not fully understood. Plasminogen activator inhibitor 1 has been suggested to contribute to tumor growth by protecting cancer cells from apoptosis, and we have previously shown that wild type murine fibrosarcoma cells are significantly more resistant to apoptosis induced by chemotherapy than PAI-1-deficient fibrosarcoma cells. Here, we further investigated the molecular mechanisms underlying the antiapoptotic function of PAI-1 focusing on the phosphatidylinositol 3-phosphate kinase (PI3K)/Akt cell survival pathway. We demonstrate that the activation level of the Akt cell survival pathway is reduced in PAI-1-deficient cells. Inhibition of either PI3K or Akt by synthetic inhibitors sensitized the wild type but not the PAI-1-deficient cells to etoposide-induced cell death. More importantly, reintroduction of PAI-1 expression in PAI-1-deficient cells induced an increase in Akt activity and protection against etoposide-induced apoptosis. Concordantly, silencing of PAI-1 by RNA interference in wild type fibrosarcoma cells decreased the level of active Akt, and this was accompanied by a sensitization of the cells to etoposide-induced cell death. Altogether, our data suggest that PAI-1 influences sensitivity to etoposide-induced apoptosis through the PI3K/Akt cell survival pathway by acting upstream of PI3K and Akt. This points to PAI-1 as a possible therapeutic target in cancer diseases where PAI-1 inhibits chemotherapy-induced apoptosis. PMID:18813358

  15. Nucleophosmin Interacts with PIN2/TERF1-interacting Telomerase Inhibitor 1 (PinX1) and Attenuates the PinX1 Inhibition on Telomerase Activity.

    Science.gov (United States)

    Cheung, Derek Hang-Cheong; Ho, Sai-Tim; Lau, Kwok-Fai; Jin, Rui; Wang, Ya-Nan; Kung, Hsiang-Fu; Huang, Jun-Jian; Shaw, Pang-Chui

    2017-03-03

    Telomerase activation and telomere maintenance are critical for cellular immortalization and transformation. PIN2/TERF1-interacting telomerase inhibitor 1 (PinX1) is a telomerase regulator and the aberrant expression of PinX1 causes telomere shortening. Identifying PinX1-interacting proteins is important for understanding telomere maintenance. We found that PinX1 directly interacts with nucleophosmin (NPM), a protein that has been shown to positively correlate with telomerase activity. We further showed that PinX1 acts as a linker in the association between NPM and hTERT, the catalytic subunit of telomerase. Additionally, the recruitment of NPM by PinX1 to the telomerase complex could partially attenuate the PinX1-mediated inhibition on telomerase activity. Taken together, our data reveal a novel mechanism that regulates telomerase activation through the interaction between NPM, PinX1 and the telomerase complex.

  16. Purification of active human plasminogen activator inhibitor 1 from Escherichia coli. Comparison with natural and recombinant forms purified from eucaryotic cells.

    Science.gov (United States)

    Lawrence, D; Strandberg, L; Grundström, T; Ny, T

    1989-12-22

    Plasminogen activator inhibitor 1 (PAI-1) inhibits both tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA) and, therefore, is an important regulator of plasminogen activation. We have developed eucaryotic and procaryotic expression systems for PAI-1 and characterized the recombinant glycosylated and non-glycosylated products, together with a non-recombinant natural control, produced in the histosarcoma cell line HT 1080. For eucaryotic expression, the PAI-1 cDNA was stably transfected into chinese hamster ovary cells (CHO cells), while procaryotic expression in Escherichia coli was examined after inserting the DNA sequence encoding the mature PAI-1 protein into an inducible expression vector. Recombinant PAI-1 from CHO cells was purified approximately 50-fold in two steps and was indistinguishable from natural PAI-1. Between 3% and 4% of total cellular protein in the procaryotic expression system consisted of PAI-1, from which it was purified approximately 30-fold, with yields of between 15% and 20%. This PAI-1 formed 1:1 complexes with uPA and also with the single- and two-chain forms of tPA. Kinetic analysis demonstrated that the procaryote-produced PAI-1 had an inhibitory activity towards all three forms of PA that resembled that of natural PAI-1 with association rate constants of approximately 10(7) M-1 s-1. In contrast to PAI-1 from eucaryotic cells, the PAI-1 from E. coli had an inherent activity equal to that of guanidine/HCl-activated natural PAI-1. The activity could not be increased by treatment with denaturants suggesting that the latent form of PAI-1 was absent. However, at 37 degrees C the procaryote-produced PAI-1 lost activity at the same rate as natural PAI-1, with approximately 50% of the activity remaining after 3 h. This activity could be partially restored by treatment with 4 M guanidine/HCl. E. coli-derived PAI-1, added to human plasma and fractionated by Sephacryl S-200 chromatography, eluted in two peaks

  17. Low plasminogen activator inhibitor-1 levels in thyroid carcinoma: uPA/PAI-1 paradox in cancer proggression

    Directory of Open Access Journals (Sweden)

    Bekir Ucan

    2017-06-01

    Conclusions: Serum PAI-1 levels were lower in patients with papillary thyroid carcinoma. Our results might support the thesis of PAI-1 is expected to suppress cancer progression due to its ability to inhibit urokinase plasminogen activator activity. [J Contemp Med 2017; 7(2.000: 121-125

  18. The -675 4G/5G polymorphism at the Plasminogen Activator Inhibitor 1 (PAI-1) gene modulates plasma Plasminogen Activator Inhibitor 1 concentrations in response to dietary fat consumption.

    Science.gov (United States)

    Pérez-Martínez, P; Adarraga-Cansino, M D; Fernández de la Puebla, R A; Blanco-Molina, A; Delgado-Lista, J; Marín, C; Ordovás, J M; López-Miranda, J; Pérez-Jiménez, F

    2008-04-01

    The objective of the study was to determine whether Plasminogen Activator Inhibitor Type 1 (PAI-1) -675 4G/5G polymorphism is associated with the response of functional plasma PAI-1 concentrations to changes in the amount and quality of dietary fat in healthy subjects. PAI-1 is the major inhibitor of fibrinolysis, and a lower level of fibrinolytic activity could be implicated in an increased risk of IHD. Fifty-nine healthy Spanish volunteers (ten 4G/4G homozygotes, twenty-eight heterozygotes 4G/5G and twenty-one 5G/5G homozygotes) consumed three diets for periods of 4 weeks each: a SFA-rich diet (38 % fat, 20 % SFA), followed by a carbohydrate-rich diet (30 % fat, 55 % carbohydrate) and a MUFA-rich diet (38 % fat, 22 % MUFA) according to a randomized crossover design. At the end of each dietary period plasma lipid and functional plasma PAI-1 concentrations were determined. Subjects carrying the 4G allele (4G/4G and 4G/5G) showed a significant decrease in PAI-1 concentrations after the MUFA diet, compared with the SFA-rich and carbohydrate-rich diets (genotype x diet interaction: P = 0.028). 5G/5G homozygotes had the lowest plasma PAI-1 concentrations compared with 4G/4G and 4G/5G subjects (genotype: P = 0.002), without any changes as a result of the amount and the quality of the dietary fat. In summary, no differences in plasma PAI-1 concentration response were found after changes in dietary fat intake in 5G/5G homozygotes, although these subjects displayed the lowest concentrations of PAI-1. On the other hand, carriers of the 4G allele are more likely to hyper-respond to the presence of MUFA in the diet because of a greater decrease in PAI-1 concentrations.

  19. Dissecting the effect of RNA aptamer binding on the dynamics of plasminogen activator inhibitor 1 using hydrogen/deuterium exchange mass spectrometry

    DEFF Research Database (Denmark)

    Trelle, Morten B; Dupont, Daniel Miotto; Madsen, Jeppe Buur

    2014-01-01

    RNA aptamers, selected from large synthetic libraries, are attracting increasing interest as protein ligands, with potential uses as prototype pharmaceuticals, conformational probes, and reagents for specific quantification of protein levels in biological samples. Very little is known, however......, about their effects on protein conformation and dynamics. We have employed hydrogen/deuterium exchange (HDX) mass spectrometry to study the effect of RNA aptamers on the structural flexibility of the serpin plasminogen activator inhibitor-1 (PAI-1). The aptamers have characteristic effects...... of the aptamers to PAI-1 is associated with substantial and widespread protection against deuterium uptake in PAI-1. The aptamers induce protection against exchange with the solvent both in the protein-aptamer interface as well as in other specific areas. Interestingly, the aptamers induce substantial protection...

  20. Plasminogen-activator inhibitor-1 polymorphisms are associated with obesity and fat distribution in the Quebec Family Study: evidence of interactions with menopause.

    Science.gov (United States)

    Bouchard, Luigi; Mauriège, Pascale; Vohl, Marie-Claude; Bouchard, Claude; Pérusse, Louis

    2005-03-01

    Obesity is associated with increased plasma levels of plasminogen-activator inhibitor-1 (PAI1), the major fibrinolysis inhibitor. PAI1 levels are also increased at menopause, a condition that is associated with fat mass gain, especially in the abdominal area. We hypothesized that genetic variations within PAI1 gene are related to the amount of body fat and its regional distribution. We genotyped 666 subjects of the Quebec Family Study for five PAI1 gene polymorphisms. Stratified analyses were performed with analysis of covariance in men (n = 280) and women (n = 386) separately. PAI1-675 4G/5G polymorphism was strongly associated with body mass index (P obesity and may modulate the changes in adipose tissue distribution generally observed at menopause.

  1. Different effects of lipopolysaccharide on plasminogen activator inhibitor-1 production in aortic media in vivo and in culture

    NARCIS (Netherlands)

    Leeuwen, R.T.J. van; Quax, P.H.A.; Tippins, J.R.; Antoniw, J.W.; Andreotti, F.; Maseri, A.; Kluft, C.; Sperti, G.

    1996-01-01

    Background: Lipopolysaccharide (endotoxin) has been shown to increase the expression of plasminogen activator inhibitor type-1 (PAI-1) in the vessel wall. Endotoxin is known to increase PAI-1 production in endothelial cells, but its action on smooth muscle cells (SMCs) is presently not clear. In

  2. Whole grain wheat sourdough bread does not affect plasminogen activator inhibitor-1 in adults with normal or impaired carbohydrate metabolism.

    Science.gov (United States)

    MacKay, K A; Tucker, A J; Duncan, A M; Graham, T E; Robinson, L E

    2012-09-01

    Epidemiological studies suggest whole grain consumption is associated with a reduced risk of cardiovascular disease (CVD), possibly through alterations in glucose metabolism and subsequent effects on plasminogen activator inhibitor (PAI)-1, a novel biomarker for CVD. Our aim was to investigate the effect of 6 wk of whole grain wheat sourdough bread consumption versus refined white bread on PAI-1. Normoglycemic/normoinsulinemic (NGI; n = 14; age 53 ± 6 y; BMI 26.5 ± 2.9 kg/m(2)) and hyperglycemic/hyperinsulinemic (HGI; n = 14; age 57 ± 7 y; BMI 35.7 ± 5.7 kg/m(2)) adults incorporated whole grain wheat sourdough (162.5 g) or white (168.8 g) bread into their diet, for 6 wk in a randomized crossover study. Pre- and post-intervention, fasting blood samples were analyzed for PAI-1 (primary outcome), as well as glucose, insulin and glucagon (secondary outcomes) at fasting and postprandially after an oral glucose tolerance test (OGTT). Anthropometric measures, fasting glucose, insulin, glucagon and PAI-1 antigen and activity were not different between treatments in either NGI or HGI adults. Glucose incremental area under the curve (iAUC) was lower (19%, P = 0.02) after 6 wk consumption of whole grain wheat sourdough bread compared to white bread in the HGI group, with no differences in insulin or glucagon iAUC in either group. Our data showed decreased glucose iAUC after an OGTT following 6 wk whole grain wheat bread consumption in adults with differing glycemic/insulinemic status, but no improvements in PAI-1 or fasting glycemic parameters. Copyright © 2010 Elsevier B.V. All rights reserved.

  3. Pentoxifylline Regulates Plasminogen Activator Inhibitor-1 Expression and Protein Kinase A Phosphorylation in Radiation-Induced Lung Fibrosis

    Directory of Open Access Journals (Sweden)

    Jong-Geol Lee

    2017-01-01

    Full Text Available Purpose. Radiation-induced lung fibrosis (RILF is a serious late complication of radiotherapy. In vitro studies have demonstrated that pentoxifylline (PTX has suppressing effects in extracellular matrix production in fibroblasts, while the antifibrotic action of PTX alone using clinical dose is yet unexplored. Materials and Methods. We used micro-computed tomography (micro-CT and histopathological analysis to evaluate the antifibrotic effects of PTX in a rat model of RILF. Results. Micro-CT findings showed that lung density, volume loss, and mediastinal shift are significantly increased at 16 weeks after irradiation. Simultaneously, histological analysis demonstrated thickening of alveolar walls, destruction of alveolar structures, and excessive collagen deposition in the irradiated lung. PTX treatment effectively attenuated the fibrotic changes based on both micro-CT and histopathological analyses. Western analysis also revealed increased levels of plasminogen activator inhibitor- (PAI- 1 and fibronectin (FN and PTX treatment reduced expression of PAI-1 and FN by restoring protein kinase A (PKA phosphorylation but not TGF-β/Smad in both irradiated lung tissues and epithelial cells. Conclusions. Our results demonstrate the antifibrotic effect of PTX on radiation-induced lung fibrosis and its effect on modulation of PKA and PAI-1 expression as possible antifibrotic mechanisms.

  4. Plasminogen activator inhibitor 1 4G/5G and -844G/A variants in idiopathic recurrent pregnancy loss.

    Science.gov (United States)

    Magdoud, Kalthoum; Herbepin, Viviana G; Touraine, Renaud; Almawi, Wassim Y; Mahjoub, Touhami

    2013-09-01

    Plasminogen activator inhibitor type 1 (PAI-1) regulates fibrinolysis, and the common promoter region variants -675G/A (4G/5G) and -844G/A are associated with increased thrombotic risk. Despite evidence linking altered fibrinolysis with adverse pregnancy events, including idiopathic recurrent pregnancy loss (RPL), the contribution of PAI-1 variants to RPL risk remains controversial. We investigated the association between the PAI-1 -844G/A and 4G/5G (-675G/A) variants with altered risk of RPL. This was a case-control study involving 304 women with confirmed RPL and 371 age- and ethnically matched control women. PAI-1 genotyping was performed by PCR single-specific primer -675 (G/A) and real-time PCR (-844G/A) analysis. Minor allele frequency (MAF) of 4G/5G (P 5G single-nucleotide polymorphism (SNP) was significantly associated with RPL under additive, dominant, and recessive genetic models; no association of -844G/A with RPL was seen irrespective of the genetic model tested. Taking common -844G/5G haplotype as reference (OR = 1.00), multivariate analysis confirmed the association of 4G-containing -844A/4G (P 5G, but not -844G/A, PAI-1 variant is associated with an increased risk of RPL. © 2013 John Wiley & Sons Ltd.

  5. Plasminogen activator inhibitor-1 gene 4G/5G polymorphism in Turkish children with asthma and allergic rhinitis.

    Science.gov (United States)

    Ozbek, Ozlem Yilmaz; Ataç, F Belgin; Ogus, Ersin; Ozbek, Namik

    2009-01-01

    Plasminogen activator inhibitor (PAI-1) has an essential role in tissue remodeling after inflammation. Recent literature revealed only one study evaluating PAI-1 4G/5G gene polymorphism in children with asthma and none in children with allergic rhinitis. We aimed to investigate distribution of PAI-1 4G/5G polymorphism in a group of Turkish children with asthma and allergic rhinitis and compare these findings with those obtained in normal peers. Patients with physician-diagnosed asthma (n = 106) and allergic rhinitis (n = 99) and 83 healthy peers were included in this study. We evaluated PAI-1 4G/5G polymorphism genotype as well as the possible association between PAI-1 4G/5G polymorphism and pulmonary function tests, serum total immunoglobulin E (IgE), total eosinophil count, and skin-prick test positivity in our study. The prevalence of the 4G allele significantly exceeded the values found in the controls both in patients with asthma (p = 0.001) and in patients with allergic rhinitis (p = 0.002). Interestingly, comparison of asthmatic patients revealed that mean baseline percent forced expiratory volume in 1 second and forced vital capacity were significantly higher in patients who bear 5G/5G genotype than in those who have 4G/4G or 4G/5G genotypes. No statistically significant relationship were found between PAI-1 polymorphism and total serum IgE levels, total eosinophil count, or selected skin test responses to aeroallergens. Our study suggests that Turkish children with asthma or allergic rhinitis have a higher prevalence of PAI-1 4G allele compared with their healthy peers.

  6. Omnidirectional Active Vision for Evolutionary Car Driving

    OpenAIRE

    Suzuki, Mototaka; van der Blij, Jacob; Floreano, Dario

    2006-01-01

    We describe a set of simulations to evolve omnidirectional active vision, an artificial retina scanning over images taken via an omnidirectional camera, being applied to a car driving task. While the retina can immediately access features in any direction, it is asked to select behaviorally-relevant features so as to drive the car on the road. Neural controllers which direct both the retinal movement and the system behavior, i.e., the speed and the steering angle of the car, are tested in thr...

  7. The lost correlation between heat shock protein 70 (HSPA1A) and plasminogen activator inhibitor-1 in patients with type 2 diabetes and albuminuria.

    Science.gov (United States)

    Nargesi, Arash Aghajani; Shalchi, Majid; Nargesi, Reihaneh Aghajani; Sadeghpour, Niloofar; Zarifkar, Mitra; Mozaffari, Majid; Imani, Mehrnaz; Esteghamati, Alireza; Nakhjavani, Manouchehr

    2016-03-01

    We aimed to study the relation between plasma levels of stress-induced heat shock protein 70 (HSPA1A) with plasminogen activator inhibitor-1 (PAI-1) and high-density lipoprotein cholesterol (HDL-C), apolipoprotein A1 (Apo-A1), and HDL-C/Apo-A1 ratio. In a matched case-control study on patients with diabetes (40 patients with albuminuria and 40 without albuminuria matched for age, sex, and body mass index), we observed that plasma levels of HSPA1A and PAI-1 are increased in patients with albuminuria (0.55 ± 0.02 vs. 0.77 ± 0.04 ng/ml, p value albuminuria (r = 0.28; p value = 0.04), but not in those with albuminuria (r = 0.07; p value = 0.63). No association was found between HSPA1A and HDL-C, between HSPA1A and Apo-A1, or between HSPA1A and HDL-C/Apo-A1 ratio. We concluded that there is a direct correlation between plasma HSPA1A and PAI-1 levels in patients with diabetes, which is lost when they develop albuminuria.

  8. Association Between Plasminogen Activator Inhibitor-1-675 4G/5G Insertion/Deletion Polymorphism and Chronic Obstructive Pulmonary Disease.

    Science.gov (United States)

    Essa, Enas S; El Wahsh, Rabab A

    2016-12-01

    Molecular pathology of chronic obstructive pulmonary disease (COPD) is still being investigated to discover relationships with disease pathogenesis. Evidence of plasminogen activator inhibitor-1 (PAI-1) overexpression in the sputum and the blood of COPD patients is growing. We aimed to investigate the potential relation between PAI-1 promoter 4G/5G insertion/deletion polymorphism and COPD development. In a case-control study, we genotyped 117 COPD patients and 160 control subjects for PAI-1 promoter 4G/5G polymorphism by an allele-specific polymerase chain reaction analysis. All subjects were male smokers. In the co-dominant model, there was a significant difference in the distribution of 5G/5G, 4G/5G and 4G/4G genotypes between COPD patients and controls (p = 0.002). In the recessive model, carriers of 4G/4G genotype were significantly higher in COPD patients than controls (p = 0.01). Carriers of 4G/4G genotype were at higher risk to develop COPD than those carrying 5G/5G or 4G/5G genotypes (crude odds ratio (OR) = 2.10, 95% confidence interval (CI) = 1.19-3.73, adjusted OR = 2.5, 95% CI = 1.22-3.99). In conclusion, PAI-1 4G/5G genetic variations are associated with COPD development in males.

  9. Association of Metabolic Syndrome with Serum Adipokines in Community-Living Elderly Japanese Women: Independent Association with Plasminogen Activator-Inhibitor-1.

    Science.gov (United States)

    Takeuchi, Mika; Tsuboi, Ayaka; Kurata, Miki; Fukuo, Keisuke; Kazumi, Tsutomu

    2015-11-01

    Associations between metabolic syndrome (MetS) with serum adipokines and basal lipoprotein lipase mass (serum LPL) have not been extensively studied in elderly Asians, who in general have lower body mass index than European populations. A cross-sectional analysis was conducted including 159 community-living elderly Japanese women whose age averaged 77 years. MetS was defined by the modified National Cholesterol Education Program Adult Treatment Panel III criteria, but using a body mass index ≥25 kg/m(2) instead of waist circumference. Serum LPL, leptin, adiponectin, plasminogen activator inhibitor 1 (PAI-1), interleukin-6, tumor necrosis factor-alpha, and high-sensitivity C-reactive protein were measured. Both the presence of MetS and the number of MetS components were associated with higher homeostasis assessment of insulin resistance, serum levels of leptin, PAI-1, and tumor necrosis factor-alpha and with lower serum levels of LPL and adiponectin (all P independent of fat mass index and insulin resistance. Although proinflammatory, prothrombotic, and anti-inflammatory states were associated with MetS, higher PAI-1 was associated with MetS independent of fat mass index and insulin resistance in elderly Japanese women, in whom obesity is rare.

  10. Association of plasminogen activator inhibitor-1 and vitamin D receptor expression with the risk of keloid disease in a Chinese population

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    Zhen-Hua Gong

    2017-01-01

    Full Text Available Keloid disease (KD is a benign fibroproliferative scarring condition of unknown etiopathogenesis. Plasminogen activator inhibitor-1 (PAI-1 and vitamin D receptor (VDR have been shown to play important roles in the progression of tissue fibrosis; therefore, both these genes are potential susceptibility genes for KD. We aimed to determine whether the gene expression levels of PAI-1 and VDR are altered in Chinese KD patients. We measured the expression of PAI and VDR in human peripheral blood lymphocytes in 236 patients with keloid and 219 age- and sex-matched healthy controls by quantitative real-time polymerase chain reaction. We found that PAI-1 expression in peripheral blood lymphocytes was significantly higher in patients with KD than in control individuals (p < 0.0001, while VDR expression was significantly lower in KD patients than in control individuals (p < 0.0001. High levels of PAI-1 and low levels of VDR expression were significantly associated with an increased risk for KD. PAI-1 and VDR might play important roles in keloid development. Gene expression levels of PAI-1 and VDR may, therefore, be used as potential markers for the prediction of keloid development after scarring.

  11. Plasminogen activator inhibitor-1 4G/5G gene polymorphism and coronary artery disease in the Chinese Han population: a meta-analysis.

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    Li, Yan-yan

    2012-01-01

    The polymorphism of plasminogen activator inhibitor-1 (PAI-1) 4G/5G gene has been indicated to be correlated with coronary artery disease (CAD) susceptibility, but study results are still debatable. The present meta-analysis was performed to investigate the association between PAI-1 4G/5G gene polymorphism and CAD in the Chinese Han population. A total of 879 CAD patients and 628 controls from eight separate studies were involved. The pooled odds ratio (OR) for the distribution of the 4G allele frequency of PAI-1 4G/5G gene and its corresponding 95% confidence interval (CI) was assessed by the random effect model. The distribution of the 4 G allele frequency was 0.61 for the CAD group and 0.51 for the control group. The association between PAI-1 4G/5G gene polymorphism and CAD in the Chinese Han population was significant under an allelic genetic model (OR = 1.70, 95% CI = 1.18 to 2.44, P = 0.004). The heterogeneity test was also significant (P5G gene polymorphism was implied to be associated with increased CAD risk. Carriers of the 4G allele of the PAI-1 4G/5G gene might predispose to CAD.

  12. [The investigation of angiotensin converting enzyme I/D and plasminogen activator inhibitor-1 4G/5G polymorphisms in venous thromboembolism patients].

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    Kaya, Halide; Karkucak, Mutlu; Salifoğlu, Hatice; Torun, Deniz; Kozan, Salih; Tunca, Yusuf

    2013-01-01

    Deep venous thrombosis and pulmonary embolism, known as venous thromboembolism and seen as a fairly common multifactorial diseases. Differ between populations due to genetic factors, several polymorphisms associated with venous thromboembolism was conducted. As a result of these studies the relationship between disease development and polymorphism is not clear yet. In this study we aimed to investigate the role of angiotensin converting enzyme insersion/deletion (ACE I/D) and plasminogen activator inhibitor-1 4G/5G (PAI-1 4G/5G) polymorphism in the development of disease. In our study, DNA isolated from 80 venous thromboembolism patients and 79 control groups was used. While the classical polymerase chain reaction method used to investigate the ACE I/D polymorphism, the polymerase chain reaction based on allele-specific amplification was used for the detection of PAI-1 4G/5G polymorphism. As a result, there were no significant statistical differences for ACE I/D and PAI-1 4G/5G polymorphism among patient and control groups (p> 0.05). These findings revealed that there is no relationship between these polymorphisms and the development of venous thromboembolism, but large-scale studies are need to be done.

  13. Ameliorative effect of nicotine exposure on insulin resistance is accompanied by decreased cardiac glycogen synthase kinase-3 and plasminogen activator inhibitor-1 during oral oestrogen-progestin therapy.

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    Michael, Olugbenga S; Olatunji, Lawrence A

    2017-09-03

    Cigarette smoking is considered to be a major risk factor for the development of diabetes and cardiovascular disease. Oestrogen-progestin combined oral contraceptive (COC) use has been associated with adverse cardiometabolic events. We hypothesized that nicotine would ameliorate insulin resistance (IR) that is accompanied by decreased cardiac glycogen synthase kinase-3 (GSK-3) and plasminogen activator inhibitor-1 (PAI-1). Female Wistar rats received (po) low-(0.1 mg/kg) or high-nicotine (1.0 mg/kg) with or without COC containing 5.0 µg levonorgestrel plus 1.0 µg ethinylestradiol daily for 8 weeks. Data showed that COC treatment or nicotine exposure led to IR, glucose deregulation, atherogenic dyslipidemia, increased corticosterone, aldosterone, cardiac and circulating GSK-3 values and PAI-1. However, these effects with the exception of corticosterone and aldosterone were ameliorated in COC + nicotine-exposed rats. Amelioration of IR induced by COC treatment is accompanied by decreased circulating PAI-1, cardiac PAI-1 and GSK-3 instead of circulating aldosterone and corticosterone.

  14. Hemostatic profile changes in patients with traumatic brain injury with regard to the genotypes of -675 4G/5G polymorphism of plasminogen activator inhibitor-1 gene

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    O. O. Potapov

    2016-10-01

    Full Text Available Traumatic brain injury (TBI is a significant problem in modern clinical medicine that has both medical and social importance. Analysis of hemostatic changes is a very important aspect of clinical course of TBI and should be paid special attention on it. This analysis is necessary to make prognosis for the treatment outcomes taking into account associations with genetic factors. The aim of research was to analyze hemostatic profile changes in patients with TBI with regard to the genotype of -675 4G/5G polymorphism of plasminogen activator inhibitor-1 gene (РАІ-1. Methods and materials. The research was based on the investigation results of 200 patients with isolated TBI, who were undergoing in-patient treatment at the neurosurgery department at Sumy Regional Clinical Hospital in 2011–2013, and 95 apparently healthy individuals of the control group. The following change cycling was confirmed during the study: a tendency to hypercoagulability on the 1st day transforming into a state of being incapable of coagulation on the 3rd day. On the 7 day hypercoagulability signs dominated and by the 14 day the laboratory findings had gradually become normal. Conclusions. According to the analysis of routine hemostatic profile parameters (activated partial thromboplastin time, prothrombin index, platelet count, plasma tolerance to heparin, activated recalcification time, euglobulin clot lysis assay, plasma fibrinogen level we concluded that there is no association between the studied parameters and the genotypes of the -675 4G/5G polymorphism in the PAI-1 gene in patients with TBI and controls. Our study confirms the necessity of further monitoring of fibrinolytic system, since routine laboratory tests of haemostasis are not always informative as for the fibrinolytic disorders in patients with TBI.

  15. Inhibition of Plasminogen Activator Inhibitor-1 Attenuates Transforming Growth Factor-β-Dependent Epithelial Mesenchymal Transition and Differentiation of Fibroblasts to Myofibroblasts.

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    Keitaro Omori

    Full Text Available Transforming growth factor-β (TGF-β is central during the pathogenesis of pulmonary fibrosis, in which the plasminogen activator inhibitor-1 (PAI-1 also has an established role. TGF-β is also known to be the strongest inducer of PAI-1. To investigate the link between PAI-1 and TGF-β in fibrotic processes, we evaluated the effect of SK-216, a PAI-1-specific inhibitor, in TGF-β-dependent epithelial-mesenchymal transition (EMT and fibroblast to myofibroblast differentiation. In human alveolar epithelial A549 cells, treatment with TGF-β induced EMT, whereas co-treatment with SK-216 attenuated the occurrence of EMT. The inhibition of TGF-β-induced EMT by SK-216 was also confirmed in the experiment using murine epithelial LA-4 cells. Blocking EMT by SK-216 inhibited TGF-β-induced endogenous production of PAI-1 and TGF-β in A549 cells as well. These effects of SK-216 were not likely mediated by suppressing either Smad or ERK pathways. Using human lung fibroblast MRC-5 cells, we demonstrated that SK-216 inhibited TGF-β-dependent differentiation of fibroblasts to myofibroblasts. We also observed this inhibition by SK-216 in human primary lung fibroblasts. Following these in vitro results, we tested oral administration of SK-216 into mice injected intratracheally with bleomycin. We found that SK-216 reduced the degree of bleomycin-induced pulmonary fibrosis in mice. Although the precise mechanisms underlying the link between TGF-β and PAI-1 regarding fibrotic process were not determined, PAI-1 seems to act as a potent downstream effector on the pro-fibrotic property of TGF-β. In addition, inhibition of PAI-1 activity by a PAI-1 inhibitor exerts an antifibrotic effect even in vivo. These data suggest that targeting PAI-1 as a downstream effector of TGF-β could be a promising therapeutic strategy for pulmonary fibrosis.

  16. Fiber intake and plasminogen activator inhibitor-1 in type 2 diabetes: Look AHEAD (Action for Health in Diabetes) trial findings at baseline and year 1.

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    Belalcazar, L Maria; Anderson, Andrea M; Lang, Wei; Schwenke, Dawn C; Haffner, Steven M; Yatsuya, Hiroshi; Rushing, Julia; Vitolins, Mara Z; Reeves, Rebecca; Pi-Sunyer, F Xavier; Tracy, Russell P; Ballantyne, Christie M

    2014-11-01

    Plasminogen activator inhibitor 1 (PAI-1) is elevated in obese individuals with type 2 diabetes and may contribute, independently of traditional factors, to increased cardiovascular disease risk. Fiber intake may decrease PAI-1 levels. We examined the associations of fiber intake and its changes with PAI-1 before and during an intensive lifestyle intervention (ILI) for weight loss in 1,701 Look AHEAD (Action for Health in Diabetes) participants with dietary, fitness, and PAI-1 data at baseline and 1 year. Look AHEAD was a randomized cardiovascular disease trial in 5,145 overweight/obese patients with type 2 diabetes, comparing ILI (goal of ≥7% reduction in baseline weight) with a control arm of diabetes support and education. ILI participants were encouraged to consume vegetables, fruits, and grain products low in sugar and fat. At baseline, median fiber intake was 17.9 g/day. Each 8.3 g/day higher fiber intake was associated with a 9.2% lower PAI-1 level (P=0.008); this association persisted after weight and fitness adjustments (P=0.03). Higher baseline intake of fruit (P=0.019) and high-fiber grain and cereal (P=0.029) were related to lower PAI-1 levels. Although successful in improving weight and physical fitness at 1 year, the ILI in Look AHEAD resulted in small increases in fiber intake (4.1 g/day, compared with -2.35 g/day with diabetes support and education) that were not related to PAI-1 change (P=0.34). Only 31.3% of ILI participants (39.8% of women, 19.1% of men) met daily fiber intake recommendations. Increasing fiber intake in overweight/obese individuals with diabetes interested in weight loss is challenging. Future studies evaluating changes in fiber consumption during weight loss interventions are warranted. Copyright © 2014 Academy of Nutrition and Dietetics. Published by Elsevier Inc. All rights reserved.

  17. 4G/5G polymorphism of plasminogen activator inhibitor-1 gene is associated with mortality in intensive care unit patients with severe pneumonia.

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    Sapru, Anil; Hansen, Helen; Ajayi, Temitayo; Brown, Ron; Garcia, Oscar; Zhuo, HanJing; Wiemels, Joseph; Matthay, Michael A; Wiener-Kronish, Jeanine

    2009-05-01

    Higher plasma and pulmonary edema fluid levels of plasminogen activator inhibitor-1 (PAI-1) are associated with increased mortality in patients with pneumonia and acute lung injury. The 4G allele of the 4G/5G polymorphism of the PAI-1 gene is associated with higher PAI-1 levels and an increased incidence of hospitalizations for pneumonia. The authors hypothesized that the 4G allele would be associated with worse clinical outcomes (mortality and ventilator-free days) in patients with severe pneumonia. The authors enrolled patients admitted with severe pneumonia in a prospective cohort. Patients were followed until hospital discharge. DNA was isolated from blood samples, and genotyping detection for the PAI-1 4G/5G polymorphism was carried out using Taqman-based allelic discrimination. A total of 111 patients were available for analysis. Distribution of genotypes was 4G/4G 26 of 111 (23%), 4G/5G 59 of 111 (53%), and 5G/5G 26 of 111 (23%). Of 111 patients, 32 (29%) died before hospital discharge and 105 patients (94%) received mechanical ventilation. Patients with the 4G/4G and the 4G/5G genotypes had higher mortality (35% vs. 8%, P = 0.007) and fewer ventilator-free days (median 4 vs. 13, P = 0.04) compared to patients with the 5G/5G genotype. The 4G allele of the 4G/5G polymorphism in the PAI-1 gene is associated with fewer ventilator-free days and increased mortality in hospitalized patients with severe pneumonia. These findings suggest that PAI-1 may have a role in pathogenesis and that the 4G/5G polymorphism may be an important biomarker of risk in patients with severe pneumonia.

  18. Impact of the -675 4G/5G polymorphism of the plasminogen activator inhibitor-1 gene on childhood IgA nephropathy.

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    Han, Su-Ryun; Kim, Cheon-Jong; Lee, Byung-Cheol

    2012-04-01

    Plasminogen activator inhibitor-1 (PAI-1) is an important regulator of the fibrinolytic pathway and extracellular matrix (ECM) turnover. The -675 4G/5G polymorphism in the PAI-1 promoter is associated with altered PAI-1 transcription, suggesting that this polymorphism may be a candidate risk factor for diseases characterized by ECM accumulation, such as immunoglobulin A nephropathy (IgAN) and mesangial proliferative glomerulonephritis (MesPGN). We genotyped childhood patients with biopsy-confirmed IgAN (n=111) and MesPGN (n=47), and healthy control subjects (n=230) for the -675 4G/5G PAI-1 polymorphism by polymerase chain reaction-restriction fragment length polymorphism methods. The distribution of the 4G/4G (27.9%), 4G/5G (45.1%) and 5G/5G (27.0%) genotypes in IgAN patients was significantly different from the healthy controls (32.2, 54.3 and 13.5%, respectively) (p=0.0092). There was no significant difference in the genotype distributions of the 4G/5G polymorphism between MesPGN patients and the healthy controls. Regarding the impact of the polymorphism on IgAN, the 4G/4G genotype was markedly increased in patients with proteinuria (≥1,000 mg/day) and/or hypertension when compared to patients without proteinuria and hypertension (OR=5.23, 95% CI 1.34-20.38, P=0.0183). These findings indicate that the PAI-1 gene polymorphism may affect the susceptibility of childhood IgAN.

  19. Polymorphism 4G/5G of the plasminogen activator inhibitor 1 gene as a risk factor for the development of allergic rhinitis symptoms in patients with asthma.

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    Lampalo, Marina; Jukic, Irena; Bingulac-Popovic, Jasna; Marunica, Ivona; Petlevski, Roberta; Pavlisa, Gordana; Popovic-Grle, Sanja

    2017-06-01

    Plasminogen activator inhibitor-1 (PAI-1) is a glycoprotein which has a role in tissue remodelling after inflammatory processes. The objective is to investigate the frequency of PAI-1 gene polymorphism (4G/5G) in patients with a lung ventilation dysfunction in asthma and allergic rhinitis. Genomic DNA was isolated and genotypes of polymorphism of PAI-1 4G/5G and ABO were determined using the methods of RT-PCR and PCR-SSP. Study group includes 145 adult patients diagnosed with chronic asthma, with all clinically relevant parameters and the laboratory markers of pO2, IgE and eosinophils in sputum and nasal swab. In the processing of data, appropriate statistical tests (Kolmogorov-Smirnov test, median, interquartile ranges, χ 2 and Mann-Whitney U tests) were used. Patients with symptoms of allergic rhinitis were significantly younger and had an almost four time higher levels of IgE (P = 0.001), higher pO2 (P = 0.002) and PEF (P = 0.036), compared to those who do not have these symptoms. Genotype PAI 4G/4G is significantly more common in patients with allergic rhinitis (28.1% vs. 16.1%; P = 0.017) compared to the genotype 5G/5G. Carriers of the genotype 4G/5G also have a borderline statistical significance. There were no statistically significant difference in the incidence of allergic rhinitis in the carriers of any ABO genotypes. The frequency of PAI genotype 4G/4G is significantly more common in patients with allergic rhinitis. The results suggest that the carriers of at least one 4G allele are at a higher risk for developing symptoms of allergic rhinitis in asthma.

  20. Association between the plasminogen activator inhibitor-1 4G/5G polymorphism and risk of venous thromboembolism: a meta-analysis.

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    Wang, Jiarong; Wang, Chengdi; Chen, Nan; Shu, Chi; Guo, Xiaojiang; He, Yazhou; Zhou, Yanhong

    2014-12-01

    The plasminogen activator inhibitor-1 (PAI-1) 4G/5G polymorphism was considered to be associated with risk of venous thromboembolism (VTE), while evidence remains inadequate. To provide a more accurate estimation of this relationship, we performed an updated meta-analysis of all eligible studies. A systematical search was performed in PubMed, EMBASE, Wanfang, China National Knowledge Infrastructure (CNKI) and Cqvip databases to identify relevant studies published before March 6(th) 2014. The odds ratios (ORs) with 95% confidence intervals (CIs) were pooled using the fixed/random-effects model using Review Manager 5.1 and STATA 12.0. A total of 34 studies with 3561 cases and 5693 controls were analyzed. Overall, significant association between the PAI-1 4G/5G variant and VTE risk in total population (dominant model: OR=1.32, 95%CI: 1.13-1.54) was observed. And this variant was also related to the deep vein thrombosis risk (dominant model: OR=1.60, 95%CI: 1.24-2.06, P=0.0003). In the subgroup analyses on ethnicity, significant results were obtained in both Asians (dominant model: OR=2.08, 95%CI: 1.29-3.35, P=0.003) and Caucasians (dominant model: OR=1.31, 95%CI: 1.10-1.56, P=0.003). However, no significant association was found in patients with provoked VTE. In terms of subgroup analyses on co-existence of other thrombotic risk factors, the PAI-1 4G/5G polymorphism was significantly associated with VTE risk in patients with factor V Leiden mutation (dominant model: OR=1.72, 95%CI: 1.17-2.53), but not in patients with cancer or surgery. Our findings demonstrate the role of PAI-1 4G/5G polymorphism being a risk candidate locus for VTE susceptibility, especially in patients with other genetic thrombophilic disorders. Copyright © 2014 Elsevier Ltd. All rights reserved.

  1. Influence of plasminogen activator inhibitor-1 (SERPINE1) 4G/5G polymorphism on circulating SERPINE-1 antigen expression in HCC associated with viral infection.

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    Divella, Rosa; Mazzocca, Antonio; Gadaleta, Cosimo; Simone, Giovanni; Paradiso, Angelo; Quaranta, Michele; Daniele, Antonella

    2012-01-01

    Hepatocarcinogenesis is heavily influenced by chronic hepatitis B (HBV) and C (HCV) infection. Elevated levels of plasminogen activator inhibitor-1 (SERPINE1/PAI-1) have been reported in patients with hepatocellular carcinoma (HCC) associated with viral infection. The gene encoding SERPINE1 is highly polymorphic and the frequently associated 4/5 guanosine (4G/5G) polymorphism in the gene promoter may influence its expression. Here, we investigated the distribution of genotypes and the frequency of alleles of the 4G/5G polymorphism in patients with HCC, the influence of the 4G/5G polymorphism on plasma SERPINE1 levels and its association with viral infection. A total of 75 patients with HCC were enrolled: 32 (42.6%) were HBV(+)/HCV(+), 11 (14.6%) were only HCV(+), and 32 (42.6%) were negative for both viruses. A control group of healthy donors was also enrolled (n=50). SERPINE1 plasma concentrations were determined by ELISA and the detection of the promoter 4G/5G polymorphism was performed by an allele-specific PCR analysis. We found that the frequency of both the 4G/4G genotype (p=0.02) and the 4G allele (p=0.006) were significantly higher in patients with HCC compared to the control group, and particularly higher in patients with HCC co-infected with HBV(+)/HCV(+) than in those with no viral infection. We also found that patients with the 4G/4G genotype had significantly higher plasma SERPINE1 protein levels when compared with patients with the 4G/5G or 5G/5G genotype (p5G SERPINE1 polymorphism with a higher level of SERPINE1 protein in patients with HCC with HBV(+)/HCV(+) than those without infection, suggest the presence of two distinct pathogenic mechanisms in hepatocarcinogenesis, depending on the etiology.

  2. miR-30b, down-regulated in gastric cancer, promotes apoptosis and suppresses tumor growth by targeting plasminogen activator inhibitor-1.

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    En-Dong Zhu

    Full Text Available BACKGROUND: Gastric cancer is one of the most common malignant diseases worldwide. Emerging evidence has shown that microRNAs (miRNAs are associated with tumor development and progression. Our previous studies have revealed that H. pylori infection was able to induce the altered expression of miR-30b in gastric epithelial cells. However, little is known about the potential role of miR-30b in gastric cancer. METHODS: We analyzed the expression of miR-30b in gastric cancer cell lines and human gastric cancer tissues. We examined the effect of miR-30b mimics on the apoptosis of gastric cancer cells in vitro by flow cytometry (FCM and caspase-3/7 activity assays. Nude mouse xenograft model was used to determine whether miR-30b is involved in tumorigenesis of gastric cancer. The target of miR-30b was identified by bioinformatics analysis, luciferase assay and Western blot. Finally, we performed the correlation analysis between miR-30b and its target expression in gastric cancer. RESULTS: miR-30b was significantly down-regulated in gastric cancer cells and human gastric cancer tissues. Enforced expression of miR-30b promoted the apoptosis of gastric cancer cells in vitro, and miR-30b could significantly inhibit tumorigenicity of gastric cancer by increasing the apoptosis proportion of cancer cells in vivo. Moreover, plasminogen activator inhibitor-1 (PAI-1 was identified as the potential target of miR-30b, and miR-30b level was inversely correlated with PAI-1 expression in gastric cancer. In addition, silencing of PAI-1 was able to phenocopy the effect of miR-30b overexpression on apoptosis regulation of cancer cells, and overexpression of PAI-1 could suppressed the effect of promoting cell apoptosis by miR-30b, indicating PAI-1 is potentially involved in miR-30b-induced apoptosis on cancer cells. CONCLUSION: miR-30b may function as a novel tumor suppressor gene in gastric cancer by targeting PAI-1 and regulating the apoptosis of cancer cells. miR-30b

  3. Plasminogen Activator Inhibitor 1 Promotes Immunosuppression in Human Non-Small Cell Lung Cancers by Enhancing TGF-Β1 Expression in Macrophage

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    Chengjun Zhu

    2017-12-01

    Full Text Available Background: Plasminogen activator inhibitor-1 (PAI-1 has been regarded as a risk factor for thrombosis and atherosclerosis. Since it has been shown that PAI-1 can activate macrophages through Toll-like receptor-4, we sought to investigate the role of PAI-1 in the tumor microenvironment. Methods: The expression and distribution patterns of PAI-1 and transforming growth factor beta (TGF-β were measured in 60 non-small cell lung cancer (NSCLC tumors. A statistical correlation analysis was performed between PAI-1 and TGF-β expression and distribution in each tumor. The distribution of tumor-associated macrophages (TAMs was also measured and its correlation to PAI-1 levels was analyzed. Levels of secreted CCL-17, CCL-22, IL-6 and TGF-β were measured in cell cultures of human macrophage cell lines THP-1 and U937 treated with PAI-1. Levels of secreted PAI-1 were monitored in cell cultures of human NSCLCs cell lines 95D and A549 treated with TGF-β. Secreted proteins were measured in cell culture supernatants using ELISA. Changes in downstream signaling pathways were investigated using western blot. Results: PAI-1 and TGF-β were found to be overexpressed in human NSCLCs. PAI-1 expression was tightly correlated to TGF-β expression as well as the percentage of TAMs. PAI-1 treatment increased the expression of TAM-associated cytokines and chemokines, including CCL-17, CCL-22, and IL-6. PAI-1 treatment was also observed to enhance TGF-β expression in macrophage cell lines through an IL-6 autocrine/paracrine manner. The effects on TGF-β expression were blocked by NF-κB and STAT3 inhibition. Interestingly, TGF-β also increased levels of secreted PAI-1 in NSCLC cells through SMAD3-dependent signaling, therefore resulting in a feed-forward loop. However, this loop could be blocked by NF-κB, STAT3 and SMAD3 signaling inhibition, as well as treatment with a high concentration of TGF-β. Conclusion: PAI-1 and TGF-β promote NSCLC tumor cells and TAMs and

  4. Plasminogen activator inhibitor-1 4G/5G gene polymorphism and coronary artery disease in the Chinese Han population: a meta-analysis.

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    Yan-yan Li

    Full Text Available BACKGROUND: The polymorphism of plasminogen activator inhibitor-1 (PAI-1 4G/5G gene has been indicated to be correlated with coronary artery disease (CAD susceptibility, but study results are still debatable. OBJECTIVE AND METHODS: The present meta-analysis was performed to investigate the association between PAI-1 4G/5G gene polymorphism and CAD in the Chinese Han population. A total of 879 CAD patients and 628 controls from eight separate studies were involved. The pooled odds ratio (OR for the distribution of the 4G allele frequency of PAI-1 4G/5G gene and its corresponding 95% confidence interval (CI was assessed by the random effect model. RESULTS: The distribution of the 4 G allele frequency was 0.61 for the CAD group and 0.51 for the control group. The association between PAI-1 4G/5G gene polymorphism and CAD in the Chinese Han population was significant under an allelic genetic model (OR = 1.70, 95% CI = 1.18 to 2.44, P = 0.004. The heterogeneity test was also significant (P<0.0001. Meta-regression was performed to explore the heterogeneity source. Among the confounding factors, the heterogeneity could be explained by the publication year (P = 0.017, study region (P = 0.014, control group sample size (P = 0.011, total sample size (P = 0.011, and ratio of the case to the control group sample size (RR (P = 0.019. In a stratified analysis by the total sample size, significantly increased risk was only detected in subgroup 2 under an allelic genetic model (OR = 1.93, 95% CI = 1.09 to 3.35, P = 0.02. CONCLUSIONS: In the Chinese Han population, PAI-1 4G/5G gene polymorphism was implied to be associated with increased CAD risk. Carriers of the 4G allele of the PAI-1 4G/5G gene might predispose to CAD.

  5. Plasminogen activator inhibitor-1 4G/5G and the MTHFR 677C/T polymorphisms and susceptibility to polycystic ovary syndrome: a meta-analysis.

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    Lee, Young Ho; Song, Gwan Gyu

    2014-04-01

    The aim of this study was to explore whether the plasminogen activator inhibitor-1 (PAI-1) 4G/5G and the methylenetetrahydrofolate reductase (MTHFR) 677C/T polymorphisms are associated with susceptibility to polycystic ovary syndrome (PCOS). Meta-analyses were conducted to determine the association between the PAI-1 4G/5G and MTHFR 677C/T polymorphisms and PCOS using: (1) allele contrast (2) homozygote contrast, (3) recessive, and (4) dominant models. For meta-analysis, nine studies of the PAI-1 4G/5G polymorphism with 2384 subjects (PCOS, 1615; controls, 769) and eight studies of the MTHFR 677C/T polymorphism with 1270 study subjects were included. Meta-analysis of all study subjects showed no association between PCOS and the PAI-1 4G allele (OR=0.949, 95% CI=0.671-1.343, p=0.767). Stratification by ethnicity, however, indicated a significant association between the PAI-1 4G allele and PCOS in Turkish and Asian populations (OR=0.776, 95% CI=0.602-0.999, p=0.049; OR=1.749, 95% CI=1.297-2.359, p=2.5×10(-5) respectively). In addition, meta-analysis indicated an association between PCOS and the PAI-1 4G4G+4G5G genotype in Europeans (OR=1.406, 95% CI=1.025-1.928, p=0.035). However, meta-analysis of all study subjects showed no association between PCOS and the MTHFR 677T allele (OR=0.998, 95% CI=0.762-1.307, p=0.989), including Europeans (OR=0.806, 95% CI=0.610-1.063, p=0.126). Meta-analysis showed no association between PCOS and the MTHFR 677C/T polymorphism using homozygote contrast, and recessive and dominant models. In conclusion, meta-analysis suggests the PAI-1 4G/5G polymorphism is associated with susceptibility to PCOS in European, Turkish, and Asian populations, but the MTHFR 677C/T polymorphism is not associated with susceptibility to PCOS in Europeans. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  6. Prothrombotic Effect of Anti-beta-2 Glycoprotein-1 Antibodies on the Expression of Tissue Factor, Thrombomodulin, and Plasminogen Activator Inhibitor-1 in Endothelial Cells

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    Rikarni Rikarni

    2015-03-01

    Full Text Available Aim: to analyse the effects of immunoglobulin (IgG and IgM anti-beta-2 glycoprotein-1 (anti-β2GP1 on the expression of tissue factor (TF, thrombomodulin (TM, and plasminogen activator inhibitor-1(PAI-1 of endothelial cells in the messenger RNA level. Methods: laboratory experimental study in human umbilical vein endothelial cells (HUVEC was done at Cipto Mangunkusumo Hospital/Faculty of Medicine, Universitas Indonesia. Samples are purified IgG anti-β2GP1 from six  antiphospholipid syndrome (APS patients serum and IgM anti-β2GP1 from six APS patients serum. For controls, purified IgG from six normal human serum (IgM-NHS and purified IgM from six normal human serum (IgM-NHS were used. HUVEC were treated with purified IgG anti-β2GP1, IgM anti-β2GP1, IgG-NHS, IgM-NHS for four hours of incubation. We measured TF, TM, and PAI-1 of HUVEC in mRNA relative expression levels (before and after treatment by real time reverse transcription polymerase chain reaction. Results: the mean value of TF, TM, and PAI-1 mRNA levels in HUVEC after treated with IgG anti-β2GP1 compared to Ig-NHS were 3.14 (0.93-, 0.31 (0.13-, 5.33 (2.75-fold respectively. In other hand, after treated with IgM anti-β2GP1 compared to IgM-NHS, mRNA levels of TF, TM, and PAI-1 were 4.33 (1.98-, 0.33 (0.22-, 5.47 (2.64-fold respectively. Before and after treatment with IgG anti-β2GP1 showed significant differences of TF mRNA levels {1.09 (0.76 versus 3.14 (0.93, p=0.003}, TM mRNA levels {0.91 (0.11 versus 0.31(0.13, p=0.001}, and PAI-1 mRNA levels 0.93 (0.13 versus 5.33 (2.75, p=0.013}. Before and after treatment with IgM anti-β2GP1 showed significant differences of TF mRNA levels {1.03 (0.11 versus 4.33 (1.98, p=0.008}, TM mRNA levels {0.93 (0.08 versus 0.33 (0.22, p=0.003}, and PAI-1 mRNA levels {1.02 (0.10 versus 5.47 (2.64, p=0.01}. Conclusion: IgG anti-β2GP1 and IgM anti-β2GP1 increased TF and PAI-1 mRNA levels. However, IgG anti-β2GP1 and IgM anti-β2GP1 decreased TM m

  7. Autonomous cross country driving using active vision

    Science.gov (United States)

    Pellkofer, Martin; Hofmann, Ulrich; Dickmanns, Ernst D.

    2003-10-01

    For robust and safe cross country driving, an autonomous ground vehicle must be able to handle conflicts, which may arise from limitations of perception performance, of the dynamics of the vehicle's active camera head and from the feasibility of locomotion maneuvers. This paper describes the interaction and coordination of image processing, gaze control and behavior decision. The behavior decision module specifies the perception tasks for the image processing experts according to the mission, the capabilities of the vehicle and the knowledge about the external world accumulated up to the present time. Depending on its perception task received, an image processing expert specifies combinations of so-called regions of attention (RoA) for each object in 3D object coordinates. These RoA cover relevant object parts and should be visible with a resolution and in a manner as required by the measurement techniques applied. The gaze control unit analyzes the combinations of RoA of all image processing experts in order to plan, optimize and perform a sequence of smooth pursuits, interrupted by saccades. This dynamic interaction has been demonstrated in different complex and scalable autonomous missions with the UBM test vehicle VAMORS. The mission described in this paper makes the vehicle meet an unexpected ditch of unknown size and position forcing the vehicle to reactive behavior regarding locomotion, gaze control as well as image processing.

  8. Influence of decreased fibrinolytic activity and plasminogen activator inhibitor-1 4G/5G polymorphism on the risk of venous thrombosis.

    Science.gov (United States)

    Vuckovic, Biljana A; Djeric, Mirjana J; Tomic, Branko V; Djordjevic, Valentina J; Bajkin, Branislav V; Mitic, Gorana P

    2018-01-01

    : Objective of our study is to determine whether decreased fibrinolytic activity or plasminogen activator inhibitor (PAI)-1 4G/5G polymorphism influence the risk of venous thrombosis.Our case-control study included 100 patients with venous thrombosis, and 100 random controls. When patients were compared with random controls, unconditional logistic regression was used to calculate odds ratios (ORs) with 95% confidence intervals (CIs).Decreased fibrinolytic activity yielded a 2.7-fold increase in risk for venous thrombosis than physiological fibrinolytic activity (OR 2.70; 95% CI 1.22-5.98), when comparing patients with random controls. Adjustment for several putative confounders did not change the estimate (OR 3.02; 95% CI 1.26-7.22). Analysis of venous thrombotic risk influenced by PAI-1 genotype, showed no influence of PAI-1 4G/5G gene variant in comparison with 5G/5G genotype (OR 0.57 95% CI; 0.27-1.20).Decreased fibrinolytic activity increased, whereas PAI-1 4G/5G polymorphism did not influence venous thrombosis risk in this study.

  9. Comparison between the clot-protecting activity of a mutant plasminogen activator inhibitor-1 with a very long half-life and 6-aminocaproic acid.

    Science.gov (United States)

    Kindell, Daniel Glenn; Keck, Rick Wayne; Jankun, Jerzy

    2015-06-01

    Plasminogen activator inhibitor (PAI)-1 is a serpin glycoprotein that can stabilize blood clots by inhibiting fibrinolysis. However, wild-type PAI-1 has the disadvantage of a short half-life of ∼2 h. A very long half-life (VLHL) PAI-1 mutant was developed previously with an active-form half-life of >700 h, making it a possible candidate for use in hemorrhagic therapy. Current treatments for mitigating hemorrhage, other than inducers of blood clotting, are limited to lysine analog antifibrinolytics, including 6-aminocaproic acid and tranexamic acid. VLHL PAI-1 has been previously demonstrated to limit bleeding; however, the efficacy of this protein compared with lysine analog antifibrinolytics has not been investigated. The aim of the current study was to compare the clot stabilizing properties of the novel antifibrinolytic VLHL PAI-1 with those of 6-aminocaproic acid in reference plasma. Using thromboelastographic analysis, VLHL PAI-1 exhibited an IC 50 (half maximal inhibitory concentration) of 8.8×10 -8 mol/l, while 6-aminocaproic acid showed an IC 50 of 1.6×10 -4 mol/l. However, at doses of >9.0×10 -7 mol/l, VLHL PAI-1 exhibited a delay in the onset of clot formation, which may be attributed to thrombin inhibition by excess PAI-1. The inhibition of tissue plasminogen activator by VLHL PAI-1 demonstrated improved efficacy over 6-aminocaproic acid in mitigating hemorrhage. In addition, patients with a PAI-1 deficiency, which causes blood clots to lyse rapidly resulting in profuse bleeding, may benefit from the application of VLHL PAI-1 as an antihemorrhagic therapy.

  10. Concentrations of plasminogen activator inhibitor-1 (PAI-1 and urokinase plasminogen activator (uPA in induced sputum of asthma patients after allergen challenge.

    Directory of Open Access Journals (Sweden)

    Marcin Moniuszko

    2011-04-01

    Full Text Available Urokinase plasminogen activator (uPA and its inhibitor (PAI-1 are involved in tiisue remodeling and repair processes associated with acute and chronic inflammation. The aim of the study was to evaluate the effect of allergen challenge on concentration of uPA and PAI-1 in induced sputum of house dust mite allergic asthmatics (HDM-AAs. Thirty HDM-AAs and ten healthy persons (HCswere recruited for the study. In 24 HDM-AAs bronchial challenge with Dermatophagoides pteronyssinus (Dp and in 6 HDM-AAs sham challenege with saline were performed. In HDM-AAs sputum was induced 24 hours before (T0 and 24 hours (T24 after the challenge. Concentration of uPA and PAI-1 in induced sputum were determined using immunoenzymatic assays. At T0 in HDM-AAs mean sputum uPA (151 Âą 96 pg/ml and PAI-1 (4341 Âą 1262 pg/ml concentrations were higher than in HC (18.8 Âą 6.7 pg/ml; p=0.0002 and 596 Âą 180 pg/ml; p<0.0001; for uPA and PAI-1 respectively. After allergen challenge further increase in sputum uPA (187 Âą 144 pg/ml; p=0.03 and PAI-1 (6252 Âą 2323 pg/ml; p<0.0001 concentrations were observed. Moreover, in Dp challenged, but not in saline challenged HDM-AAs the mean uPA/PAI-1 ratio decreased significantly at T24. No significant increase in the studied parameters were found in sham challenged patients. In HDM-AAs allergen exposure leads to activation of the plasmin system in the airways. Greater increase of the PAI-1 concentration than uPA concentration after allergen challenge may promote airway remodeling and play an important role in the development of bronchial hyperreactivity.

  11. New active machine tool drive mounting on the frame

    Directory of Open Access Journals (Sweden)

    Švéda J.

    2007-10-01

    Full Text Available The paper deals with the new active mounting of the machine tool drives. The commonly used machine tools are at this time mainly equipped with fix-mounting of the feed drives. This structure causes full transmission of the force shocks to the machine bed and thereby restricts the dynamic properties of the motion axis and the whole machine. The spring-mounting of the feed drives is one of the possibilities how to partially suppress the vibrations. The force that reacts to the machine tool bed is transformed thereby the vibrations are lightly reduced. Unfortunately the transformation is not fully controlled. The new active mounting of the machine tool drives allows to fully control the force behaviour that react to the machine body. Thereby the number of excited frequencies on the machine tool bed is significantly reduced. The active variant of the feed drive mounting is characterized by the synergistic cooperation between two series-connected actuators (“motor on motor”. The paper briefly describes design, control techniques and optimization of the feed drives with the new active mounting conception.

  12. Nrf2 Mutagenic Activation Drives Hepatocarcinogenesis.

    Science.gov (United States)

    Ngo, Hoang Kieu Chi; Kim, Do-Hee; Cha, Young-Nam; Na, Hye-Kyung; Surh, Young-Joon

    2017-09-15

    Nrf2, a master regulator of oxidative stress, is considered a prominent target for prevention of hepatocellular carcinoma (HCC), one of the leading causes of cancer-related deaths worldwide. Here we report that Nrf2-deficient mice resisted diethylnitrosamine (DEN)-induced hepatocarcinogenesis without affecting P450-mediated metabolic activation of DEN. Nrf2 expression, nuclear translocation, and transcriptional activity were enhanced in liver tumors. Overactivated Nrf2 was required for hepatoma growth in DEN-induced HCC. Following DEN treatment, Nrf2 genetic disruption reduced expression of pentose phosphate pathway-related enzymes, the depletion of which has been associated with an amelioration of HCC incidence. Conversely, enhanced Nrf2 activity was attributable to alterations in the ability to bind its endogenous inhibitor Keap1. Our findings provide a mechanistic rationale for Nrf2 blockade to prevent and possibly treat liver cancer. Cancer Res; 77(18); 4797-808. ©2017 AACR. ©2017 American Association for Cancer Research.

  13. Phosphorylation of the type II transmembrane serine protease, TMPRSS13, in hepatocyte growth factor activator inhibitor-1 and -2-mediated cell-surface localization.

    Science.gov (United States)

    Murray, Andrew S; Varela, Fausto A; Hyland, Thomas E; Schoenbeck, Andrew J; White, Jordan M; Tanabe, Lauren M; Todi, Sokol V; List, Karin

    2017-09-08

    TMPRSS13 is a member of the type II transmembrane serine protease (TTSP) family. Although various TTSPs have been characterized in detail biochemically and functionally, the basic properties of TMPRSS13 remain unclear. Here, we investigate the activation, inhibition, post-translational modification, and localization of TMPRSS13. We show that TMPRSS13 is a glycosylated, active protease and that its own proteolytic activity mediates zymogen cleavage. Full-length, active TMPRSS13 exhibits impaired cell-surface expression in the absence of the cognate Kunitz-type serine protease inhibitors, hepatocyte growth factor activator inhibitor (HAI)-1 or HAI-2. Concomitant presence of TMPRSS13 with either HAI-1 or -2 mediates phosphorylation of residues in the intracellular domain of the protease, and it coincides with efficient transport of the protease to the cell surface and its subsequent shedding. Cell-surface labeling experiments indicate that the dominant form of TMPRSS13 on the cell surface is phosphorylated, whereas intracellular TMPRSS13 is predominantly non-phosphorylated. These data provide novel insight into the cellular properties of TMPRSS13 and highlight phosphorylation of TMPRSS13 as a novel post-translational modification of this TTSP family member and potentially other members of this family of proteases. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  14. Plasminogen activator inhibitor-1 regulation in cultured rat peritubular cells by basic fibroblast growth factor and transforming growth factor-alpha.

    Science.gov (United States)

    Le Magueresse-Battistoni, B; Pernod, G; Kolodié, L; Benahmed, M

    1996-10-01

    In the present study we examined the in vitro regulation of plasminogen activator inhibitor I (PAI-1) expression in peritubular cells recovered from 20-day-old rat testes. We tested two growth factors, basic fibroblast growth factor (bFGF) and transforming growth factor-alpha (TGF alpha). They are synthesized by Sertoli cells, and peritubular cells exhibit the corresponding high affinity receptors. After exposure to bFGF or TGF alpha (0.1-30 ng/ml), PAI-1 messenger RNA levels, as determined by Northern hybridization analysis, increased in a dose-dependent manner. The first significant effects were noted after 2-h exposure to bFGF or TGF alpha (10 ng/ml), and PAI-1 messenger RNA levels were maximally stimulated approximately 12-fold (bFGF) and 8-fold (TGF alpha) after 4 h. The two growth factors increased the amount of immunoreactive (Western blots) and biologically active (Stachrom) PAI-1 measured in the culture medium. Actinomycin D inhibited the effects of these factors, whereas cycloheximide augmented them. Phorbol myristate acetate, an activator of protein kinase C, mimicked the effects of bFGF and TGF alpha. Interestingly, long term (24-h) pretreatment with phorbol myristate acetate resulted in a severe loss of responsiveness to bFGF or TGF alpha. Staurosporine, an inhibitor of protein kinase C, also significantly reduced the effects of bFGF and TGF alpha. Given that PAI-1 inhibits Sertoli cell plasminogen activator activity and that bFGF and TGF alpha are synthesized by Sertoli cells, these factors are likely to interact to regulate protease activity in localized regions of the seminiferous tubule.

  15. Drive for activity in patients with anorexia nervosa

    NARCIS (Netherlands)

    Sternheim, Lot; Danner, Unna; Adan, Roger; van Elburg, Annemarie

    2014-01-01

    OBJECTIVE: Hyperactivity and elevated physical activity are both considered symptom characteristics of anorexia nervosa (AN). It has been suggested that a drive for activity (DFA) may underlie these expressions, yet research into DFA in AN remains scant. This study investigated DFA levels in

  16. Plasminogen activator inhibitor-1 4G/5G genotype and residual venous occlusion following acute unprovoked deep vein thrombosis of the lower limb: A prospective cohort study.

    Science.gov (United States)

    Giurgea, Georgiana-Aura; Brunner-Ziegler, Sophie; Jilma, Bernd; Sunder-Plassmann, Raute; Koppensteiner, Renate; Gremmel, Thomas

    2017-05-01

    A recent study suggested that the plasminogen activator inhibitor (PAI)-1 4G/5G genotype may play a role in the resolution of deep vein thrombosis (DVT) after surgery. In the present study, we investigated the association between PAI-1 4G/5G genotype and the persistence of venous occlusion after acute idiopathic DVT of the lower limb. The PAI-1 4G/5G genotype was determined by real-Time PCR in 43 patients with unprovoked DVT of the lower limb. Residual venous occlusion was assessed by duplex sonography 1, 3, 6, 12 and 24months after the acute event. The PAI-1 Activity was determined by ELISA. Ten patients (23%) were homozygous for 4G (4G/4G), 27 patients (63%) were heterozygous 4G/5G and 6 patients (14%) were homozygous for 5G (5G/5G). Residual venous occlusion (RVO) was found in 77%, 65%, 58%, 56% and 37% of the overall study population, at 1, 3, 6, 12 and 24months after acute DVT, respectively. The presence of residual venous occlusion at 1, 3, 6, 12 and 24months after acute unprovoked DVT did not differ significantly between genotypes, but age was associated with RVO. Plasma levels of PAI-1 activity correlated with body mass index but was not associated with genotypes in our study. The PAI-1 4G/5G genotype was not a relevant predictor of persistent residual venous occlusion after idiopathic DVT, which however was associated with age. Copyright © 2017 Elsevier Ltd. All rights reserved.

  17. Dosing time-dependent effect of raloxifene on plasma plasminogen activator inhibitor-1 concentrations in post-menopausal women with osteoporosis.

    Science.gov (United States)

    Ando, Hitoshi; Otoda, Toshiki; Ookami, Hitoshi; Nagai, Yukihiro; Inano, Akihiro; Takamura, Toshinari; Ushijima, Kentarou; Hosohata, Keiko; Matsushita, Eiki; Saito, Tetsuo; Kaneko, Shuichi; Fujimura, Akio

    2013-03-01

    Raloxifene, a selective oestrogen receptor modulator commonly used for the treatment of post-menopausal osteoporosis, affects the coagulation and fibrinolytic systems and consequently increases the risk of venous thromboembolism. Because both the coagulation and fibrinolytic systems exhibit circadian rhythms, the aim of the present study was to investigate the effects of dosing time of raloxifene on markers of coagulation and fibrinolysis, as well as on markers of bone metabolism. Thirty-nine post-menopausal patients with osteoporosis were randomly allocated to two groups: one received 60 mg raloxifene once daily in the morning, whereas the other received 60 mg raloxifene once daily in the evening, for 12 months. In both groups, the activity of coagulation Factors IX and XII was increased significantly after 12 months treatment compared with baseline. The activity of coagulation Factors II and V and levels of markers of bone metabolism (i.e. bone alkaline phosphatase and tartrate-resistant acid phosphatase 5b) decreased in both groups. The changes in these markers did not differ between the two groups. In contrast, the plasma concentration of plasminogen activator inhibitor (PAI)-1 increased in the group receiving the morning dose (mean change 40.9%; 95% confidence interval (CI) 9.4, 72.5), but not in the groups receiving the evening dose (mean change -0.3%; 95% CI -31.5, 30.9); these percentage changes differed significantly (P raloxifene influences its safety. Further larger-scale studies are needed to determine the clinical usefulness of chronotherapy with raloxifene. © 2013 The Authors Clinical and Experimental Pharmacology and Physiology © 2013 Wiley Publishing Asia Pty Ltd.

  18. Binding of upstream stimulatory factor 1 to the E-box regulates the 4G/5G polymorphism-dependent plasminogen activator inhibitor 1 expression in mast cells.

    Science.gov (United States)

    Ma, Zhongcai; Jhun, Bongsook; Jung, Sandy Y; Oh, Chad K

    2008-04-01

    Plasminogen activator inhibitor (PAI)-1 is a key regulator of the fibrinolytic system. PAI-1 levels are markedly elevated in the asthmatic airways. The 4G/5G polymorphism of the PAI-1 gene is associated with allergic asthma. To characterize the mechanisms of the 4G/5G-dependent PAI-1 expression in mast cells (MCs), a major source of PAI-1 and key effector cells in asthma. Transcription of PAI-1 was assessed by transiently transfecting human MC line (HMC-1) cells with the luciferase-tagged PAI-1 promoters containing the 4G or 5G allele (4G-PAI-1 or 5G-PAI-1 promoter). Upstream stimulatory factor (USF)-1 and the E-box interactions were studied by electrophoretic mobility shift assays and supershift assays. Expression of USF-1 was determined by Western blot analysis. The 4G-PAI-1 promoter has higher promoter activity than the 5G-PAI-1 promoter in stimulated HMC-1 cells, and the E-box adjacent to the 4G/5G site (E-4G/5G) regulates the genotype-specific PAI-1 transcription. USF-1 binds to the E-4G with greater affinity than to the E-5G. USF-1 level is increased in HMC-1 cells after stimulation, and elevated USF-1 enhances PAI-1 transcription. Overexpression of wild-type USF-1 or dominant-negative USF remedies the 4G/5G-dependent PAI-1 transcription. Binding of USF-1 to the E-4G/5G regulates the 4G/5G polymorphism-dependent PAI-1 expression in MCs.

  19. Neurobiology driving hyperactivity in activity-based anorexia.

    Science.gov (United States)

    Adan, R A H; Hillebrand, J J G; Danner, U N; Cardona Cano, S; Kas, M J H; Verhagen, L A W

    2011-01-01

    Hyperactivity in anorexia nervosa is difficult to control and negatively impacts outcome. Hyperactivity is a key driving force to starvation in an animal model named activity-based anorexia (ABA). Recent research has started unraveling what mechanisms underlie this hyperactivity. Besides a general increase in locomotor activity that may be an expression of foraging behavior and involves frontal brain regions, the increased locomotor activity expressed before food is presented (food anticipatory behavior or FAA) involves hypothalamic neural circuits. Ghrelin plays a role in FAA, whereas decreased leptin signaling is involved in both aspects of increased locomotor activity. We hypothesize that increased ghrelin and decreased leptin signaling drive the activity of dopamine neurons in the ventral tegmental area. In anorexia nervosa patients, this altered activity of the dopamine system may be involved not only in hyperactivity but also in aberrant cognitive processing related to food.

  20. The -675 4G/5G polymorphism in plasminogen activator inhibitor-1 gene is associated with risk of asthma: a meta-analysis.

    Directory of Open Access Journals (Sweden)

    Wei Nie

    Full Text Available BACKGROUND: A number of studies assessed the association of -675 4G/5G polymorphism in the promoter region of plasminogen activator inhibitor (PAI-1 gene with asthma in different populations. However, most studies reported inconclusive results. A meta-analysis was conducted to investigate the association between polymorphism in the PAI-1 gene and asthma susceptibility. METHODS: Databases including Pubmed, EMBASE, HuGE Literature Finder, Wanfang Database, China National Knowledge Infrastructure (CNKI and Weipu Database were searched to find relevant studies. Odds ratios (ORs with 95% confidence intervals (CIs were used to assess the strength of association in the dominant model, recessive model, codominant model, and additive model. RESULTS: Eight studies involving 1817 cases and 2327 controls were included. Overall, significant association between 4G/5G polymorphism and asthma susceptibility was observed for 4G4G+4G5G vs. 5G5G (OR = 1.56, 95% CI 1.12-2.18, P = 0.008, 4G/4G vs. 4G/5G+5G/5G (OR = 1.38, 95% CI 1.06-1.80, P = 0.02, 4G/4G vs. 5G/5G (OR = 1.80, 95% CI 1.17-2.76, P = 0.007, 4G/5G vs. 5G/5G (OR = 1.40, 95% CI 1.07-1.84, P = 0.02, and 4G vs. 5G (OR = 1.35, 95% CI 1.08-1.68, P = 0.008. CONCLUSIONS: This meta-analysis suggested that the -675 4G/5G polymorphism of PAI-1 gene was a risk factor of asthma.

  1. The −675 4G/5G Polymorphism in Plasminogen Activator Inhibitor-1 Gene Is Associated with Risk of Asthma: A Meta-Analysis

    Science.gov (United States)

    Xiu, Qing-yu

    2012-01-01

    Background A number of studies assessed the association of −675 4G/5G polymorphism in the promoter region of plasminogen activator inhibitor (PAI)-1 gene with asthma in different populations. However, most studies reported inconclusive results. A meta-analysis was conducted to investigate the association between polymorphism in the PAI-1 gene and asthma susceptibility. Methods Databases including Pubmed, EMBASE, HuGE Literature Finder, Wanfang Database, China National Knowledge Infrastructure (CNKI) and Weipu Database were searched to find relevant studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association in the dominant model, recessive model, codominant model, and additive model. Results Eight studies involving 1817 cases and 2327 controls were included. Overall, significant association between 4G/5G polymorphism and asthma susceptibility was observed for 4G4G+4G5G vs. 5G5G (OR = 1.56, 95% CI 1.12–2.18, P = 0.008), 4G/4G vs. 4G/5G+5G/5G (OR = 1.38, 95% CI 1.06–1.80, P = 0.02), 4G/4G vs. 5G/5G (OR = 1.80, 95% CI 1.17–2.76, P = 0.007), 4G/5G vs. 5G/5G (OR = 1.40, 95% CI 1.07–1.84, P = 0.02), and 4G vs. 5G (OR = 1.35, 95% CI 1.08–1.68, P = 0.008). Conclusions This meta-analysis suggested that the −675 4G/5G polymorphism of PAI-1 gene was a risk factor of asthma. PMID:22479620

  2. 4G/5G Polymorphism of the plasminogen activator inhibitor-1 gene is associated with multiple organ dysfunction in critically ill patients.

    Science.gov (United States)

    Huq, Muhammad Aminul; Takeyama, Naoshi; Harada, Makoto; Miki, Yasuo; Takeuchi, Akinori; Inoue, Sousuke; Nakagawa, Takashi; Kanou, Hideki; Hirakawa, Akihiko; Noguchi, Hiroshi

    2012-01-01

    Impaired fibrinolysis is associated with a higher incidence of both multiple organ dysfunction and mortality in the intensive care unit (ICU). Plasminogen activator inhibitor (PAI)-1 is the chief inhibitor of fibrinolysis. We investigated the influence of the 4G/5G polymorphism (rs1799768) of the PAI-1 gene on the plasma PAI-1 level and the outcome of critically ill patients. In 41 consecutive patients admitted to the ICU, PAI-1 gene polymorphism was assessed, plasma PAI-1 and arterial lactate concentrations were measured and clinical severity scores were recorded. Homozygotes for the 4G allele had higher plasma levels of PAI-1 antigen. The mean ± SD PAI-1 antigen level was 193.31 ± 167.93 ng/ml for the 4G/4G genotype, 100.67 ± 114.16 ng/ml for the 4G/5G genotype and 0.43 ± 0.53 ng/ml for the 5G/5G genotype. There was a significant correlation between plasma PAI-1 and arterial lactate concentrations, as well as between PAI-1 and severity scores. The mortality rate was 63, 33 and 0% for patients with the 4G/4G, 4G/5G and 5G/5G genotypes, respectively. These results demonstrate that the 4G/5G polymorphism of the PAI-1 gene affects the plasma PAI-1 concentration, which could impair fibrinolysis and cause organ failure, and thus the presence of the 4G allele increases the risk of death. Copyright © 2011 S. Karger AG, Basel.

  3. The -675 4G/5G polymorphism in plasminogen activator inhibitor-1 gene is associated with risk of asthma: a meta-analysis.

    Science.gov (United States)

    Nie, Wei; Li, Bing; Xiu, Qing-Yu

    2012-01-01

    A number of studies assessed the association of -675 4G/5G polymorphism in the promoter region of plasminogen activator inhibitor (PAI)-1 gene with asthma in different populations. However, most studies reported inconclusive results. A meta-analysis was conducted to investigate the association between polymorphism in the PAI-1 gene and asthma susceptibility. Databases including Pubmed, EMBASE, HuGE Literature Finder, Wanfang Database, China National Knowledge Infrastructure (CNKI) and Weipu Database were searched to find relevant studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association in the dominant model, recessive model, codominant model, and additive model. Eight studies involving 1817 cases and 2327 controls were included. Overall, significant association between 4G/5G polymorphism and asthma susceptibility was observed for 4G4G+4G5G vs. 5G5G (OR = 1.56, 95% CI 1.12-2.18, P = 0.008), 4G/4G vs. 4G/5G+5G/5G (OR = 1.38, 95% CI 1.06-1.80, P = 0.02), 4G/4G vs. 5G/5G (OR = 1.80, 95% CI 1.17-2.76, P = 0.007), 4G/5G vs. 5G/5G (OR = 1.40, 95% CI 1.07-1.84, P = 0.02), and 4G vs. 5G (OR = 1.35, 95% CI 1.08-1.68, P = 0.008). This meta-analysis suggested that the -675 4G/5G polymorphism of PAI-1 gene was a risk factor of asthma.

  4. NGF upregulates the plasminogen activation inhibitor-1 in neurons via the calcineurin/NFAT pathway and the Down syndrome-related proteins DYRK1A and RCAN1 attenuate this effect.

    Science.gov (United States)

    Stefos, Georgios C; Soppa, Ulf; Dierssen, Mara; Becker, Walter

    2013-01-01

    Plasminogen activator inhibitor 1 (PAI-1) is a key regulator of the plasminogen activation system. Although several lines of evidence support a significant role of PAI-1 in the brain, the regulation of its expression in neurons is poorly understood. In the present study we tested the hypothesis that NGF induces the upregulation of PAI-1 via the calcineurin/nuclear factor of activated T cells (NFAT) pathway and analysed whether the overexpression of the Down syndrome-related proteins DYRK1A and RCAN1 modulated the effect of NGF on PAI-1 expression. NGF upregulated PAI-1 mRNA levels in primary mouse hippocampal neurons cultured for 3 days in vitro and in the rat pheochromocytoma cell line PC12. Reporter gene assays revealed that NGF activated the calcineurin/NFAT pathway in PC12 cells. Induction of PAI-1 by NGF was sensitive to the calcineurin inhibitor FK506 and the specific inhibition of NFAT activation by the cell permeable VIVIT peptide. Activation of calcineurin/NFAT signalling through other stimuli resulted in a much weaker induction of PAI-1 expression, suggesting that other NGF-induced pathways are involved in PAI-1 upregulation. Overexpression of either DYRK1A or RCAN1 negatively regulated NFAT-dependent transcriptional activity and reduced the upregulation of PAI-1 levels by NGF. The present results show that the calcineurin/NFAT pathway mediates the upregulation of PAI-1 by NGF. The negative effect of DYRK1A and RCAN1 overexpression on NGF signal transduction in neural cells may contribute to the altered neurodevelopment and brain function in Down syndrome.

  5. NGF upregulates the plasminogen activation inhibitor-1 in neurons via the calcineurin/NFAT pathway and the Down syndrome-related proteins DYRK1A and RCAN1 attenuate this effect.

    Directory of Open Access Journals (Sweden)

    Georgios C Stefos

    Full Text Available BACKGROUND: Plasminogen activator inhibitor 1 (PAI-1 is a key regulator of the plasminogen activation system. Although several lines of evidence support a significant role of PAI-1 in the brain, the regulation of its expression in neurons is poorly understood. In the present study we tested the hypothesis that NGF induces the upregulation of PAI-1 via the calcineurin/nuclear factor of activated T cells (NFAT pathway and analysed whether the overexpression of the Down syndrome-related proteins DYRK1A and RCAN1 modulated the effect of NGF on PAI-1 expression. RESULTS: NGF upregulated PAI-1 mRNA levels in primary mouse hippocampal neurons cultured for 3 days in vitro and in the rat pheochromocytoma cell line PC12. Reporter gene assays revealed that NGF activated the calcineurin/NFAT pathway in PC12 cells. Induction of PAI-1 by NGF was sensitive to the calcineurin inhibitor FK506 and the specific inhibition of NFAT activation by the cell permeable VIVIT peptide. Activation of calcineurin/NFAT signalling through other stimuli resulted in a much weaker induction of PAI-1 expression, suggesting that other NGF-induced pathways are involved in PAI-1 upregulation. Overexpression of either DYRK1A or RCAN1 negatively regulated NFAT-dependent transcriptional activity and reduced the upregulation of PAI-1 levels by NGF. CONCLUSION: The present results show that the calcineurin/NFAT pathway mediates the upregulation of PAI-1 by NGF. The negative effect of DYRK1A and RCAN1 overexpression on NGF signal transduction in neural cells may contribute to the altered neurodevelopment and brain function in Down syndrome.

  6. Association of the plasminogen activator inhibitor-1 (PAI-1) Gene -675 4G/5G and -844 A/G promoter polymorphism with risk of keloid in a Chinese Han population.

    Science.gov (United States)

    Wang, Yongjie; Long, Jianhong; Wang, Xiaoyan; Sun, Yang

    2014-10-28

    A keloid is pathological scar caused by aberrant response to skin injuries, characterized by excessive accumulation of histological extracellular matrix, and occurs in genetically susceptible individuals. Plasminogen activator inhibitor-1 (PAI-1) has been implicated in the pathogenesis of keloid. We investigated the association between PAI-1 polymorphisms and plasma PAI-1 level with keloid risk. A total of 242 Chinese keloid patients and 207 controls were enrolled in this study. Polymerase chain reaction-restriction technique was used to determine PAI-1 promoter polymorphism (-675 4G/5G and -844 A/G) distribution. Plasma PAI-1 levels were detected using enzyme-linked immunosorbent assay (ELISA). There was a statistically significant difference in the distribution of PAI-1 -675 4G/5G polymorphism between keloid patients and healthy controls. 4G/4G carriers were more likely to develop keloid. In contrast, the -844 A/G polymorphism distribution did not vary significantly between keloid patients and controls. The keloid patients group had a significantly higher plasma PAI-1 level than the control group. In the -675 4G/4G carrier population, the plasma PAI-1 levels were significant higher in keloid patients compared with controls. Our study provides evidence that PAI-1 promoter polymorphism -675 4G/5G and plasma PAI-1 level are associated with keloid risk. PAI-1 -675 4G/5G polymorphism may be an important hereditary factor responsible for keloid development in the Chinese Han population.

  7. Association of plasminogen activator inhibitor-1 and low-density lipoprotein heterogeneity as a risk factor of atherosclerotic cardiovascular disease with triglyceride metabolic disorder: a pilot cross-sectional study.

    Science.gov (United States)

    Iida, Kiyoshi; Tani, Shigemasa; Atsumi, Wataru; Yagi, Tsukasa; Kawauchi, Kenji; Matsumoto, Naoya; Hirayama, Atsushi

    2017-11-01

    We hypothesized that an increase in plasminogen activator inhibitor 1 (PAI-1) might reduce low-density lipoprotein (LDL) particle size in conjunction with triglyceride (TG) metabolism disorder, resulting in an increased risk of atherosclerotic cardiovascular disease (ASCVD). This study was carried out as a hospital-based cross-sectional study in 537 consecutive outpatients (mean age: 64 years; men: 71%) with one or more risk factors for ASCVD from April 2014 to October 2014 at the Cardiovascular Center of Nihon University Surugadai Hospital. The estimated LDL-particle size was measured as relative LDL migration using polyacrylamide gel electrophoresis with the LipoPhor system.The plasma PAI-1 level, including the tissue PA/PAI-1 complex and the active and latent forms of PAI-1, was determined using a latex photometric immunoassay method. A multivariate regression analysis after adjustments for ASCVD risk factors showed that an elevated PAI-1 level was an independent predictor of smaller-sized LDL-particle in both the overall patients population (β=0.209, PLDL-C) level lower than 100 mg/dl (β=0.276, PLDL-C levels yielded similar findings. Furthermore, in the 310 patients followed up for at least 6 months, a multiple-logistic regression analysis after adjustments for ASCVD risk factors identified the percent changes of the plasma PAI-1 level in the third tertile compared with those in the first tertile as being independently predictive of decreased LDL-particle size [odds ratio (95% confidence interval): 2.11 (1.12/3.40), P=0.02]. The plasma PAI-1 levels may be determined by the degree of obesity and TG metabolic disorders. These factors were also shown to be correlated with a decreased LDL-particle size, increasing the risk of ASCVD, even in nondiabetic patients with well-controlled serum LDL-C levels.

  8. Prothrombin polymorphism A19911G, factor V HR2 haplotype A4070G, and plasminogen activator-inhibitor-1 polymorphism 4G/5G and the risk of retinal vein occlusion.

    Science.gov (United States)

    Kuhli-Hattenbach, Claudia; Hellstern, Peter; Nägler, Dorit Karin; Kohnen, Thomas; Hattenbach, Lars-Olof

    2017-01-01

    Thus far, no data has become available to evaluate systematically the prevalences of prothrombin polymorphism A19911G (PT A19911G), factor V HR2 haplotype A4070G (FV A4070G), or plasminogen activator-inhibitor-1 polymorphism 4G/5G (PAI-1 4G/5G) in patients who develop retinal vein occlusion (RVO) without cardiovascular risk factors. We retrospectively evaluated comprehensive thrombophilia data from 42 preselected RVO patients without cardiovascular risk factors. The prevalences of different gene mutations and polymorphisms including factor V Leiden mutation G1691A (FVL), FV A4070G, prothrombin mutation G20210A, PT A19911G, and PAI-1 4G/5G were compared with 241 healthy controls matched for age and sex. A total of 20 patients (47.7%) were found to carry thrombophilic gene polymorphisms including FVL, FV A4070G, and homozygous PT A19911G compared with 72 of 241 controls (29.9%; p = 0.03). Subgroup analysis of patients with a significant personal or family history of thromboembolism revealed a high prevalence of FVL, FV A4070G, and homozygous PT A19911G (p = 0.005). FV A4070G was found to be significantly associated with at least two other heterozygous or one homozygous gene polymorphisms (p = 0.02). Multivariate analysis revealed the presence of FVL (p = 0.0017) and homozygous PT A19911G (p = 0.03) polymorphism as independent risk factors for the development of RVO. Our results indicate that in selected RVO patients screening for thrombophilic gene polymorphisms including FVL, FV A4070G and homozygous PT G19911A may be helpful in a high percentage of cases. Our findings suggest that hereditary thrombophilia associated with RVO is more likely to be multigenic than caused by any single risk factor.

  9. The plasminogen activator inhibitor-1 (PAI-1) gene -844 A/G and -675 4G/5G promoter polymorphism significantly influences plasma PAI-1 levels in women with polycystic ovary syndrome.

    Science.gov (United States)

    Lin, Sun; Huiya, Zhang; Bo, Liu; Wei, Wei; Yongmei, Guan

    2009-12-01

    Mutations in the plasminogen activator inhibitor-1 (PAI-1) gene, along with increased PAI-1 levels, have been implicated in the pathogenesis of polycystic ovarian syndrome (PCOS). We investigated a possible influence of the promoter polymorphism (-844 A/G and -675 4G/5G) in the PAI-1 gene on plasma PAI-1 levels in 126 PCOS patients and 97 healthy controls. Levels of total testosterone, luteinizing hormone (LH), follicle stimulating hormone (FSH), fasting plasma glucose (FPG), fasting insulin, and PAI-1 were measured, and body mass index (BMI), waist-to-hip ratio (WHR), LH/FSH ratio, and homeostasis model assessment for insulin resistance (HOMA-IR) were calculated. PAI-1 -675 4G/5G and -844 A/G gene polymorphisms were also performed. Total testosterone, fasting insulin, and PAI-1 levels; BMI, LH/FSH, and HOMA-IR were significantly higher in PCOS patients than controls (P 5G or 5G/5G genotype. The plasma PAI-1 levels of the combination of the PAI-1 -844 A/A and -675 4G/4G or 4G/5G genotypes, or the coadunation of 4G/4G and -844 non-G/G (A/A + A/G) genotypes were significantly high in PCOS women compared with controls. A trend to a positive interaction between PAI-1 -675 4G/5G and -844 A/G gene polymorphism may elevate plasma PAI-1 levels and hypofibrinolysis, which is probably an important hereditary risk factor in PCOS.

  10. Design and Analysis of an Active Helical Drive Downhole Tractor

    Science.gov (United States)

    LI, Yujia; LIU, Qingyou; CHEN, Yonghua; REN, Tao

    2017-03-01

    During oil-gas well drilling and completion, downhole tools and apparatus should be conveyed to the destination to complete a series of downhole works. Downhole tractors have been used to convey tools in complex wellbores, however a very large tractive force is needed to carry more downhole tools to accomplish works with high efficiency. A novel serial active helical drive downhole tractor which has significantly improved performance compared with previous work is proposed. All previously reported helical drive downhole tractors need stators to balance the torque generated by the rotator. By contrast, the proposed serial downhole tractor does not need a stator; several rotator-driven units should only be connected to one another to achieve a tractive force multifold higher than that was previously reported. As a result, the length of a single unit is shortened, and the motion flexibility of the downhole tractor is increased. The major performance indicators, namely, gear ratio, velocity, and tractive force, are analyzed. Experimental results show that the maximum tractive force of a single-unit prototype with a length of 900 mm is 165.3 kg or 1620 N. The analysis and experimental results show that the proposed design has considerable potential for downhole works.

  11. Plasminogen activator inhibitor-1 5G/5G genotype is associated with early spontaneous recanalization of the infarct-related artery in patients presenting with acute ST-elevation myocardial infarction.

    Science.gov (United States)

    Cagliyan, Caglar E; Yuregir, Ozge O; Balli, Mehmet; Tekin, Kamuran; Akilli, Rabia E; Bozdogan, Sevcan T; Turkmen, Serdar; Deniz, Ali; Baykan, Oytun A; Aslan, Huseyin; Cayli, Murat

    2013-05-01

    We aimed to examine the association between plasminogen activator inhibitor-1 (PAI-1) genetic polymorphism and early spontaneous recanalization in patients presenting with acute ST-elevation myocardial infarction. Patients admitted to our emergency department with ST-elevation myocardial infarction in the first 6 h of symptom onset were included. An immediate primary percutaneous coronary intervention was performed. Patients were grouped according to the initial patency of the infarct-related artery (IRA) as follows: total occlusion (TO) group [Thrombolysis in Myocardial Infarction (TIMI) 0-1 flow in the IRA], partial recanalization group (TIMI 2 flow in the IRA), and complete recanalization (CR) group (TIMI 3 flow in the IRA). PAI-1 4G/5G polymorphism was detected using the real-time PCR method. There were 107 patients in the TO group, 30 patients in the partial recanalization group, and 45 patients in the CR group. When we evaluated degrees of patency according to the PAI-1 genotype, TO of the IRA was the highest in patients with the PAI 4G/4G genotype (PAI-1 4G/4G: 66.7%, PAI-1 4G/5G: 65.9%, PAI-1 5G/5G: 40.4%) and CR of the IRA was the highest in patients with the PAI 5G/5G genotype (PAI-1 5G/5G: 38.5%, PAI-1 4G/5G: 19.8%, PAI-1 4G/4G: 17.9%). The distribution of genotypes in different degrees of patency of IRA was statistically significant (P=0.029). In logistic regression analysis, the PAI-1 5G/5G genotype was associated independently with the spontaneous CR of the IRA (odds ratio: 2.875, 95% confidence interval [1.059-7.086], P=0.038). Patients with the PAI-1 5G/5G genotype seem to be luckier than others in terms of early spontaneous recanalization of the IRA. Further prospective studies with large patient populations are required for more precise results.

  12. Drive for activity in patients with anorexia nervosa.

    Science.gov (United States)

    Sternheim, Lot; Danner, Unna; Adan, Roger; van Elburg, Annemarie

    2015-01-01

    Hyperactivity and elevated physical activity are both considered symptom characteristics of anorexia nervosa (AN). It has been suggested that a drive for activity (DFA) may underlie these expressions, yet research into DFA in AN remains scant. This study investigated DFA levels in patients with AN and its relation to AN severity. Furthermore, as physical exercise may be a way to reduce negative affect, the influence of negative affect (anxiety) on the role of DFA in AN was tested. Two hundred and forty female patients with AN completed measures for DFA, eating disorder (ED) pathology, anxiety, and clinical parameters. A strong relation between DFA levels and ED pathology was found, which remained significant even after controlling for negative affect (anxiety). After much theorizing about DFA in AN this study provides empirical evidence for DFA as a hallmark feature of AN, independent of anxiety levels. Future research should shed light on the relationships between DFA, actual physical activity, and the course of AN. © 2014 Wiley Periodicals, Inc.

  13. Brain activity during driving with distraction: an immersive fMRI study

    Directory of Open Access Journals (Sweden)

    Tom A Schweizer

    2013-02-01

    Full Text Available Introduction: Non-invasive measurements of brain activity have an important role to play in understanding driving ability. The current study aimed to identify the neural underpinnings of human driving behavior by visualizing the areas of the brain involved in driving under different levels of demand, such as driving while distracted or making left turns at busy intersections. Methods: To capture brain activity during driving, we placed a driving simulator with a fully functional steering wheel and pedals in a 3.0 Tesla functional magnetic resonance imaging (fMRI system. To identify the brain areas involved while performing different real-world driving maneuvers, participants completed tasks ranging from simple (right turns to more complex (left turns at busy intersections. To assess the effects of driving while distracted, participants were asked to perform an auditory task while driving analogous to speaking on a hands-free device and driving. Results: A widely distributed brain network was identified, especially when making left turns at busy intersections compared to more simple driving tasks. During distracted driving, brain activation shifted dramatically from the posterior, visual and spatial areas to the prefrontal cortex. Conclusions: Our findings suggest that the distracted brain sacrificed areas in the posterior brain important for visual attention and alertness to recruit enough brain resources to perform a secondary, cognitive task. The present findings offer important new insights into the scientific understanding of the neuro-cognitive mechanisms of driving behavior and lay down an important foundation for future clinical research.

  14. Oncogenes Activate an Autonomous Transcriptional Regulatory Circuit That Drives Glioblastoma

    Directory of Open Access Journals (Sweden)

    Dinesh K. Singh

    2017-01-01

    Full Text Available Efforts to identify and target glioblastoma (GBM drivers have primarily focused on receptor tyrosine kinases (RTKs. Clinical benefits, however, have been elusive. Here, we identify an SRY-related box 2 (SOX2 transcriptional regulatory network that is independent of upstream RTKs and capable of driving glioma-initiating cells. We identified oligodendrocyte lineage transcription factor 2 (OLIG2 and zinc-finger E-box binding homeobox 1 (ZEB1, which are frequently co-expressed irrespective of driver mutations, as potential SOX2 targets. In murine glioma models, we show that different combinations of tumor suppressor and oncogene mutations can activate Sox2, Olig2, and Zeb1 expression. We demonstrate that ectopic co-expression of the three transcription factors can transform tumor-suppressor-deficient astrocytes into glioma-initiating cells in the absence of an upstream RTK oncogene. Finally, we demonstrate that the transcriptional inhibitor mithramycin downregulates SOX2 and its target genes, resulting in markedly reduced proliferation of GBM cells in vivo.

  15. Closed Loop Control of Active Damped Small DC-link Capacitor Based Drive

    DEFF Research Database (Denmark)

    Maheshwari, Ram Krishan; Munk-Nielsen, Stig

    2010-01-01

    A new method of active damping for small DC-link capacitor based drive system is implemented in stator flux oriented control for an induction machine. The active damping technique is based on a detailed model of the drive system which leads to a very simple implementation. The active damping can ...

  16. Nonconscious activation of an elderly stereotype and speed of driving.

    Science.gov (United States)

    Branaghan, Russell J; Gray, Rob

    2010-04-01

    Under the guise of evaluating a head-up display in a driving simulator, 11 participants (5 men), ages 21 to 35 years, completed scrambled-sentence tasks (while waiting at stop signs) designed to prime an elderly stereotype. Each driver completed both the Elderly Stereotype and Control conditions with order counterbalanced across participants. Further, order of presentation of word sets for each trial was random. Driving speed and driving time between stop signs in the Elderly Stereotype condition were compared to the Control condition in which nonspecific age words were substituted for elderly stereotyped words. Participants showed lower maximum speed and longer driving time in the Elderly Stereotype condition than in the Control condition, even though participants reported no awareness of the theme in the experimental condition.

  17. Endocardial Activation Drives Activation Patterns During Long-Duration Ventricular Fibrillation and Defibrillation.

    Science.gov (United States)

    Panitchob, Nuttanont; Li, Li; Huang, Jian; Ranjan, Ravi; Ideker, Raymond E; Dosdall, Derek J

    2017-12-01

    Understanding the mechanisms that drive ventricular fibrillation is essential for developing improved defibrillation techniques to terminate ventricular fibrillation (VF). Distinct organization patterns of chaotic, regular, and synchronized activity were previously demonstrated in VF that persisted over 1 to 2 minutes (long-duration VF [LDVF]). We hypothesized that activity on the endocardium may be driving these activation patterns in LDVF and that unsuccessful defibrillation shocks may alter activation patterns. The study was performed using a 64-electrode basket catheter on the left ventricle endocardium and 54 6-electrode plunge needles inserted into the left ventricles of 6 dogs. VF was induced electrically, and after short-duration VF (10 seconds) and LDVF (7 minutes), shocks of increasing strengths were delivered every 10 seconds until VF was terminated. Endocardial activation patterns were classified as chaotic (varying cycle lengths and nonsynchronous activations), regular (highly repeatable cycle lengths), and synchronized (activation that spreads rapidly over the endocardium with diastolic periods between activations). The results showed that the chaotic pattern was predominant in early VF, but the regular pattern emerges as VF progressed. The synchronized pattern only emerged occasionally during late VF. Failed defibrillation shocks changed chaotic and regular activation patterns to synchronized patterns in LDVF but not in short-duration VF. The regular and synchronized patterns of activation were driven by rapid activations on the endocardial surface that blocked and broke up transmurally, leading to an endocardial to epicardial activation rate gradient as LDVF progressed. © 2017 American Heart Association, Inc.

  18. Driving an Active Vibration Balancer to Minimize Vibrations at the Fundamental and Harmonic Frequencies

    Science.gov (United States)

    Holliday, Ezekiel S. (Inventor)

    2014-01-01

    Vibrations of a principal machine are reduced at the fundamental and harmonic frequencies by driving the drive motor of an active balancer with balancing signals at the fundamental and selected harmonics. Vibrations are sensed to provide a signal representing the mechanical vibrations. A balancing signal generator for the fundamental and for each selected harmonic processes the sensed vibration signal with adaptive filter algorithms of adaptive filters for each frequency to generate a balancing signal for each frequency. Reference inputs for each frequency are applied to the adaptive filter algorithms of each balancing signal generator at the frequency assigned to the generator. The harmonic balancing signals for all of the frequencies are summed and applied to drive the drive motor. The harmonic balancing signals drive the drive motor with a drive voltage component in opposition to the vibration at each frequency.

  19. Active training and driving-specific feedback improve older drivers' visual search prior to lane changes.

    Science.gov (United States)

    Lavallière, Martin; Simoneau, Martin; Tremblay, Mathieu; Laurendeau, Denis; Teasdale, Normand

    2012-03-02

    Driving retraining classes may offer an opportunity to attenuate some effects of aging that may alter driving skills. Unfortunately, there is evidence that classroom programs (driving refresher courses) do not improve the driving performance of older drivers. The aim of the current study was to evaluate if simulator training sessions with video-based feedback can modify visual search behaviors of older drivers while changing lanes in urban driving. In order to evaluate the effectiveness of the video-based feedback training, 10 older drivers who received a driving refresher course and feedback about their driving performance were tested with an on-road standardized evaluation before and after participating to a simulator training program (Feedback group). Their results were compared to a Control group (12 older drivers) who received the same refresher course and in-simulator active practice as the Feedback group without receiving driving-specific feedback. After attending the training program, the Control group showed no increase in the frequency of the visual inspection of three regions of interests (rear view and left side mirrors, and blind spot). In contrast, for the Feedback group, combining active training and driving-specific feedbacks increased the frequency of blind spot inspection by 100% (32.3 to 64.9% of verification before changing lanes). These results suggest that simulator training combined with driving-specific feedbacks helped older drivers to improve their visual inspection strategies, and that in-simulator training transferred positively to on-road driving. In order to be effective, it is claimed that driving programs should include active practice sessions with driving-specific feedbacks. Simulators offer a unique environment for developing such programs adapted to older drivers' needs.

  20. Active training and driving-specific feedback improve older drivers' visual search prior to lane changes

    Directory of Open Access Journals (Sweden)

    Lavallière Martin

    2012-03-01

    Full Text Available Abstract Background Driving retraining classes may offer an opportunity to attenuate some effects of aging that may alter driving skills. Unfortunately, there is evidence that classroom programs (driving refresher courses do not improve the driving performance of older drivers. The aim of the current study was to evaluate if simulator training sessions with video-based feedback can modify visual search behaviors of older drivers while changing lanes in urban driving. Methods In order to evaluate the effectiveness of the video-based feedback training, 10 older drivers who received a driving refresher course and feedback about their driving performance were tested with an on-road standardized evaluation before and after participating to a simulator training program (Feedback group. Their results were compared to a Control group (12 older drivers who received the same refresher course and in-simulator active practice as the Feedback group without receiving driving-specific feedback. Results After attending the training program, the Control group showed no increase in the frequency of the visual inspection of three regions of interests (rear view and left side mirrors, and blind spot. In contrast, for the Feedback group, combining active training and driving-specific feedbacks increased the frequency of blind spot inspection by 100% (32.3 to 64.9% of verification before changing lanes. Conclusions These results suggest that simulator training combined with driving-specific feedbacks helped older drivers to improve their visual inspection strategies, and that in-simulator training transferred positively to on-road driving. In order to be effective, it is claimed that driving programs should include active practice sessions with driving-specific feedbacks. Simulators offer a unique environment for developing such programs adapted to older drivers' needs.

  1. A five-wheel wheelchair with an active-caster drive system.

    Science.gov (United States)

    Munakata, Yu; Tanaka, Aki; Wada, Masayoshi

    2013-06-01

    A novel wheelchair system with an active-caster drive mechanism is presented in this paper. A manual (hand propelled) wheelchair with an external single-wheel drive system forms a five-wheel configuration. The active-caster mechanism is applied to a drive system to motorize a manual wheelchair. Two electric motors which drive a wheel axis and a steering axis of a drive wheel independently are equipped on the active-caster. A coordinated control of the two motors enables the velocity vector on the steering shaft to direct in an arbitrary direction with an arbitrary magnitude. The generated velocity vector allows a wheelchair to go straight and/or rotate completely in a same way as a standard electric wheelchair. Namely 2DOF of the wheelchair can be controlled independently by a single drive wheel without any constraint, such as the orientation of the drive wheel which is well known as a non-holonomic constraint. In addition to the 2DOF mobility, the proposed system enables wheelchair users to change drive modes, a rear drive and a front drive. The drive wheel on the back side of the wheelchair is vertically actuated by a linear motor to change the height of the drive wheel that can vary load distribution and the number of wheels contacting to the ground. The five-wheel-contact makes the wheelchair to move as the normal mode in which the center of rotation is located at the midpoint of the main wheels. Depressing the drive wheel results in lost contacts of the main wheels from the ground in which the center of rotation is jumped at the midpoint of the front wheels, namely it performs as a front drive wheelchair. In this paper, kinematic models of the wheelchair and that with an active-caster drive system are analyzed and a control method by using a 2DOF joystick is derived. Based on the kinematic model, a prototype mechanism of the active-caster is designed and mounted on a manual wheelchair to realize the five-wheel wheelchair. In the experiments, the independent 2

  2. Active Damping Control Methods for Three-Phase Slim DC-link Drive System

    DEFF Research Database (Denmark)

    Yang, Feng; Wang, Dong; Blaabjerg, Frede

    2017-01-01

    for stabilizing such slim dc-link drives together with the benefit of low cost and high flexibility. This paper gives an overview of the state-of-the-art active damping methods for the three-phase slim dc-link drive. The main pros and cons of each method are identified. The theoretical comparison is validated...

  3. Simulated driving and brain imaging: combining behavior, brain activity, and virtual reality.

    Science.gov (United States)

    Carvalho, Kara N; Pearlson, Godfrey D; Astur, Robert S; Calhoun, Vince D

    2006-01-01

    Virtual reality in the form of simulated driving is a useful tool for studying the brain. Various clinical questions can be addressed, including both the role of alcohol as a modulator of brain function and regional brain activation related to elements of driving. We reviewed a study of the neural correlates of alcohol intoxication through the use of a simulated-driving paradigm and wished to demonstrate the utility of recording continuous-driving behavior through a new study using a programmable driving simulator developed at our center. Functional magnetic resonance imaging data was collected from subjects while operating a driving simulator. Independent component analysis (ICA) was used to analyze the data. Specific brain regions modulated by alcohol, and relationships between behavior, brain function, and alcohol blood levels were examined with aggregate behavioral measures. Fifteen driving epochs taken from two subjects while also recording continuously recorded driving variables were analyzed with ICA. Preliminary findings reveal that four independent components correlate with various aspects of behavior. An increase in braking while driving was found to increase activation in motor areas, while cerebellar areas showed signal increases during steering maintenance, yet signal decreases during steering changes. Additional components and significant findings are further outlined. In summary, continuous behavioral variables conjoined with ICA may offer new insight into the neural correlates of complex human behavior.

  4. An Active Damping Technique for Small DC-Link Capacitor Based Drive System

    DEFF Research Database (Denmark)

    Maheshwari, Ram Krishan; Munk-Nielsen, Stig; Lu, Kaiyuan

    2013-01-01

    A small dc-link capacitor based drive system shows instability when it is operated with large input line inductance at operating points with high power. This paper presents a simple, new active damping technique that can stabilize effectively the drive system at unstable operating points, offering...... greatly reduced input line current total harmonic distortion (THD). The proposed method requires only a first-order, high-pass filter with a gain. Active damping voltage terms, linked directly to the dc-link voltage ripple through gain units, are injected to the drive machine for stabilizing the operating...... points. The stabilizing effect of the active damping terms is demonstrated for an induction machine based drive system. The effects of the added damping terms on the machine current and dc-link voltage are analyzed in detail. A design recommendation for the proposed active damping terms is given...

  5. A longitudinal study of driving instructor guidance from an activity oriented perspective

    OpenAIRE

    BOCCARA, Vincent; Vidal-Gomel, Christine; Rogalski, Janine; Delhomme, Patricia

    2015-01-01

    The aim of this study was to provide a better understanding of the scaffolding activity of instructors during driving lessons in a French urban traffic context. It focuses on three common and risky tasks: turning right, turning left and overtaking. Data were based on fine-grained longitudinal analyses of the records of five driving lessons involving four student-instructor dyads. The instructor scaffolding activity was analyzed throughout training - an original approach in the sphere of drivi...

  6. Age differences in the takeover of vehicle control and engagement in non-driving-related activities in simulated driving with conditional automation.

    Science.gov (United States)

    Clark, Hallie; Feng, Jing

    2017-09-01

    High-level vehicle automation has been proposed as a valuable means to enhance the mobility of older drivers, as older drivers experience age-related declines in many cognitive functions that are vital for safe driving. Recent research attempted to examine age differences in how engagement in non-driving-related activities impact driving performance, by instructing drivers to engage in mandatory pre-designed activities. While the mandatory engagement method allows a precise control of the timing and mental workload of the non-driving-related activities, it is different from how a driver would naturally engage in these activities. This study allowed younger (age 18-35, mean age=19.9years) and older drivers (age 62-81, mean age=70.4years) to freely decide when and how to engage in voluntarily chosen non-driving-related activities during simulated driving with conditional automation. We coded video recordings of participants' engagement in non-driving-related activities. We examined the effect of age, level of activity-engagement and takeover notification interval on vehicle control performance during the takeover, by comparing between the high and low engagement groups in younger and older drivers, across two takeover notification interval conditions. We found that both younger and older drivers engaged in various non-driving-related activities during the automated driving portion, with distinct preferences on the type of activity for each age group (i.e., while younger drivers mostly used an electronic device, older drivers tended to converse). There were also significant differences between the two age groups and between the two notification intervals on various driving performance measures. Older drivers benefited more than younger drivers from the longer interval in terms of response time to notifications. Voluntary engagement in non-driving-related activities did not impair takeover performance in general, although there was a trend of older drivers who were

  7. Interharmonic mitigation of adjustable speed drives using an active DC-link capacitor

    DEFF Research Database (Denmark)

    Soltani, Hamid; Loh, Poh Chiang; Blaabjerg, Frede

    2015-01-01

    operating frequency. As there is a growing discussion about the interharmonic effects on the grid and its limitation, the reduction and mitigation of these components is worthwhile especially when more drives are tied to the grid. This paper proposes a new dc-link active capacitor in order to reduce...... the drive input current interharmonic components. Although the proposed active device is only applied on a voltage source ASD with unbalance load, the concept is general and can also be applied on the multi-pulse thyristor based adjustable speed drives. The study clearly verifies the effectiveness......Current and voltage source Adjustable - Speed Drives (ASDs) exert distortion currents in the grid which may lead to some interharmonic components other than the characteristic harmonic components. The frequencies of the line current interharmonics, generated by these ASDs, depend on the motor...

  8. Spontaneous Activity Drives Local Synaptic Plasticity In Vivo

    NARCIS (Netherlands)

    Winnubst, Johan; Cheyne, Juliette E; Niculescu, Dragos; Lohmann, C.

    2015-01-01

    Spontaneous activity fine-tunes neuronal connections in the developing brain. To explore the underlying synaptic plasticity mechanisms, we monitored naturally occurring changes in spontaneous activity at individual synapses with whole-cell patch-clamp recordings and simultaneous calcium imaging in

  9. 77 FR 32943 - Takes of Marine Mammals Incidental to Specified Activities; Pile Driving in the Columbia River, WA

    Science.gov (United States)

    2012-06-04

    ... Specified Activities; Pile Driving in the Columbia River, WA AGENCY: National Marine Fisheries Service (NMFS..., incidental to pile driving during construction of the Terminal 5 Bulk Potash Handling Facility. DATES... (Eumatopius jubatus) ] incidental to pile driving activities conducted during the construction of the Terminal...

  10. The Use of Active Elements to Reduce the Size and Weight of Passive Components in Adjustable Speed Drives

    DEFF Research Database (Denmark)

    Maheshwari, Ram Krishan

    . To facilitate the design and analysis of the active damping terms, the effects of the active damping terms on the machine current and the DC-link voltage of the drive system are discussed. A design recommendation for the proposed active damping terms is given. Simulation and experimental results verifying......Adjustable speed drives are considered as workhorse of industry due to various applications in different kind of industries. According to a market survey, low voltage drives are most profitable in the drive industries. The drive consists of a machine and a converter, which processes grid power...... and converts into usable power for the machine. The converter consists of active and passive components. The size, weight, and volume of the drive are decided by the passive components since they typically contribute to 75% of the weight and volume of the drive. Most popular topology for the low voltage drive...

  11. Active damping technique for small DC-link capacitor based drive system

    DEFF Research Database (Denmark)

    Maheshwari, Ram Krishan; Munk-Nielsen, Stig; Henriksen, Bjarne

    2010-01-01

    A detailed model of Adjustable Speed Drive (ASD) is discussed, which yield a general rule for active damping in a small DC link based drive. A desired value of input LC resonance damping coefficient can be achieved by changing gain parameters. The modified state space matrix due to active damping...... terms is also presented. The performance of the active damping is evaluated based on experimental results. A simple model is presented which can be used to measure the damping factor provided by the system parameters only....

  12. Membrane hyperpolarization drives cation influx and fungicidal activity of amiodarone.

    Science.gov (United States)

    Maresova, Lydie; Muend, Sabina; Zhang, Yong-Qiang; Sychrova, Hana; Rao, Rajini

    2009-01-30

    Cationic amphipathic drugs, such as amiodarone, interact preferentially with lipid membranes to exert their biological effect. In the yeast Saccharomyces cerevisiae, toxic levels of amiodarone trigger a rapid influx of Ca(2+) that can overwhelm cellular homeostasis and lead to cell death. To better understand the mechanistic basis of antifungal activity, we assessed the effect of the drug on membrane potential. We show that low concentrations of amiodarone (0.1-2 microm) elicit an immediate, dose-dependent hyperpolarization of the membrane. At higher doses (>3 microm), hyperpolarization is transient and is followed by depolarization, coincident with influx of Ca(2+) and H(+) and loss in cell viability. Proton and alkali metal cation transporters play reciprocal roles in membrane polarization, depending on the availability of glucose. Diminishment of membrane potential by glucose removal or addition of salts or in pma1, tok1Delta, ena1-4Delta, or nha1Delta mutants protected against drug toxicity, suggesting that initial hyperpolarization was important in the mechanism of antifungal activity. Furthermore, we show that the link between membrane hyperpolarization and drug toxicity is pH-dependent. We propose the existence of pH- and hyperpolarization-activated Ca(2+) channels in yeast, similar to those described in plant root hair and pollen tubes that are critical for cell elongation and growth. Our findings illustrate how membrane-active compounds can be effective microbicidals and may pave the way to developing membrane-selective agents.

  13. Drive for activity in patients with anorexia nervosa

    NARCIS (Netherlands)

    Sternheim, Lot; Danner, Unna; Adan, Roger; Van Elburg, Annemarie

    2015-01-01

    Method Two hundred and forty female patients with AN completed measures for DFA, eating disorder (ED) pathology, anxiety, and clinical parameters. Objective Hyperactivity and elevated physical activity are both considered symptom characteristics of anorexia nervosa (AN). It has been suggested that a

  14. A longitudinal study of driving instructor guidance from an activity-oriented perspective.

    Science.gov (United States)

    Boccara, V; Vidal-Gomel, C; Rogalski, J; Delhomme, P

    2015-01-01

    The aim of this study was to provide a better understanding of the scaffolding activity of instructors during driving lessons in a French urban traffic context. It focuses on three common and risky tasks: turning right, turning left and overtaking. Data were based on fine-grained longitudinal analyses of the records of five driving lessons involving four student-instructor dyads. The instructor scaffolding activity was analyzed throughout training - an original approach in the sphere of driving. The results show that the instructors implemented the learning process using an integrative approach based on 'cutting' and 'decoupling' the driving task rather than the step-by-step method recommended in the curriculum. They transferred the responsibility of the driving components to the students in a similar order: 1) technical maneuvers, 2) situation identification and 3) goals focusing on other road-users. As expected, student autonomy and efficiency in driving increased as the training progressed. However, at the end of training, uncertainties remained with regard to the execution of basic sub-goals in complex situation; moreover, the instructors were still in charge of the navigational task. The results were discussed and suggestions were made to improve instructor training with a view to increasing their efficiency in teaching students. Copyright © 2014 Elsevier Ltd and The Ergonomics Society. All rights reserved.

  15. Regional Quality Assurance Activity in Higher Education in Southeast Asia: Its Characteristics and Driving Forces

    Science.gov (United States)

    Umemiya, Naoki

    2008-01-01

    This article analyses the characteristics and driving forces of regional quality assurance activity in Southeast Asia, which has been actively promoted in recent years by the ASEAN University Network, an organisation for higher education under the auspices of the Association of Southeast Asian Nations (ASEAN). There are now more collaborative…

  16. Notch activation drives adipocyte dedifferentiation and tumorigenic transformation in mice.

    Science.gov (United States)

    Bi, Pengpeng; Yue, Feng; Karki, Anju; Castro, Beatriz; Wirbisky, Sara E; Wang, Chao; Durkes, Abigail; Elzey, Bennett D; Andrisani, Ourania M; Bidwell, Christopher A; Freeman, Jennifer L; Konieczny, Stephen F; Kuang, Shihuan

    2016-09-19

    Liposarcomas (LPSs) are the most common soft-tissue cancer. Because of the lack of animal models, the cellular origin and molecular regulation of LPS remain unclear. Here, we report that mice with adipocyte-specific activation of Notch signaling (Ad/N1ICD) develop LPS with complete penetrance. Lineage tracing confirms the adipocyte origin of Ad/N1ICD LPS. The Ad/N1ICD LPS resembles human dedifferentiated LPS in histological appearance, anatomical localization, and gene expression signature. Before transformation, Ad/N1ICD adipocytes undergo dedifferentiation that leads to lipodystrophy and metabolic dysfunction. Although concomitant Pten deletion normalizes the glucose metabolism of Ad/N1ICD mice, it dramatically accelerates the LPS prognosis and malignancy. Transcriptomes and lipidomics analyses indicate that Notch activation suppresses lipid metabolism pathways that supply ligands to Pparγ, the master regulator of adipocyte homeostasis. Accordingly, synthetic Pparγ ligand supplementation induces redifferentiation of Ad/N1ICD adipocytes and tumor cells, and prevents LPS development in Ad/N1ICD mice. Importantly, the Notch target HES1 is abundantly expressed in human LPS, and Notch inhibition suppresses the growth of human dedifferentiated LPS xenografts. Collectively, ectopic Notch activation is sufficient to induce dedifferentiation and tumorigenic transformation of mature adipocytes in mouse. © 2016 Bi et al.

  17. Glial activation: a driving force for pathological pain.

    Science.gov (United States)

    Watkins, L R; Milligan, E D; Maier, S F

    2001-08-01

    Pain is classically viewed as being mediated solely by neurons, as are other sensory phenomena. The discovery that spinal cord glia (microglia and astrocytes) amplify pain requires a change in this view. These glia express characteristics in common with immune cells in that they respond to viruses and bacteria, releasing proinflammatory cytokines, which create pathological pain. These spinal cord glia also become activated by certain sensory signals arriving from the periphery. Similar to spinal infection, these signals cause release of proinflammatory cytokines, thus creating pathological pain. Taken together, these findings suggest a new, dramatically different approach to pain control, as all clinical therapies are focused exclusively on altering neuronal, rather than glial, function.

  18. Active waveshaping of AC mains current in direct torque-controlled permanent magnet synchronous motor drive

    Energy Technology Data Exchange (ETDEWEB)

    Singh, Bim; Singh, B.P.; Dwivedi, Sanjeet [Indian Inst. of Technology, Dept. of Electrical Engineering, New Delhi (India)

    2006-07-01

    This paper deals with the power quality improvement of AC mains in Direct Torque-Controlled (DTC) permanent magnet synchronous motor (PMSM) drive using active wave shaping techniques. For this purpose, different topologies for active wave shaping of AC mains current in DTC-based PMSM drive such as single- and two-switch boost power factor correction (PFC) AC-DC converter, asymmetrical two-switch boost PFC AC-DC converter and single-phase voltage source AC-DC converter (VSC) are considered. The models are developed and simulated in MATLAB environment along with the Power System Blockset (PSB) and Simulink toolboxes to compute the relevant power quality performance indices. The simulated results demonstrate the effectiveness of different topologies in improving the power quality of the input AC mains in DTC-based PMSM drive. (Author)

  19. Variant alleles in factor V, prothrombin, plasminogen activator inhibitor-1, methylenetetrahydrofolate reductase and risk of thromboembolism in metastatic colorectal cancer patients treated with first-line chemotherapy plus bevacizumab.

    Science.gov (United States)

    Falvella, F S; Cremolini, C; Miceli, R; Nichetti, F; Cheli, S; Antoniotti, C; Infante, G; Martinetti, A; Marmorino, F; Sottotetti, E; Berenato, R; Caporale, M; Colombo, A; de Braud, F; Di Bartolomeo, M; Clementi, E; Loupakis, F; Pietrantonio, F

    2017-07-01

    Single-nucleotide polymorphisms (SNPs) related to hereditary thrombophilia were investigated as risk factors for thromboembolism in cancer patients. Their effect in metastatic colorectal cancer (mCRC) has never been explored so far. Our aim was to analyse the effect of coagulation factor V (FVL G1691A), prothrombin (PT G20210A), methylenetetrahydrofolate reductase (MTHFR C677T and A1298C) and plasminogen activator inhibitor type 1 (PAI-1 5G/4G) allelic variants in this setting. Fifty-two patients treated with first-line chemotherapy plus bevacizumab who developed a thromboembolic event in their lifetime were initially genotyped. A contemporary cohort of 127 patients who did not experience any thromboembolic event was also analysed. DNA was extracted from peripheral blood and genotypes were determined by real-time PCR, using LightSNiP (TIB MOLBIOL) on LightCcler 480 (Roche). The association between thromboembolism and SNPs was investigated by univariable and multivariable analyses. All SNPs were in Hardy-Weinberg equilibrium (χ2 test P>0.20). FVL G1691A and PT G20210A were present only in heterozygosis in 4 (2.2%) and 7 (3.9%) patients, respectively; MTHFR C677T in homozygosis in 29 (16.2%), MTHFR A1298C in homozygosis in 13 (7.3%); PAI-1 5G/4G in 98 (54.7%) and 4G/4G in 41 (23%) patients. At univariable analysis, treatment duration was significantly associated with thromboembolism (P<0.001), whereas gender, age, obesity, platelets count and chemotherapy backbone were not. Similarly, FVL G1691A and PT G20210A as well as MTHFR C677T and PAI-1 4G allele were significantly associated, whereas MTHFR A1298C was not. At multivariable model including PT G20210A, MTHFR C677T and PAI-1 4G (age, obesity, treatment duration and chemotherapy backbone were included as adjustment factors), the three SNPs were significantlty associated with higher risk of thromboembolism (P=0.025, <0.0001 and P=0.033, respectively). Further validation studies are warranted in order to design a

  20. Early pregnancy plasminogen activator inhibitor-1 levels in Nigerian ...

    African Journals Online (AJOL)

    1 (PAI‑1) in normal pregnancy and preeclampsia and determined its relationship with disease severity. Subjects and Methods: This was a prospective cohort study of 195 normotensive, aproteinuric pregnant women without prior history of ...

  1. The effect of low-level laser therapy as an adjunct to non-surgical periodontal treatment on gingival crevicular fluid levels of transforming growth factor-beta 1, tissue plasminogen activator and plasminogen activator inhibitor 1 in smoking and non-smoking chronic periodontitis patients: A split-mouth, randomized control study.

    Science.gov (United States)

    Pamuk, F; Lütfioğlu, M; Aydoğdu, A; Koyuncuoglu, C Z; Cifcibasi, E; Badur, O S

    2017-10-01

    This study aimed to investigate the effects of low-level laser therapy (LLLT) as an adjunct to scaling and root planing (SRP) on smoking and non-smoking patients with chronic periodontitis. The study was conducted using a split-mouth design with 30 patients with chronic periodontitis (15 smokers, 15 non-smokers) and 30 healthy individuals matched for age, sex and smoking status as controls. Groups were constituted as follows: Cp+SRP+Sham: non-smokers with chronic periodontitis treated with SRP; Cp+SRP+LLLT: non-smokers with chronic periodontitis treated with SRP+LLLT; SCp+SRP+Sham: smokers with chronic periodontitis treated with SRP; SCp+SRP+LLLT: smokers with chronic periodontitis treated with SRP+LLLT; C: control group comprised of periodontally healthy non-smokers; SC: control group comprised of periodontally healthy smokers. LLLT was first applied on the same day as SRP and again on days 2 and 7 after SRP treatment. Clinical parameters were recorded before non-surgical periodontal treatment (baseline) and on day 30. Gingival crevicular fluid samples were collected before periodontal treatment (baseline) and during follow-up visits on days 7, 14 and 30. Gingival crevicular fluid transforming growth factor (TGF)-β1, tissue plasminogen activator (tPA) and plasminogen activator inhibitor 1 (PAI-1) levels were measured using enzyme-linked immunosorbent assay. All clinical parameters showed significant reductions between baseline and day 30 following SRP treatment in both the LLLT and sham groups (P.05). Gingival crevicular fluid PAI-1 levels decreased significantly in the SCp+SRP+sham and SCp+SRP+LLLT groups (P.05) at any of the time points measured, both LLLT groups showed significant reductions in tPA/PAI-1 ratios over time. Within the limits of this study, LLLT may be understood to play a role in the modulation of periodontal tissue tPA and PAI-1 gingival crevicular fluid levels, particularly in smoking patients with chronic periodontitis, and may thus be

  2. Influence of seat tilt motion on discomfort perception during a simulated driving activity.

    Science.gov (United States)

    Maradei, Fernanda; Quintana, Leonardo; Castellanos, Javier

    2017-01-01

    Discomfort perceived in activities where there is a prolonged sitting posture are normally compensated in a natural way by means of macro-repositioning movements in the seat. Nevertheless, evidence shows that such movements are not able to palliate discomfort due to lumbar pain. This study involves research performed to demonstrate whether induced postural changes are able to mitigate this type of discomfort during a simulated driving activity. Twenty-four subjects with lumbar pain (LBP) and without lumbar pain (WLBP) underwent 90 min of simulated driving activities while periodic variations of seat tilt (Tt) were implemented. Discomfort perception due to lumbar pain significantly decreased in the case of Tt compared with the case of WTt (without seat tilt), and significant differences were found (p = 0.02). However, treatments with Tt indicated that no substantial differences exist between LBP and WLBP subjects when considering discomfort perception due to lumbar pain and the erector spinae activity. This study revealed that periodic variations on seat tilt can help to reduce discomfort perception due to lumbar pain during driving activities, regardless of the health condition of the subject.

  3. Modelling and Design of Active Thermal Controls for Power Electronics of Motor Drive Applications

    DEFF Research Database (Denmark)

    Vernica, Ionut; Blaabjerg, Frede; Ma, Ke

    2017-01-01

    of active thermal control methods for the power devices of a motor drive application. The motor drive system together with the thermal cycling of the power devices have been modelled, and adverse temperature swings could be noticed during the start-up and deceleration periods of the motor. Based......One of the major factors that affects the overall efficiency and reliability of power electronics systems is the dynamical variation of the thermal stress which occurs in the power semiconductor devices. Therefore, the main objective of this paper consists of designing and implementing a series...... on the electrical response of the system, the junction temperature of the semiconductor devices is estimated, and consequently three active thermal control methods are proposed and practically designed with respect to the following parameters: switching frequency, deceleration slope and modulation technique...

  4. Positive correlation between drowsiness and prefrontal activation during a simulated speed-control driving task.

    Science.gov (United States)

    Liu, Tao

    2014-11-12

    The present study aimed to examine the relationship between drowsiness and prefrontal activation during simulated driving tasks using a wireless portable near-infrared spectroscopy device. Participants drove from start to goal along default routes with either intentional control of their driving speed (speed-control group) or not (speed-free group). Drowsiness level was assessed using a five-item Likert-type questionnaire. The behavioral data indicated longer driving time in the speed-control group than in the speed-free group, whereas no difference in the number of errors was found between the two groups. Importantly, the speed-control group showed a significant positive correlation between the drowsiness score and left prefrontal activation, whereas the speed-free group did not. The results suggest that drowsy individuals may show increased prefrontal activation as compensatory efforts to maintain the desired level of performance in tasks that require deliberate control of behaviors. Furthermore, the present study shows that near-infrared spectroscopy may provide us with a possibility to examine the state of drowsiness during daily-life operations.

  5. Driving things

    DEFF Research Database (Denmark)

    Nevile, Maurice Richard

    2015-01-01

    I explore how participants organise involvement with objects brought into the car, relative to the demands of driving and social activity. Objects in cars commonly include phones or other technologies, food, body care products, texts, clothing, bags and carry items, toys, and even animals...... 2004, Haddington et al. 2012). I focus here especially on how the practical and interactional work of locating, seeing, placing, handling, hearing, and relinquishing, is ordered and accomplished relative to the emerging and contingent demands of both driving and social participation...... of in-car distractions, and how they impact driving activities (Nevile & Haddington 2010). Data are video recordings of ordinary journeys, capturing drivers and passengers in real-world real-time driving situations (27 hours, 90 journeys). For driving and road safety, research and experience has...

  6. Improving long term driving comfort by taking breaks - How break activity affects effectiveness.

    Science.gov (United States)

    Sammonds, George M; Mansfield, Neil J; Fray, Mike

    2017-11-01

    During long duration journeys, drivers are encouraged to take regular breaks. The benefits of breaks have been documented for safety; breaks may also be beneficial for comfort. The activity undertaken during a break may influence its effectiveness. Volunteers completed 3 journeys on a driving simulator. Each 130 min journey included a 10 min break after the first hour. During the break volunteers either stayed seated, left the simulator and sat in an adjacent room, or took a walk on a treadmill. The results show a reduction in driver discomfort during the break for all 3 conditions, but the effectiveness of the break was dependent on activity undertaken. Remaining seated in the vehicle provided some improvement in comfort, but more was experienced after leaving the simulator and sitting in an adjacent room. The most effective break occurred when the driver walked for 10 min on a treadmill. The benefits from taking a break continued until the end of the study (after a further hour of driving), such that comfort remained the best after taking a walk and worst for those who remained seated. It is concluded that taking a break and taking a walk is an effective method for relieving driving discomfort. Copyright © 2017 Elsevier Ltd. All rights reserved.

  7. 76 FR 51947 - Small Takes of Marine Mammals Incidental to Specified Activities; Pile Driving in the Columbia...

    Science.gov (United States)

    2011-08-19

    ... Specified Activities; Pile Driving in the Columbia River, WA AGENCY: National Marine Fisheries Service (NMFS... marine mammals, by harassment, incidental to pile driving during construction of the Terminal 5 Bulk...), California sea lions (Zalophus californianus), and Steller sea lions (Eumatopius jubatus) incidental to pile...

  8. 77 FR 39471 - Small Takes of Marine Mammals Incidental to Specified Activities; Pile Driving in Port Townsend...

    Science.gov (United States)

    2012-07-03

    ... Specified Activities; Pile Driving in Port Townsend Bay, WA AGENCY: National Marine Fisheries Service (NMFS... Harassment Authorization (IHA) to take marine mammals, by harassment, incidental to pile driving during... elephant seals (Mirounga angustirostris) and Steller sea lions (Eumatopius jubatus) incidental to pile...

  9. Analysis of voltage modulation based active damping techniques for small DC-link drive system

    DEFF Research Database (Denmark)

    Wang, Dong; Lu, Kaiyuan; Rasmussen, Peter Omand

    2015-01-01

    Small DC-link drive system, built with film capacitor in the DC link, may have the advantages of longer lifetime and the possibility to achieve a more compact design of capacitor bank at medium and high power rates. However, it exhibits instability problem, especially when it is fed by a soft grid...... without the requirements of the information of system parameters and operating conditions. Finally, active damping techniques with minimized current magnitude and total duty cycle are discussed, in order to fit various operating conditions. Simulation and experimental results are presented to verify...

  10. Integrin adhesion drives the emergent polarization of active cytoskeletal stresses to pattern cell delamination.

    Science.gov (United States)

    Meghana, C; Ramdas, Nisha; Hameed, Feroz Meeran; Rao, Madan; Shivashankar, G V; Narasimha, Maithreyi

    2011-05-31

    Tissue patterning relies on cellular reorganization through the interplay between signaling pathways and mechanical stresses. Their integration and spatiotemporal coordination remain poorly understood. Here we investigate the mechanisms driving the dynamics of cell delamination, diversely deployed to extrude dead cells or specify distinct cell fates. We show that a local mechanical stimulus (subcellular laser perturbation) releases cellular prestress and triggers cell delamination in the amnioserosa during Drosophila dorsal closure, which, like spontaneous delamination, results in the rearrangement of nearest neighbors around the delaminating cell into a rosette. We demonstrate that a sequence of "emergent cytoskeletal polarities" in the nearest neighbors (directed myosin flows, lamellipodial growth, polarized actomyosin collars, microtubule asters), triggered by the mechanical stimulus and dependent on integrin adhesion, generate active stresses that drive delamination. We interpret these patterns in the language of active gels as asters formed by active force dipoles involving surface and body stresses generated by each cell and liken delamination to mechanical yielding that ensues when these stresses exceed a threshold. We suggest that differential contributions of adhesion, cytoskeletal, and external stresses must underlie differences in spatial pattern.

  11. Lower Cortisol Activity is Associated with First-Time Driving while Impaired

    Directory of Open Access Journals (Sweden)

    Sophie Couture

    2015-01-01

    Full Text Available Driving while impaired (DWI is a grave and persistent high-risk behavior. Previous work demonstrated that DWI recidivists had attenuated cortisol reactivity compared to non-DWI drivers. This suggests that cortisol is a neurobiological marker of high-risk driving. The present study tested the hypothesis that this initial finding would extend to first-time DWI (fDWI offenders compared to non-DWI drivers. Male fDWI offenders ( n = 139 and non-DWI drivers ( n = 31 were exposed to a stress task, and their salivary cortisol activity (total output and reactivity was measured. Participants also completed questionnaires on sensation seeking, impulsivity, substance use, and engagement in risky and criminal behaviors. As hypothesized, fDWI offenders, compared to non-DWI drivers, had lower cortisol reactivity; fDWI offenders also showed lower total output. In addition, cortisol activity was the most important predictor of group membership, after accounting for alcohol misuse patterns and consequences and other personality and problem behavior characteristics. The findings indicate that attenuated cortisol activity is an independent factor associated with DWI offending risk at an earlier stage in the DWI trajectory than previously detected.

  12. Driving dreams: cortical activations during imagined passive and active whole body movement.

    Science.gov (United States)

    Flanagin, Virginia L; Wutte, Magdalena; Glasauer, Stefan; Jahn, Klaus

    2009-05-01

    It is unclear how subjects perceive and process self-motion cues in virtual reality environments. Movement could be perceived as passive, akin to riding in a car, or active, such as walking down the street. These two very different types of self-motion were studied here using motor imagery in fMRI. In addition, the relative importance of visual and proprioceptive training cues was examined. Stronger activations were found during proprioceptive motor imagery compared with visual motor imagery, suggesting that proprioceptive signals are important for successful imagined movement. No significant activations were found during active movement with proprioceptive training. Passive locomotion, however, was correlated with activity in an occipital-parietal and parahippocampal cortical network, which are the same regions found during navigation with virtual reality stimuli.

  13. Tonic activity of carotid body chemoreceptors contributes to the increased sympathetic drive in essential hypertension.

    Science.gov (United States)

    Siński, Maciej; Lewandowski, Jacek; Przybylski, Jacek; Bidiuk, Joanna; Abramczyk, Piotr; Ciarka, Agnieszka; Gaciong, Zbigniew

    2012-05-01

    Carotid chemoreceptors provoke an increase in muscle sympathetic nerve activation (MSNA) in response to hypoxia; they are also tonically active during normoxic breathing. The contribution of peripheral chemoreceptors to sympathetic activation in hypertension is incompletely understood. The aim of our study was to investigate the effect of chemoreceptor deactivation on sympathetic activity in untreated patients with hypertension. A total of 12 untreated hypertensive males and 11 male controls participated in this randomized, crossover, placebo-controlled study. MSNA, systolic blood pressure(BP), diastolic BP, heart rate (HR), electrocardiogram, hemoglobin oxygen saturation (Sat%) and respiratory movements were measured during repeated 10-min periods of respiration with 100% oxygen or 21% oxygen in a blinded fashion. Compared with controls, hypertensives had higher resting MSNA (38 ± 10 vs. 29 ± 0.9 burst per min, Pchemoreceptor deactivation with hyperoxia. HR decreased and Sat% increased in both the study groups. These results confirm the role of tonic chemoreceptor drive in the development of sympathetic overactivity in hypertension.

  14. EEG-based decoding of error-related brain activity in a real-world driving task

    Science.gov (United States)

    Zhang, H.; Chavarriaga, R.; Khaliliardali, Z.; Gheorghe, L.; Iturrate, I.; Millán, J. d. R.

    2015-12-01

    Objectives. Recent studies have started to explore the implementation of brain-computer interfaces (BCI) as part of driving assistant systems. The current study presents an EEG-based BCI that decodes error-related brain activity. Such information can be used, e.g., to predict driver’s intended turning direction before reaching road intersections. Approach. We executed experiments in a car simulator (N = 22) and a real car (N = 8). While subject was driving, a directional cue was shown before reaching an intersection, and we classified the presence or not of an error-related potentials from EEG to infer whether the cued direction coincided with the subject’s intention. In this protocol, the directional cue can correspond to an estimation of the driving direction provided by a driving assistance system. We analyzed ERPs elicited during normal driving and evaluated the classification performance in both offline and online tests. Results. An average classification accuracy of 0.698 ± 0.065 was obtained in offline experiments in the car simulator, while tests in the real car yielded a performance of 0.682 ± 0.059. The results were significantly higher than chance level for all cases. Online experiments led to equivalent performances in both simulated and real car driving experiments. These results support the feasibility of decoding these signals to help estimating whether the driver’s intention coincides with the advice provided by the driving assistant in a real car. Significance. The study demonstrates a BCI system in real-world driving, extending the work from previous simulated studies. As far as we know, this is the first online study in real car decoding driver’s error-related brain activity. Given the encouraging results, the paradigm could be further improved by using more sophisticated machine learning approaches and possibly be combined with applications in intelligent vehicles.

  15. Alternaria-derived serine protease activity drives IL-33-mediated asthma exacerbations.

    Science.gov (United States)

    Snelgrove, Robert J; Gregory, Lisa G; Peiró, Teresa; Akthar, Samia; Campbell, Gaynor A; Walker, Simone A; Lloyd, Clare M

    2014-09-01

    The fungal allergen Alternaria alternata is implicated in severe asthma and rapid onset life-threatening exacerbations of disease. However, the mechanisms that underlie this severe pathogenicity remain unclear. We sought to investigate the mechanism whereby Alternaria was capable of initiating severe, rapid onset allergic inflammation. IL-33 levels were quantified in wild-type and ST2(-/-) mice that lacked the IL-33 receptor given inhaled house dust mite, cat dander, or Alternaria, and the effect of inhibiting allergen-specific protease activities on IL-33 levels was assessed. An exacerbation model of allergic airway disease was established whereby mice were sensitized with house dust mite before subsequently being challenged with Alternaria (with or without serine protease activity), and inflammation, remodeling, and lung function assessed 24 hours later. Alternaria, but not other common aeroallergens, possessed intrinsic serine protease activity that elicited the rapid release of IL-33 into the airways of mice through a mechanism that was dependent upon the activation of protease activated receptor-2 and adenosine triphosphate signaling. The unique capacity of Alternaria to drive this early IL-33 release resulted in a greater pulmonary inflammation by 24 hours after challenge relative to the common aeroallergen house dust mite. Furthermore, this Alternaria serine protease-IL-33 axis triggered a rapid, augmented inflammation, mucus release, and loss of lung function in our exacerbation model. Alternaria-specific serine protease activity causes rapid IL-33 release, which underlies the development of a robust TH2 inflammation and exacerbation of allergic airway disease. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

  16. Alternaria-derived serine protease activity drives IL-33–mediated asthma exacerbations

    Science.gov (United States)

    Snelgrove, Robert J.; Gregory, Lisa G.; Peiró, Teresa; Akthar, Samia; Campbell, Gaynor A.; Walker, Simone A.; Lloyd, Clare M.

    2014-01-01

    Background The fungal allergen Alternaria alternata is implicated in severe asthma and rapid onset life-threatening exacerbations of disease. However, the mechanisms that underlie this severe pathogenicity remain unclear. Objective We sought to investigate the mechanism whereby Alternaria was capable of initiating severe, rapid onset allergic inflammation. Methods IL-33 levels were quantified in wild-type and ST2−/− mice that lacked the IL-33 receptor given inhaled house dust mite, cat dander, or Alternaria, and the effect of inhibiting allergen-specific protease activities on IL-33 levels was assessed. An exacerbation model of allergic airway disease was established whereby mice were sensitized with house dust mite before subsequently being challenged with Alternaria (with or without serine protease activity), and inflammation, remodeling, and lung function assessed 24 hours later. Results Alternaria, but not other common aeroallergens, possessed intrinsic serine protease activity that elicited the rapid release of IL-33 into the airways of mice through a mechanism that was dependent upon the activation of protease activated receptor-2 and adenosine triphosphate signaling. The unique capacity of Alternaria to drive this early IL-33 release resulted in a greater pulmonary inflammation by 24 hours after challenge relative to the common aeroallergen house dust mite. Furthermore, this Alternaria serine protease–IL-33 axis triggered a rapid, augmented inflammation, mucus release, and loss of lung function in our exacerbation model. Conclusion Alternaria-specific serine protease activity causes rapid IL-33 release, which underlies the development of a robust TH2 inflammation and exacerbation of allergic airway disease. PMID:24636086

  17. Imidazoline 1 receptor activation preserves respiratory drive in spontaneously breathing newborn rats during dexmedetomidine administration.

    Science.gov (United States)

    Sato, Nana; Saiki, Chikako; Tamiya, Junko; Imai, Toshio; Sunada, Katsuhisa

    2017-05-01

    Dexmedetomidine is an alpha-2 (α2 ) adrenoceptor and imidazoline 1 (I1 ) receptor agonist that provides sedation without loss of respiratory drive. The aim of this study was to elucidate the involvement of α2 -adrenoceptor and I1 receptor in the cardiorespiratory changes induced by dexmedetomidine in spontaneously breathing newborn rats. An abdominal catheter to administer drugs and three subcutaneous electrodes to record electrocardiographic data were inserted into 2- to 5-day-old Wistar rats under isoflurane anesthesia. In individual chambers, each rat was intraperitoneally administered dexmedetomidine (50 μg·kg(-1) ) followed 5 min later by normal saline or 1, 5, or 10 mg·kg(-1) atipamezole (selective α2 -adrenoceptor antagonist) or efaroxan (α2 -adrenoceptor/I1 receptor antagonist). Cardiorespiratory indices were recorded before and after drug administration. The administration of dexmedetomidine alone resulted in significant changes to most of the cardiorespiratory indices examined. The addition of 5 or 10 mg·kg(-1) atipamezole or 1 mg·kg(-1) efaroxan completely ameliorated the dexmedetomidine-associated reduction in heart rate (HR). The addition of 1 mg·kg(-1) atipamezole or 1 or 5 mg·kg(-1) efaroxan completely ameliorated the dexmedetomidine-associated reduction in respiratory frequency. Mean inspiratory flow (VT /TI ; VT is tidal volume and TI is inspiratory time), which is an index of respiratory drive, was not significantly affected by the administration of dexmedetomidine alone (P = 0.273) or dexmedetomidine + atipamezole (P = 0.605, 0.153, 0.138 for 1, 5, 10 mg·kg(-1) atipamezole, respectively); however, it was significantly decreased after the administration of dexmedetomidine + efaroxan (P = 0.029, dexmedetomidine sedation, the α2 -adrenoceptor, but not I1 receptor, is involved in the regulation of HR and respiratory frequency, and that activation of the I1 receptor plays a major role in the maintenance of respiratory drive. © 2017 John

  18. Inductance and Active Phase Vector Based Torque Control for Switched Reluctance Motor Drives.

    Science.gov (United States)

    Kalpathi, Ramani Raman

    The Switched Reluctance Motor (SRM) drive technology has developed significantly over the last few years. The simplicity in both motor design and power converter requirement along with the availability of high frequency, high power semiconductor switches have made SRMs compete with conventional adjustable speed drive technologies. The subject of winding current control in switched reluctance machines has always been associated with the shaft position information. The use of inductance for direct commutation control is the central subject of this dissertation. In contrast to the conventional methods based on position commutation, new methods of control based on inductance commutation are presented. The object of a commutation algorithm is to switch the currents in the phase coils, in order to provide continuous energy conversion with maximum torque output for a given unit of input current. Since torque production in a SRM is based on the concept of variable reluctance, it makes more sense to observe the instantaneous phase inductance or reluctance instead of estimating the rotor position. The inductance sensors observe the machine parameters and provide sufficient information on the electrical characteristics of the coils. This control strategy avoids the inductance to position transformation blocks conventionally used in SRM control systems. In a typical SRM, the phase coils have a nonlinear behavior of inductance due to effects of current saturation. Also the parameters of one phase coil differ from those of the other due to manufacturing tolerances or due to bearing wear. In such cases, the algorithms written during the stage of manufacturing may not be valid after parameter changes. Optimizing torque production in the event of phase asymmetry and saturation is developed in this research. Indirect sensors connected to the active phase coil of the SRM are based on sensing the flux level in the active coil. New commutation algorithms based on flux sensing concepts

  19. Wind from the black-hole accretion disk driving a molecular outflow in an active galaxy.

    Science.gov (United States)

    Tombesi, F; Meléndez, M; Veilleux, S; Reeves, J N; González-Alfonso, E; Reynolds, C S

    2015-03-26

    Powerful winds driven by active galactic nuclei are often thought to affect the evolution of both supermassive black holes and their host galaxies, quenching star formation and explaining the close relationship between black holes and galaxies. Recent observations of large-scale molecular outflows in ultraluminous infrared galaxies support this quasar-feedback idea, because they directly trace the gas from which stars form. Theoretical models suggest that these outflows originate as energy-conserving flows driven by fast accretion-disk winds. Proposed connections between large-scale molecular outflows and accretion-disk activity in ultraluminous galaxies were incomplete because no accretion-disk wind had been detected. Conversely, studies of powerful accretion-disk winds have until now focused only on X-ray observations of local Seyfert galaxies and a few higher-redshift quasars. Here we report observations of a powerful accretion-disk wind with a mildly relativistic velocity (a quarter that of light) in the X-ray spectrum of IRAS F11119+3257, a nearby (redshift 0.189) optically classified type 1 ultraluminous infrared galaxy hosting a powerful molecular outflow. The active galactic nucleus is responsible for about 80 per cent of the emission, with a quasar-like luminosity of 1.5 × 10(46) ergs per second. The energetics of these two types of wide-angle outflows is consistent with the energy-conserving mechanism that is the basis of the quasar feedback in active galactic nuclei that lack powerful radio jets (such jets are an alternative way to drive molecular outflows).

  20. Avoidance of wind farms by harbour seals is limited to pile driving activities.

    Science.gov (United States)

    Russell, Debbie J F; Hastie, Gordon D; Thompson, David; Janik, Vincent M; Hammond, Philip S; Scott-Hayward, Lindesay A S; Matthiopoulos, Jason; Jones, Esther L; McConnell, Bernie J

    2016-12-01

    As part of global efforts to reduce dependence on carbon-based energy sources there has been a rapid increase in the installation of renewable energy devices. The installation and operation of these devices can result in conflicts with wildlife. In the marine environment, mammals may avoid wind farms that are under construction or operating. Such avoidance may lead to more time spent travelling or displacement from key habitats. A paucity of data on at-sea movements of marine mammals around wind farms limits our understanding of the nature of their potential impacts.Here, we present the results of a telemetry study on harbour seals Phoca vitulina in The Wash, south-east England, an area where wind farms are being constructed using impact pile driving. We investigated whether seals avoid wind farms during operation, construction in its entirety, or during piling activity. The study was carried out using historical telemetry data collected prior to any wind farm development and telemetry data collected in 2012 during the construction of one wind farm and the operation of another.Within an operational wind farm, there was a close-to-significant increase in seal usage compared to prior to wind farm development. However, the wind farm was at the edge of a large area of increased usage, so the presence of the wind farm was unlikely to be the cause.There was no significant displacement during construction as a whole. However, during piling, seal usage (abundance) was significantly reduced up to 25 km from the piling activity; within 25 km of the centre of the wind farm, there was a 19 to 83% (95% confidence intervals) decrease in usage compared to during breaks in piling, equating to a mean estimated displacement of 440 individuals. This amounts to significant displacement starting from predicted received levels of between 166 and 178 dB re 1 μPa(p-p). Displacement was limited to piling activity; within 2 h of cessation of pile driving, seals were distributed as per

  1. MRL proteins cooperate with activated Ras in glia to drive distinct oncogenic outcomes

    Science.gov (United States)

    Taylor, E; Alqadri, N; Dodgson, L; Mason, D; Lyulcheva, E; Messina, G; Bennett, D

    2017-01-01

    The Mig10/RIAM/Lpd (MRL) adapter protein Lpd regulates actin dynamics through interactions with Scar/WAVE and Ena/VASP proteins to promote the formation of cellular protrusions and to stimulate invasive migration. However, the ability of MRL proteins to interact with multiple actin regulators and to promote serum response factor (SRF) signalling has raised the question of whether MRL proteins employ alternative downstream mechanisms to drive oncogenic processes in a context-dependent manner. Here, using a Drosophila model, we show that overexpression of either human Lpd or its Drosophila orthologue Pico can promote growth and invasion of RasV12-induced cell tumours in the brain. Notably, effects were restricted to two populations of Repo-positive glial cells: an invasive population, characterized by JNK-dependent elevation of Mmp1 expression, and a hyperproliferative population lacking elevated JNK signalling. JNK activation was not triggered by reactive immune cell signalling, implicating the involvement of an intrinsic stress response. The ability to promote dissemination of RasV12-induced tumours was shared by a subset of actin regulators, including, most prominently, Chicadee/Profilin, which directly interacts with Pico, and, Mal, a cofactor for serum response factor that responds to changes in G:F actin dynamics. Suppression of Mal activity partially abrogated the ability of pico to promote invasion of RasV12 tumours. Furthermore, we found that larval glia are enriched for serum response factor expression, explaining the apparent sensitivity of glial cells to Pico/RasV12 overexpression. Taken together, our findings indicate that MRL proteins cooperate with oncogenic Ras to promote formation of glial tumours, and that, in this context, Mal/serum response factor activation is rate-limiting for tumour dissemination. PMID:28346426

  2. Evaluation of the Ride-Through Capability of an Active-Front-End Adjustable Speed Drive under Real Grid Conditions

    DEFF Research Database (Denmark)

    Liserre, Marco; Klumpner, Christian; Blaabjerg, Frede

    2004-01-01

    Better quality of the input currents, unity power factor and regenerative capability are not the only benefits of equipping an Adjustable Speed Drive (ASD) with an active front-end-stage. Controlling the power inflow may enable also the reduction of the dc-link energy storage, which will then lea...

  3. Practical Wide-speed-range Sensorless Control System for Permanent Magnet Reluctance Synchronous Motor Drives via Active Flux Model

    DEFF Research Database (Denmark)

    Ancuti, Mihaela Codruta; Tutelea, Lucian; Andreescu, Gheorghe-Daniel

    2014-01-01

    This article introduces a control strategy to obtain near-maximum available torque in a wide speed range with sensorless operation via the active flux concept for permanent magnet-reluctance synchronous motor drives. A new torque dq current reference calculator is proposed, with reference torque...

  4. 77 FR 69797 - Small Takes of Marine Mammals Incidental to Specified Activities; Pile Driving in Port Townsend...

    Science.gov (United States)

    2012-11-21

    ... Specified Activities; Pile Driving in Port Townsend Bay, WA AGENCY: National Marine Fisheries Service (NMFS... elephant seals (Mirounga angustirostris) and Steller sea lions (Eumatopius jubatus) incidental to pile... transfer span, bridge seat, and lift cylinder shafts. During the project, up to 56 piles will be removed...

  5. Driving p53 Response to Bax Activation Greatly Enhances Sensitivity to Taxol by Inducing Massive Apoptosis

    Directory of Open Access Journals (Sweden)

    Paola De Feudis

    2000-05-01

    Full Text Available The proapoptotic gene bax is one of the downstream effectors of p53. The p53 binding site in the bax promoter is less responsive to p53 than the one in the growth arrest mediating gene p21. We introduced the bax gene under the control of 13 copies of a strong p53 responsive element into two ovarian cancer cell lines. The clones expressing bax under the control of p53 obtained from the wild-type (wt p53-expressing cell line A2780 were much more sensitive (500- to 1000-fold to the anticancer agent taxol than the parent cell line, with a higher percentage of cells undergoing apoptosis after drug treatment that was clearly p53-dependent and bax-mediated. Xenografts established in nude mice from one selected clone (A2780/C3 were more responsive to taxol than the parental line and the apoptotic response of A2780/C3 tumors was also increased after treatment. Introduction of the same plasmid into the p53 null SKOV3 cell line did not alter the sensitivity to taxol or the induction of apoptosis. In conclusion, driving the p53 response (after taxol treatment by activating the bax gene rather than the p21 gene results in induction of massive apoptosis, in vitro and in vivo, and greatly enhances sensitivity to the drug.

  6. Driving p53 Response to Bax Activation Greatly Enhances Sensitivity to Taxol by Inducing Massive Apoptosis

    Science.gov (United States)

    De Feudis, Paola; Vignati, Sara; Rossi, Cosmo; Mincioni, Tatiana; Giavazzi, Raffaella; D'Incalci, Maurizio; Broggini, Massimo

    2000-01-01

    Abstract The proapoptotic gene bax is one of the downstream effectors of p53. The p53 binding site in the bax promoter is less responsive to p53 than the one in the growth arrest mediating gene p21. We introduced the bax gene under the control of 13 copies of a strong p53 responsive element into two ovarian cancer cell lines. The clones expressing bax under the control of p53 obtained from the wild-type (wt) p53-expressing cell line A2780 were much more sensitive (500- to 1000-fold) to the anticancer agent taxol than the parent cell line, with a higher percentage of cells undergoing apoptosis after drug treatment that was clearly p53-dependent and bax-mediated. Xenografts established in nude mice from one selected clone (A2780/C3) were more responsive to taxol than the parental line and the apoptotic response of A2780/C3 tumors was also increased after treatment. Introduction of the same plasmid into the p53 null SKOV3 cell line did not alter the sensitivity to taxol or the induction of apoptosis. In conclusion, driving the p53 response (after taxol treatment) by activating the bax gene rather than the p21 gene results in induction of massive apoptosis, in vitro and in vivo, and greatly enhances sensitivity to the drug. PMID:10935506

  7. Characterizing differential poststroke corticomotor drive to the dorsi- and plantarflexor muscles during resting and volitional muscle activation.

    Science.gov (United States)

    Palmer, Jacqueline A; Zarzycki, Ryan; Morton, Susanne M; Kesar, Trisha M; Binder-Macleod, Stuart A

    2017-04-01

    Imbalance of corticomotor excitability between the paretic and nonparetic limbs has been associated with the extent of upper extremity motor recovery poststroke, is greatly influenced by specific testing conditions such as the presence or absence of volitional muscle activation, and may vary across muscle groups. However, despite its clinical importance, poststroke corticomotor drive to lower extremity muscles has not been thoroughly investigated. Additionally, whereas conventional gait rehabilitation strategies for stroke survivors focus on paretic limb foot drop and dorsiflexion impairments, most contemporary literature has indicated that paretic limb propulsion and plantarflexion impairments are the most significant limiters to poststroke walking function. The purpose of this study was to compare corticomotor excitability of the dorsi- and plantarflexor muscles during resting and active conditions in individuals with good and poor poststroke walking recovery and in neurologically intact controls. We found that plantarflexor muscles showed reduced corticomotor symmetry between paretic and nonparetic limbs compared with dorsiflexor muscles in individuals with poor poststroke walking recovery during active muscle contraction but not during rest. Reduced plantarflexor corticomotor symmetry during active muscle contraction was a result of reduced corticomotor drive to the paretic muscles and enhanced corticomotor drive to the nonparetic muscles compared with the neurologically intact controls. These results demonstrate that atypical corticomotor drive exists in both the paretic and nonparetic lower limbs and implicate greater severity of corticomotor impairments to plantarflexor vs. dorsiflexor muscles during muscle activation in stroke survivors with poor walking recovery.NEW & NOTEWORTHY The present study observed that lower-limb corticomotor asymmetry resulted from both reduced paretic and enhanced nonparetic limb corticomotor excitability compared with

  8. Carer levels of concern on driving and other activities in older people that put others at risk.

    Science.gov (United States)

    Helmes, Edward; Pachana, Nancy A

    2014-03-01

    Early signs of dementia may raise concerns in family members as to the safety of the affected person when engaged in common activities. Here we report on the relative frequency of such concerns using data from the three waves of the Canadian Study of Health and Aging (CSHA). Our focus is on driving, cooking and paying bills, with a prediction that most carers' concern would be over driving. Participants were 2780 Canadians over 65 years, who underwent the first wave of CSHA and were subsequently followed during the next two waves. As predicted, concerns about driving were relatively more common than concerns about cooking and handling finances (P = 0.021) in the cognitively intact group, with the opposite order observed in the group with dementia. Carer concerns for those diagnosed with dementia shift with the progression of cognitive changes, with concerns declining over the 10-year period. © 2013 The Authors. Australasian Journal on Ageing © 2013 ACOTA.

  9. A decrease in brain activation associated with driving when listening to someone speak

    Science.gov (United States)

    2008-02-01

    Behavioral studies have shown that engaging in a secondary task, such as talking on a cellular : telephone, disrupts driving performance. This study used functional magnetic resonance : imaging (fMRI) to investigate the impact of concurrent auditory ...

  10. Distance From Public Transportation and Physical Activity in Japanese Older Adults: The Moderating Role of Driving Status.

    Science.gov (United States)

    Harada, Kazuhiro; Lee, Sangyoon; Lee, Sungchul; Bae, Seongryu; Anan, Yuya; Harada, Kenji; Shimada, Hiroyuki

    2018-01-25

    Although previous studies have shown that good access to public transportation is positively related with physical activity, the moderators of this relationship have not been explored sufficiently in older adults. It is possible that driving status could moderate this relationship. The present study examined whether the objectively measured distance between public transportation and the home was associated with physical activity levels, and whether this association was moderated by driving status among Japanese older adults. In this cross-sectional study, participants (n = 2,878) completed questionnaires and wore accelerometers for at least 7 days, to measure their average daily step counts and minutes spent engaging in moderate-to-vigorous physical activity. Road network distances between the home and the nearest bus stop or train station were measured using geographic information systems. Driving status was assessed using questionnaires. Multiple regression analyses stratified by driving status revealed that, among nondrivers, living further away from public transportation was associated with higher step counts (β = 0.08, p public transportation was significantly associated with higher moderate-to-vigorous physical activity levels (β = -0.05, p = .042). Despite the small effect sizes, the direction of the association between distance from public transportation and physical activity was different for current drivers and nondrivers. These findings imply that good access to public transportation does not positively relate with greater engagement in physical activity among nondriving older adults. Shorter distances to public transportation might reduce opportunities for engaging in physical activity for them. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

  11. Greater Activity in the Frontal Cortex on Left Curves: A Vector-Based fNIRS Study of Left and Right Curve Driving.

    Directory of Open Access Journals (Sweden)

    Noriyuki Oka

    Full Text Available In the brain, the mechanisms of attention to the left and the right are known to be different. It is possible that brain activity when driving also differs with different horizontal road alignments (left or right curves, but little is known about this. We found driver brain activity to be different when driving on left and right curves, in an experiment using a large-scale driving simulator and functional near-infrared spectroscopy (fNIRS.The participants were fifteen healthy adults. We created a course simulating an expressway, comprising straight line driving and gentle left and right curves, and monitored the participants under driving conditions, in which they drove at a constant speed of 100 km/h, and under non-driving conditions, in which they simply watched the screen (visual task. Changes in hemoglobin concentrations were monitored at 48 channels including the prefrontal cortex, the premotor cortex, the primary motor cortex and the parietal cortex. From orthogonal vectors of changes in deoxyhemoglobin and changes in oxyhemoglobin, we calculated changes in cerebral oxygen exchange, reflecting neural activity, and statistically compared the resulting values from the right and left curve sections.Under driving conditions, there were no sites where cerebral oxygen exchange increased significantly more during right curves than during left curves (p > 0.05, but cerebral oxygen exchange increased significantly more during left curves (p < 0.05 in the right premotor cortex, the right frontal eye field and the bilateral prefrontal cortex. Under non-driving conditions, increases were significantly greater during left curves (p < 0.05 only in the right frontal eye field.Left curve driving was thus found to require more brain activity at multiple sites, suggesting that left curve driving may require more visual attention than right curve driving. The right frontal eye field was activated under both driving and non-driving conditions.

  12. Greater Activity in the Frontal Cortex on Left Curves: A Vector-Based fNIRS Study of Left and Right Curve Driving.

    Science.gov (United States)

    Oka, Noriyuki; Yoshino, Kayoko; Yamamoto, Kouji; Takahashi, Hideki; Li, Shuguang; Sugimachi, Toshiyuki; Nakano, Kimihiko; Suda, Yoshihiro; Kato, Toshinori

    2015-01-01

    In the brain, the mechanisms of attention to the left and the right are known to be different. It is possible that brain activity when driving also differs with different horizontal road alignments (left or right curves), but little is known about this. We found driver brain activity to be different when driving on left and right curves, in an experiment using a large-scale driving simulator and functional near-infrared spectroscopy (fNIRS). The participants were fifteen healthy adults. We created a course simulating an expressway, comprising straight line driving and gentle left and right curves, and monitored the participants under driving conditions, in which they drove at a constant speed of 100 km/h, and under non-driving conditions, in which they simply watched the screen (visual task). Changes in hemoglobin concentrations were monitored at 48 channels including the prefrontal cortex, the premotor cortex, the primary motor cortex and the parietal cortex. From orthogonal vectors of changes in deoxyhemoglobin and changes in oxyhemoglobin, we calculated changes in cerebral oxygen exchange, reflecting neural activity, and statistically compared the resulting values from the right and left curve sections. Under driving conditions, there were no sites where cerebral oxygen exchange increased significantly more during right curves than during left curves (p > 0.05), but cerebral oxygen exchange increased significantly more during left curves (p right premotor cortex, the right frontal eye field and the bilateral prefrontal cortex. Under non-driving conditions, increases were significantly greater during left curves (p right frontal eye field. Left curve driving was thus found to require more brain activity at multiple sites, suggesting that left curve driving may require more visual attention than right curve driving. The right frontal eye field was activated under both driving and non-driving conditions.

  13. Predicting drunk driving: contribution of alcohol use and related problems, traffic behaviour, personality and platelet monoamine oxidase (MAO) activity.

    Science.gov (United States)

    Eensoo, Diva; Paaver, Marika; Harro, Maarike; Harro, Jaanus

    2005-01-01

    The aim of the study was to characterize the predictive value of socio-economic data, alcohol consumption measures, smoking, platelet monoamine oxidase (MAO) activity, traffic behaviour habits and impulsivity measures for actual drunk driving. Data were collected from 203 male drunk driving offenders and 211 control subjects using self-reported questionnaires, and blood samples were obtained from the two groups. We identified the combination of variables, which predicted correctly, approximately 80% of the subjects' belonging to the drunk driving and control groups. Significant independent discriminators in the final model were, among the health-behaviour measures, alcohol-related problems, frequency of using alcohol, the amount of alcohol consumed and smoking. Predictive traffic behaviour measures were seat belt use and paying for parking. Among the impulsivity measures, dysfunctional impulsivity was the best predictor; platelet MAO activity and age also had an independent predictive value. Our results support the notion that drunk driving is the result of a combination of various behavioural, biological and personality-related risk factors.

  14. Evaluation of the workload and drowsiness during car driving by using high resolution EEG activity and neurophysiologic indices.

    Science.gov (United States)

    Maglione, A; Borghini, G; Aricò, P; Borgia, F; Graziani, I; Colosimo, A; Kong, W; Vecchiato, G; Babiloni, F

    2014-01-01

    Sleep deprivation and/or a high workload situation can adversely affect driving performance, decreasing a driver's capacity to respond effectively in dangerous situations. In this context, to provide useful feedback and alert signals in real time to the drivers physiological and brain activities have been increasingly investigated in literature. In this study, we analyze the increase of cerebral workload and the insurgence of drowsiness during car driving in a simulated environment by using high resolution electroencephalographic techniques (EEG) as well as neurophysiologic variables such as heart rate (HR) and eye blinks rate (EBR). The simulated drive tasks were modulated with five levels of increasing difficulty. A workload index was then generated by using the EEG signals and the related HR and EBR signals. Results suggest that the derived workload index is sensitive to the mental efforts of the driver during the different drive tasks performed. Such workload index was based on the estimation the variation of EEG power spectra in the theta band over prefrontal cortical areas and the variation of the EEG power spectra over the parietal cortical areas in alpha band. In addition, results suggested as HR increases during the execution of the difficult driving tasks while instead it decreases at the insurgence of the drowsiness. Finally, the results obtained showed as the EBR variable increases of its values when the insurgence of drowsiness in the driver occurs. The proposed workload index could be then used in a near future to assess on-line the mental state of the driver during a drive task.

  15. Leisure-time activities of patients with ICDs: findings of a survey with respect to sports activity, high altitude stays, and driving patterns.

    Science.gov (United States)

    Kobza, Richard; Duru, Firat; Erne, Paul

    2008-07-01

    Physicians who are caring for patients with implantable cardioverter-defibrillators (ICDs) are regularly confronted with questions concerning daily activities. This study evaluates the habits of ICD patients with respect to sports activities, stays at high-altitude, and driving patterns. A survey was performed in 387 patients with ICDs who were followed at two hospitals in Switzerland. The special-designed questionnaire addressed lifestyle practices concerning sports activity, high-altitude visits, and driving motor vehicles. Fifty-nine percent of ICD patients participated in some kind of sports activity; an ICD shock was experienced in 14% of these patients. Fifty-six percent of the patients reported a stay at high altitudes at least 2,000 m above the sea level; 11% of them stayed regularly above 2,500 m; 4% of these patients experienced an ICD shock during high altitude stay. Seventy-nine percent of the patients drove a motor vehicle; 2% of them experienced an ICD shock during driving, but none of them reported loss of consciousness or a traffic accident. It is accepted that ICD patients disqualify for competitive sports. However, the patients may be encouraged to continue leisure-time physical activities at low-to-moderate intensity. Staying at high altitudes and driving motor vehicles are very rarely associated with ICD shocks. Therefore, these activities that are likely to contribute to a better quality of life should not be discouraged in most ICD recipients in the absence of other medical reasons.

  16. Automation of project activities in modernization of drive of operating cement mill

    Science.gov (United States)

    Troshina, A. G.; Trushin, N. N.

    2017-10-01

    The article presents an approach to automation of modernization project for cement mill drives with replacement of the gearbox for which its service life has expired. The parameters of quality assessment of the chosen solution in the modernization project have been determined. It is mentioned that one of the problems of this stage of modernization is to offer the option of arrangement of the new drive on existing site. The paper offers the variant of the software structure that allows one to automate the considered process.

  17. Drive Stands

    Data.gov (United States)

    Federal Laboratory Consortium — The Electrical Systems Laboratory (ESL)houses numerous electrically driven drive stands. A drive stand consists of an electric motor driving a gearbox and a mounting...

  18. Impact of distracting activities and drivers' cognitive failures on driving performance

    NARCIS (Netherlands)

    Farah, H.; Zatmeh, S.; Toledo, T.

    2015-01-01

    The rapid increase in the availability of smart phones and other infotainment devices, and their widespread use while driving, contributes significantly to car crash rates. This is since the human brain has limited capacity and cannot perform two tasks at the same time, but rather switches from one

  19. Analysis of Harmonics Suppression by Active Damping Control on Multi Slim DC-link Drives

    DEFF Research Database (Denmark)

    Yang, Feng; Máthé, Lászlo; Lu, Kaiyuan

    2016-01-01

    with the benefit of low cost and also low loss. A new analysis method, based on the frequency domain impedance model, is presented to explore the mechanism of harmonics suppression. Also, a general method is presented to build the impedance model of a PMSM drive system using Field Oriented Control (FOC) method...

  20. 76 FR 28733 - Takes of Marine Mammals Incidental to Specified Activities; Pile-Driving and Renovation...

    Science.gov (United States)

    2011-05-18

    ... Indian Community for the Trinidad Rancheria in Trinidad, CA AGENCY: National Marine Fisheries Service... pile-driving and renovation operations for the Trinidad Pier Reconstruction Project in Trinidad... Resources, National Marine Fisheries Service, 1315 East-West Highway, Silver Spring, MD 20910-3225. The...

  1. Direct drive TFPM wind generator analytical design optimised for minimum active mass usage

    DEFF Research Database (Denmark)

    Nica, Florin Valentin Traian; Leban, Krisztina Monika; Ritchie, Ewen

    2013-01-01

    The paper focuses of the Transverse Flux Permanent (TFPM) Generator as a solution for offshore direct drive wind turbines. A complex design algorithm is presented. Two topologies (U core and C core) of TFPM were considered. The analytical design is optimised using a combination of genetic...

  2. A role for cortical nNOS/NK1 neurons in coupling homeostatic sleep drive to EEG slow wave activity

    OpenAIRE

    Morairty, Stephen R.; Dittrich, Lars; Pasumarthi, Ravi K.; Valladao, Daniel; Heiss, Jaime E.; Gerashchenko, Dmitry; Kilduff, Thomas S.

    2013-01-01

    Sleep is a homeostatically regulated process. Slow wave sleep is characterized by slow waves detectable from the cerebral cortex by EEG. When homeostatic sleep “drive” is manipulated by varying durations of sleep deprivation, the intensity of EEG slow waves proportionally increases. The neural circuitry underlying this homeostatic response is little understood. In this study we describe a systematic relationship between homeostatic sleep drive and activation of cortical neurons that express n...

  3. The Effects of External Focus of Attention on Shoulder Muscle Activities during Forehand Drive in Table Tennis

    Directory of Open Access Journals (Sweden)

    Mohammad Reza Hatami

    2016-06-01

    Full Text Available Objective: The aim of this study was to evaluate the impact of the external focus of attention on the rotator cuff muscle activity for the timely hit forehand drive by table tennis players. Methods: Twelve professional table tennis players with mean age of 26.5 years voluntarily participated in this study. The electrical activities of the muscles of the shoulder girdle using M.A 300 machine and bipolar electrodes surface under two conditions .First with external focus of attention and then without such attention were recorded, first without any guidance blows forehand drive was carried out by subjects (without focus. Then such subject was asked to focus their attention on the area marked for the ball landing (external focus of attention.      Muscle activities in both preparation and tapping phases were analyzed the three –dimensional (200 Hz, Vicon, with four camera series T motion analysis system was used to obtain the data. Data was analyzed by running reported measures ANOVA at a significance level of p0.05 but the different between the intensity of muscle activity was meaningful. This suggests that there is a mutual influence between the two attention factors and muscles (p=0.03, that is, orientation can have a significant effect on the severity of muscle contraction. Intensities of muscle contraction in the preparation and tapping were different (p<0.05. Conclusion: On the forehand drive technique, the anterior deltoid muscle has the most activity. The type of focus and attention had a significant impact on the change of activity of muscles relative to each other, and the greatest impact is on the reduction of activity of the infraspinatus muscle. This type of focus delays fatigue and results in an increase in the efficiency of neuromuscular in the activities of skills.

  4. A Transformerless Hybrid Active Filter Capable of Complying with Harmonic Guidelines for Medium-Voltage Motor Drives

    Science.gov (United States)

    Kondo, Ryota; Akagi, Hirofumi

    This paper presents a transformerless hybrid active filter that is integrated into medium-voltage adjustable-speed motor drives for fans, pumps, and compressors without regenerative braking. The authors have designed and constructed a three-phase experimental system rated at 400V and 15kW, which is a downscaled model from a feasible 6.6-kV 1-MW motor drive system. This system consists of the hybrid filter connecting a passive filter tuned to the 7th harmonic filter in series with an active filter that is based on a three-level diode-clamped PWM converter, as well as an adjustable-speed motor drive in which a diode rectifier is used as the front end. The hybrid filter is installed on the ac side of the diode rectifier with no line-frequency transformer. The downscaled system has been exclusively tested so as to confirm the overall compensating performance of the hybrid filter and the filtering performance of a switching-ripple filter for mitigating switching-ripple voltages produced by the active filter. Experimental results verify that the hybrid filter achieves harmonic compensation of the source current in all the operating regions from no-load to the rated-load conditions, and that the switching-ripple filter reduces the switching-ripple voltages as expected.

  5. The IRE1/bZIP60 pathway and Bax inhibitor 1 suppress systemic accumulation of potyviruses and potexviruses in Arabidopsis and Nicotiana benthamiana plants

    Science.gov (United States)

    The inositol requiring enzyme (IRE1) is an endoplasmic reticulum (ER) stress sensor and when activated it splices the bZIP60 mRNA producing a truncated transcription factor that upregulates expression of genes involved in the unfolded protein response (UPR). Bax inhibitor 1 (BI-1) is another ER stre...

  6. Analysis of Dielectric Electro Active Polymer Actuator and its High Voltage Driving Circuits

    DEFF Research Database (Denmark)

    Thummala, Prasanth; Huang, Lina; Zhang, Zhe

    2012-01-01

    Actuators based on dielectric elastomers have promising applications in artificial muscles, space robotics, mechatronics, micro-air vehicles, pneumatic and electric automation technology, heating valves, loud speakers, tissue engineering, surgical tools, wind turbine flaps, toys, rotary motors...... actuator is analyzed in detail and the actuator structures, for the wind turbine flap and the heating valve applications are shown. Different high voltage switch mode power supply topologies for driving the DEAP actuator are discussed. The simulation and experimental results are discussed....

  7. A conserved TATA-less proximal promoter drives basal transcription from the urokinase-type plasminogen activator receptor gene

    DEFF Research Database (Denmark)

    Soravia, E; Grebe, A; De Luca, P

    1995-01-01

    have cloned an uPAR DNA segment containing upstream regulatory sequences from both the human and murine genomes. We report that a proximal promoter, contained within 180 bp from the major transcription start sites of the human uPAR gene, drives basal transcription. This region lacks TATA and CAAT boxes......The urokinase-type plasminogen activator receptor (uPAR) focuses at the cell surface the activation of pro-uPA and, hence, the formation of plasmin, thus enhancing directional extracellular proteolysis. To characterize the transcriptional regulatory mechanisms that control receptor expression, we...

  8. Impaired Driving

    Science.gov (United States)

    Impaired driving is dangerous. It's the cause of more than half of all car crashes. It means operating ... texting Having a medical condition which affects your driving For your safety and the safety of others, do not drive while impaired. Have someone else drive you or take public ...

  9. Active Vibration Control of a Microactuator for the Hard Disk Drive Using Self-Sensing Actuation

    Directory of Open Access Journals (Sweden)

    Minoru Sasaki

    2012-01-01

    Full Text Available This paper presents the self-sensing control of a microactuator for hard disk drives. The microactuator uses a PZT actuator pair installed on the suspension assembly. The self-sensing microactuator forms a combined sensing and actuation mechanism. Direct velocity feedback and positive position feedback are used in this paper. Our experimental results show that both strategies are effective in suppressing vibrational modes and successfully demonstrate the feasibility of using a self-sensing actuator on an HDD suspension assembly.

  10. Resonant Activation in a Stochastic Hodgkin-Huxley Model: Interplay between noise and suprathreshold driving effect

    DEFF Research Database (Denmark)

    Pankratova, Evgeniya; Polovinkin, A.V.; Mosekilde, Erik

    2005-01-01

    a minimum as functions of the forcing frequency. The destructive influence of noise on the interspike interval can also be reduced. With driving signals in a certain frequency range, the system can show stable periodic spiking even for relatively large noise intensities. Outside this frequency range, noise......The paper considers an excitable Hodgkin-Huxley system subjected to a strong periodic forcing in the presence of random noise. The influence of the forcing frequency on the response of the system is examined in the realm of suprathreshold amplitudes. Our results confirm that the presence of noise...

  11. Proportion of injured drivers presenting to a tertiary care emergency department who engage in future impaired driving activities.

    Science.gov (United States)

    Purssell, Roy; Brown, Douglas; Brubacher, Jeffery R; Wilson, Jean; Fang, Ming; Schulzer, Michael; Mak, Edwin; Abu-Laban, Riyad B; Simons, Richard; Walker, Tristan

    2010-02-01

    We determined the rate of, and predictive factors for, subsequent impaired driving activity (IDA) by injured drivers treated in a Canadian tertiary care emergency department (ED) following a motor vehicle crash (MVC). We retrospectively identified all drivers injured in a MVC who presented to our tertiary care, urban ED (1999-2003) and had their blood alcohol content (BAC) measured. Injured drivers were categorized by BAC: group 1, BAC = 0; group 2, 0 17.3 mM. IDA was defined as any of the following: a conviction for impaired driving; a 24-h or 90-day license suspension for impaired driving; involvement in alcohol-related MVC. Time to IDA following the index event between groups was compared with Kaplan-Meier survival analyses. Effects of covariates on time to IDA were analyzed using Cox proportional hazards models. During the study period, 1489 injured drivers met study criteria: 1171 in group 1, 51 in group 2, and 267 in group 3. During an average follow-up of 52.4 months, 82 (30.7%) group 3 drivers engaged in subsequent IDA, compared with 80 (6.8%) group 1 drivers (p impaired drivers who present to hospital engage in repeat IDA following discharge. Besides impairment at time of hospital visit, the best predictor of future IDA is a history of IDA prior to the index event.

  12. Promoting Active Transport in Older Adolescents Before They Obtain Their Driving Licence: A Matched Control Intervention Study.

    Science.gov (United States)

    Verhoeven, Hannah; Simons, Dorien; Van Cauwenberg, Jelle; Van Dyck, Delfien; Vandelanotte, Corneel; de Geus, Bas; De Bourdeaudhuij, Ilse; Clarys, Peter; Deforche, Benedicte

    2016-01-01

    Active transport has great potential to increase physical activity in older adolescents (17-18 years). Therefore, a theory- and evidence-based intervention was developed aiming to promote active transport among older adolescents. The intervention aimed to influence psychosocial factors of active transport since this is the first step in order to achieve a change in behaviour. The present study aimed to examine the effect of the intervention on the following psychosocial factors: intention to use active transport after obtaining a driving licence, perceived benefits, perceived barriers, subjective norm, self-efficacy, habit and awareness towards active transport. A matched control three-arm study was conducted and consisted of a pre-test post-test design with intervention and control schools in Flanders (northern part of Belgium). A lesson promoting active transport was implemented as the last lesson in the course 'Driving Licence at School' in intervention schools (intervention group 1). Individuals in intervention group 2 received this active transport lesson and, in addition, they were asked to become a member of a Facebook group on active transport. Individuals in the control group only attended the regular course 'Driving Licence at School'. Participants completed a questionnaire assessing socio-demographics and psychosocial variables at baseline, post (after one week) and follow-up (after eight weeks). To assess intervention effects, multilevel linear mixed models analyses were performed. A sample of 441 older adolescents (56.8% female; 17.4 (0.7) years) was analysed. For awareness regarding the existence of car sharing schemes, a significant increase in awareness from baseline to post measurement was found within intervention group 1 (p = 0.001) and intervention group 2 (p = 0.030) compared to the control group in which no change was found. In addition, a significant increase in awareness from baseline to follow-up measurement was found within intervention

  13. Promoting Active Transport in Older Adolescents Before They Obtain Their Driving Licence: A Matched Control Intervention Study.

    Directory of Open Access Journals (Sweden)

    Hannah Verhoeven

    Full Text Available Active transport has great potential to increase physical activity in older adolescents (17-18 years. Therefore, a theory- and evidence-based intervention was developed aiming to promote active transport among older adolescents. The intervention aimed to influence psychosocial factors of active transport since this is the first step in order to achieve a change in behaviour. The present study aimed to examine the effect of the intervention on the following psychosocial factors: intention to use active transport after obtaining a driving licence, perceived benefits, perceived barriers, subjective norm, self-efficacy, habit and awareness towards active transport.A matched control three-arm study was conducted and consisted of a pre-test post-test design with intervention and control schools in Flanders (northern part of Belgium. A lesson promoting active transport was implemented as the last lesson in the course 'Driving Licence at School' in intervention schools (intervention group 1. Individuals in intervention group 2 received this active transport lesson and, in addition, they were asked to become a member of a Facebook group on active transport. Individuals in the control group only attended the regular course 'Driving Licence at School'. Participants completed a questionnaire assessing socio-demographics and psychosocial variables at baseline, post (after one week and follow-up (after eight weeks. To assess intervention effects, multilevel linear mixed models analyses were performed.A sample of 441 older adolescents (56.8% female; 17.4 (0.7 years was analysed. For awareness regarding the existence of car sharing schemes, a significant increase in awareness from baseline to post measurement was found within intervention group 1 (p = 0.001 and intervention group 2 (p = 0.030 compared to the control group in which no change was found. In addition, a significant increase in awareness from baseline to follow-up measurement was found within

  14. The Drive-Wise Project: Driving Simulator Training increases real driving performance in healthy older drivers

    OpenAIRE

    Gianclaudio eCasutt; Gianclaudio eCasutt; Gianclaudio eCasutt; Nathan eTheill; Mike eMartin; Mike eMartin; Martin eKeller; Martin eKeller; Lutz eJäncke; Lutz eJäncke; Lutz eJäncke; Lutz eJäncke

    2014-01-01

    Background: Age-related cognitive decline is often associated with unsafe driving behavior. We hypothesized that 10 active training sessions in a driving simulator increase cognitive and on-road driving performance. In addition, driving simulator training should outperform cognitive training.Methods: Ninety-one healthy active drivers (62 – 87 years) were randomly assigned to either (1) a driving simulator training group, (2) an attention training group (vigilance and selective attention), or ...

  15. The drive-wise project: driving simulator training increases real driving performance in healthy older drivers

    OpenAIRE

    Casutt, Gianclaudio; Theill, Nathan; Martin, Mike; Keller, Martin; Jäncke, Lutz

    2014-01-01

    Background: Age-related cognitive decline is often associated with unsafe driving behavior. We hypothesized that 10 active training sessions in a driving simulator increase cognitive and on-road driving performance. In addition, driving simulator training should outperform cognitive training. Methods: Ninety-one healthy active drivers (62-87 years) were randomly assigned to one of three groups: (1) a driving simulator training group, (2) an attention training group (vigilance and selective at...

  16. Active-Flux-Based, V/f-with-Stabilizing-Loops Versus Sensorless Vector Control of IPMSM Drives

    DEFF Research Database (Denmark)

    Moldovan, Ana; Blaabjerg, Frede; Boldea, Ion

    2011-01-01

    This paper proposes two control methods for Interior Permanent Magnet Synchronous Motor (IPMSM) Drives. The first one is a V/f control with two stabilizing loops: one loop based on active flux balance for voltage magnitude correction and a second, based on speed error, with voltage phase correction....... By this control strategy, a fast dynamic speed response, without steady state error and without speed or current regulators, for all AC machines is obtained. The second control method is a sensorless vector control strategy which also has been implemented and tested, just for comparison....

  17. Galaxies in turmoil the active and starburst galaxies and the black holes that drive them

    CERN Document Server

    Kitchin, C R

    2007-01-01

    Aimed at active amateur astronomers this book provides an up-to-date account of active galaxies. Lists and images of such objects are an important component of this book. The book makes sense of the chaotic and apparently innumerable types of violently active galaxies.

  18. Sleepy driving.

    Science.gov (United States)

    Powell, Nelson B; Chau, Jason K M

    2010-05-01

    Sleepiness and drowsiness are neurophysiologic states that may cause attenuation of vigilance and slowing of reaction times, and thus increase the risks of driving. This article reviews selected peer-reviewed publications from the past and present body of knowledge regarding sleepiness and drowsiness while driving and related accidents, injuries, and possible death. Comparative studies of driving drunk and driving sleepy are reviewed because both exhibit similarly dangerous driving behaviors. It is hoped that some of the information from this article could provide new interest in the necessity of education for sleepy drivers.

  19. Electric drives

    CERN Document Server

    Boldea, Ion

    2005-01-01

    ENERGY CONVERSION IN ELECTRIC DRIVESElectric Drives: A DefinitionApplication Range of Electric DrivesEnergy Savings Pay Off RapidlyGlobal Energy Savings Through PEC DrivesMotor/Mechanical Load MatchMotion/Time Profile MatchLoad Dynamics and StabilityMultiquadrant OperationPerformance IndexesProblemsELECTRIC MOTORS FOR DRIVESElectric Drives: A Typical ConfigurationElectric Motors for DrivesDC Brush MotorsConventional AC MotorsPower Electronic Converter Dependent MotorsEnergy Conversion in Electric Motors/GeneratorsPOWER ELECTRONIC CONVERTERS (PECs) FOR DRIVESPower Electronic Switches (PESs)The

  20. Competition as an Effective Tool in Developing Social Marketing Programs: Driving Behavior Change through Online Activities

    Directory of Open Access Journals (Sweden)

    Corina ŞERBAN

    2011-12-01

    Full Text Available Nowadays, social marketing practices represent an important part of people’s lives. Consumers’ understanding of the need for change has become the top priority for social organizations worldwide. As a result, the number of social marketing programs has increased, making people reflect more on their behaviors and on the need to take action. Competition in social marketing can bring many benefits. The more programs initiated, the more people will start to involve in society’s problems, hereby contributing to beneficial causes. However, social organizations are in the search for competitive advantages to differentiate them on the market. This paper aims to present the role of online communication in driving competitive advantage for social organizations. Using the structural equation model, the paper describes the relations between four characteristics of the online communication: credibility, attractiveness, persuasion and promotion and then presents the correlations between these variables and website competitiveness. The resulting model shows that owning a competitive advantage in social marketing can bring many advantages to both the non-profit organization and the consumer. Therefore, the online environment can be considered a good solution for better serving consumers’ social needs. Its contribution is significant especially in programs for children and adolescents, since teenagers spend more time on the Internet than adults and are more open to using the online channels of communication. In conclusion, this article opens new opportunities for social marketers to address society’s problems and supports the integration of the online communication tools in the competition strategy.

  1. Effects of Non-Driving Cognitive Activity on Driver's Eye Movement and Their Individual Difference

    Science.gov (United States)

    Itoh, Makoto; Inagaki, Toshiyuki

    This paper investigates effects on driver's eye movement when the driver is distracted by a secondary cognitive task that demands a high mental workload. By observing drivers behavior in a fixed-base driving simulator, we analyze how the time lengths of eye fixations change when a driver is imposed to perform a cognitive secondary task. The results show that two types (Type 1: the number of short fixations increases, Type 2: the number of short fixations decreases) are found. Interestingly, our data show that both types can be seen even in one driver depending on traffic conditions. It is also shown that likelihood of occurring Type 1 or Type 2 effects depends on driver. The data suggest that it is possible to predict which effect is likely to occur for a driver if we analyze his or her eye movement under normal conditions. With these findings, this study developed and improved a driver-adaptable algorithm for detecting the state of being under high mental workload. The results suggest that the time length of an eye fixation can be useful index at least several drivers.

  2. Stimulating ammonia oxidizing bacteria (AOB) activity drives the ammonium oxidation rate in a constructed wetland (CW).

    Science.gov (United States)

    Su, Yu; Wang, Weidong; Wu, Di; Huang, Wei; Wang, Mengzi; Zhu, Guibing

    2017-12-14

    An integrated approach to document high ammonium oxidation rate in Guanjinggang constructed wetland (GJG-CW) was performed and the results showed that the substantial ammonium oxidation rate could be obtained by enhancing Ammonia Oxidizing Bacteria (AOB) activity rather than Ammonia Oxidizing Archaea (AOA) activity. In the plant-bed/ditch system, ditch center and plant-bed fringe were two active zones for NH4+-N removal with ammonium oxidation rate peaking at 2.98±0.04 and 2.15±0.02mgNkg-1d-1, respectively. The enhanced AOB activity were achieved by increasing water level fluctuations, extending hydraulic retention time (HRT) and stimulating substrate availability, which subsequently enhanced NH4+-N removal by 34.06% in GJG-CW. However, the high AOB activity was not correlated with high AOB abundance, but was instead mostly determined by specific AOB taxa, particularly Nitrosomonas, which dominated in the active AOB. The increased cell-specific AOA activity and high AOA diversity were also achieved using those engineering measures. Although the AOA activity decreased overall with extended HRT and increased NH4+-N contents in GJG-CW, AOA still played a major role on ammonium oxidation in plant-bed soil. The study illustrated that artificially enhancing AOB activity and certain species in anthropogenically polluted water ecosystems would be an effective strategy to improve NH4+-N removal. Copyright © 2017. Published by Elsevier B.V.

  3. Performance analysis of active damped small DC-link capacitor based drive for unbalanced input voltage supply

    DEFF Research Database (Denmark)

    Maheshwari, Ram Krishan; Munk-Nielsen, Stig

    2011-01-01

    A small DC-link capacitor based drive is presented in this paper. The drive shows negative impedance instability at operating points with high power load. A phase portrait is presented for input filter states which exhibit a limit cycle. When the drive is operated with unbalanced input supply vol...

  4. Stepping towards causation: do built environments or neighborhood and travel preferences explain physical activity, driving, and obesity?

    Science.gov (United States)

    Frank, Lawrence Douglas; Saelens, Brian E; Powell, Ken E; Chapman, James E

    2007-11-01

    Evidence documents associations between neighborhood design and active and sedentary forms of travel. Most studies compare travel patterns for people located in different types of neighborhoods at one point in time adjusting for demographics. Most fail to account for either underlying neighborhood selection factors (reasons for choosing a neighborhood) or preferences (neighborhoods that are preferred) that impact neighborhood selection and behavior. Known as self-selection, this issue makes it difficult to evaluate causation among built form, behavior, and associated outcomes and to know how much more walking and less driving could occur through creating environments conducive to active transport. The current study controls for neighborhood selection and preference and isolates the effect of the built environment on walking, car use, and obesity. Separate analyses were conducted among 2056 persons in the Atlanta, USA based Strategies for Metropolitan Atlanta's Regional Transportation and Air Quality (SMARTRAQ) travel survey on selection factors and 1466 persons in the SMARTRAQ community preference sub-survey. A significant proportion of the population are "mismatched" and do not live in their preferred neighborhood type. Factors influencing neighborhood selection and individual preferences, and current neighborhood walkability explained vehicle travel distance after controlling for demographic variables. Individuals who preferred and lived in a walkable neighborhood walked most (33.9% walked) and drove 25.8 miles per day on average. Individuals that preferred and lived in car dependent neighborhoods drove the most (43 miles per day) and walked the least (3.3%). Individuals that do not prefer a walkable environment walked little and show no change in obesity prevalence regardless of where they live. About half as many participants were obese (11.7%) who prefer and live in walkable environments than participants who prefer car dependent environments (21.6%). Findings

  5. Commutation effect of Adjustable Speed Drives due to installation of active harmonic filters

    DEFF Research Database (Denmark)

    Asiminoaei, Lucian; Kalaschnikow, Sergej; Hansen, Steffan

    2011-01-01

    The success of designing an industrial installation with Active Filters depends on how precise the load profile of the application is known, because this determines the amount of harmonic currents to be compensated. However, once the Active Filter is added to the installation, the harmonic currents...... may increase due to changes in the commutation behavior of diode rectifier converters. The change of natural commutation determines higher harmonics currents of the diode rectifiers and therefore higher harmonic loading of the Active Filter in the installation. This paper presents a method to estimate...

  6. Norepinephrine drives persistent activity in prefrontal cortex via synergistic α1 and α2 adrenoceptors.

    Directory of Open Access Journals (Sweden)

    Zizhen Zhang

    Full Text Available Optimal norepinephrine levels in the prefrontal cortex (PFC increase delay-related firing and enhance working memory, whereas stress-related or pathologically high levels of norepinephrine are believed to inhibit working memory via α1 adrenoceptors. However, it has been shown that activation of Gq-coupled and phospholipase C-linked receptors can induce persistent firing, a cellular correlate of working memory, in cortical pyramidal neurons. Therefore, despite its importance in stress and cognition, the exact role of norepinephrine in modulating PFC activity remains elusive. Using electrophysiology and optogenetics, we report here that norepinephrine induces persistent firing in pyramidal neurons of the PFC independent of recurrent fast synaptic excitation. This persistent excitatory effect involves presynaptic α1 adrenoceptors facilitating glutamate release and subsequent activation of postsynaptic mGluR5 receptors, and is enhanced by postsynaptic α2 adrenoceptors inhibiting HCN channel activity. Activation of α2 adrenoceptors or inhibition of HCN channels also enhances cholinergic persistent responses in pyramidal neurons, providing a mechanism of crosstalk between noradrenergic and cholinergic inputs. The present study describes a novel cellular basis for the noradrenergic control of cortical information processing and supports a synergistic combination of intrinsic and network mechanisms for the expression of mnemonic properties in pyramidal neurons.

  7. Enhancing Diversity in Undergraduate Science: Self-Efficacy Drives Performance Gains with Active Learning.

    Science.gov (United States)

    Ballen, Cissy J; Wieman, Carl; Salehi, Shima; Searle, Jeremy B; Zamudio, Kelly R

    2017-01-01

    Efforts to retain underrepresented minority (URM) students in science, technology, engineering, and mathematics (STEM) have shown only limited success in higher education, due in part to a persistent achievement gap between students from historically underrepresented and well-represented backgrounds. To test the hypothesis that active learning disproportionately benefits URM students, we quantified the effects of traditional versus active learning on student academic performance, science self-efficacy, and sense of social belonging in a large (more than 250 students) introductory STEM course. A transition to active learning closed the gap in learning gains between non-URM and URM students and led to an increase in science self-efficacy for all students. Sense of social belonging also increased significantly with active learning, but only for non-URM students. Through structural equation modeling, we demonstrate that, for URM students, the increase in self-efficacy mediated the positive effect of active-learning pedagogy on two metrics of student performance. Our results add to a growing body of research that supports varied and inclusive teaching as one pathway to a diversified STEM workforce. © 2017 C. J. Ballen et al. CBE—Life Sciences Education © 2017 The American Society for Cell Biology. This article is distributed by The American Society for Cell Biology under license from the author(s). It is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

  8. Pile Driving

    Science.gov (United States)

    1987-01-01

    Machine-oriented structural engineering firm TERA, Inc. is engaged in a project to evaluate the reliability of offshore pile driving prediction methods to eventually predict the best pile driving technique for each new offshore oil platform. Phase I Pile driving records of 48 offshore platforms including such information as blow counts, soil composition and pertinent construction details were digitized. In Phase II, pile driving records were statistically compared with current methods of prediction. Result was development of modular software, the CRIPS80 Software Design Analyzer System, that companies can use to evaluate other prediction procedures or other data bases.

  9. Convergent Akt activation drives acquired EGFR inhibitor resistance in lung cancer

    DEFF Research Database (Denmark)

    Jacobsen, Kirstine; Bertran-Alamillo, Jordi; Molina, Miguel Angel

    2017-01-01

    Non-small-cell lung cancer patients with activating epidermal growth factor receptor (EGFR) mutations typically benefit from EGFR tyrosine kinase inhibitor treatment. However, virtually all patients succumb to acquired EGFR tyrosine kinase inhibitor resistance that occurs via diverse mechanisms....... The diversity and unpredictability of EGFR tyrosine kinase inhibitor resistance mechanisms presents a challenge for developing new treatments to overcome EGFR tyrosine kinase inhibitor resistance. Here, we show that Akt activation is a convergent feature of acquired EGFR tyrosine kinase inhibitor resistance...... phospho-Akt levels to therapeutically combat the heterogeneity of EGFR tyrosine kinase inhibitor resistance mechanisms.EGFR-mutant non-small cell lung cancer are often resistant to EGFR tyrosine kinase inhibitor treatment. In this study, the authors show that resistant tumors display high Akt activation...

  10. Passive Joint Forces Are Tuned to Limb Use in Insects and Drive Movements without Motor Activity

    Science.gov (United States)

    Ache, Jan M.; Matheson, Thomas

    2013-01-01

    Summary Background Limb movements are generally driven by active muscular contractions working with and against passive forces arising in muscles and other structures. In relatively heavy limbs, the effects of gravity and inertia predominate, whereas in lighter limbs, passive forces intrinsic to the limb are of greater consequence. The roles of passive forces generated by muscles and tendons are well understood, but there has been little recognition that forces originating within joints themselves may also be important, and less still that these joint forces may be adapted through evolution to complement active muscle forces acting at the same joint. Results We examined the roles of passive joint forces in insect legs with different arrangements of antagonist muscles. We first show that passive forces modify actively generated movements of a joint across its working range, and that they can be sufficiently strong to generate completely passive movements that are faster than active movements observed in natural behaviors. We further demonstrate that some of these forces originate within the joint itself. In legs of different species adapted to different uses (walking, jumping), these passive joint forces complement the balance of strength of the antagonist muscles acting on the joint. We show that passive joint forces are stronger where they assist the weaker of two antagonist muscles. Conclusions In limbs where the dictates of a key behavior produce asymmetry in muscle forces, passive joint forces can be coadapted to provide the balance needed for the effective generation of other behaviors. PMID:23871240

  11. A damping circadian clock drives weak oscillations in metabolism and locomotor activity of aphids (Acyrthosiphon pisum).

    Science.gov (United States)

    Beer, Katharina; Joschinski, Jens; Arrazola Sastre, Alazne; Krauss, Jochen; Helfrich-Förster, Charlotte

    2017-11-02

    Timing seasonal events, like reproduction or diapause, is crucial for the survival of many species. Global change causes phenologies worldwide to shift, which requires a mechanistic explanation of seasonal time measurement. Day length (photoperiod) is a reliable indicator of winter arrival, but it remains unclear how exactly species measure day length. A reference for time of day could be provided by a circadian clock, by an hourglass clock, or, as some newer models suggest, by a damped circadian clock. However, damping of clock outputs has so far been rarely observed. To study putative clock outputs of Acyrthosiphon pisum aphids, we raised individual nymphs on coloured artificial diet, and measured rhythms in metabolic activity in light-dark illumination cycles of 16:08 hours (LD) and constant conditions (DD). In addition, we kept individuals in a novel monitoring setup and measured locomotor activity. We found that A. pisum is day-active in LD, potentially with a bimodal distribution. In constant darkness rhythmicity of locomotor behaviour persisted in some individuals, but patterns were mostly complex with several predominant periods. Metabolic activity, on the other hand, damped quickly. A damped circadian clock, potentially driven by multiple oscillator populations, is the most likely explanation of our results.

  12. Medications and impaired driving.

    Science.gov (United States)

    Hetland, Amanda; Carr, David B

    2014-04-01

    To describe the association of specific medication classes with driving outcomes and provide clinical recommendations. The MEDLINE and EMBASE databases were searched for articles published from January 1973 to June 2013 on classes of medications associated with driving impairment. The search included outcome terms such as automobile driving, motor vehicle crash, driving simulator, and road tests. Only English-language articles that contained findings from observational or interventional designs with ≥ 10 participants were included in this review. Cross-sectional studies, case series, and case reports were excluded. Driving is an important task and activity for the majority of adults. Some commonly prescribed medications have been associated with driving impairment measured by road performance, driving simulation, and/or motor vehicle crashes. This review of 30 studies identified findings with barbiturates, benzodiazepines, hypnotics, antidepressants, opioid and nonsteroidal analgesics, anticonvulsants, antipsychotics, antiparkinsonian agents, skeletal muscle relaxants, antihistamines, anticholinergic medications, and hypoglycemic agents. Additional studies of medication impact on sedation, sleep latency, and psychomotor function, as well as the role of alcohol, are also discussed. Psychotropic agents and those with central nervous system side effects were associated with measures of impaired driving performance. It is difficult to determine if such associations are actually a result of medication use or the medical diagnosis itself. Regardless, clinicians should be aware of the increased risk of impaired driving with specific classes of medications, educate their patients, and/or consider safer alternatives.

  13. Enhancing neural activity to drive respiratory plasticity following cervical spinal cord injury.

    Science.gov (United States)

    Hormigo, Kristiina M; Zholudeva, Lyandysha V; Spruance, Victoria M; Marchenko, Vitaliy; Cote, Marie-Pascale; Vinit, Stephane; Giszter, Simon; Bezdudnaya, Tatiana; Lane, Michael A

    2017-01-01

    Cervical spinal cord injury (SCI) results in permanent life-altering sensorimotor deficits, among which impaired breathing is one of the most devastating and life-threatening. While clinical and experimental research has revealed that some spontaneous respiratory improvement (functional plasticity) can occur post-SCI, the extent of the recovery is limited and significant deficits persist. Thus, increasing effort is being made to develop therapies that harness and enhance this neuroplastic potential to optimize long-term recovery of breathing in injured individuals. One strategy with demonstrated therapeutic potential is the use of treatments that increase neural and muscular activity (e.g. locomotor training, neural and muscular stimulation) and promote plasticity. With a focus on respiratory function post-SCI, this review will discuss advances in the use of neural interfacing strategies and activity-based treatments, and highlights some recent results from our own research. Copyright © 2016 Elsevier Inc. All rights reserved.

  14. Sensorless sliding mode torque control of an IPMSM drive based on active flux concept

    OpenAIRE

    Hassan, A.A.; El-Sawy, A.M.; Mohamed, Y.S.; Shehata, E.G.

    2012-01-01

    This paper investigates a novel direct torque control of a sensorless interior permanent magnet synchronous motor based on a sliding mode technique. The speed and position of the interior permanent magnet synchronous motor are estimated online based on active flux concept. To overcome the large ripple content associated with the direct torque, a torque/flux sliding mode controller has been employed. Two integral surface functions are used to construct the sliding mode controller. The command ...

  15. HIV-1 Activates T Cell Signaling Independently of Antigen to Drive Viral Spread.

    Science.gov (United States)

    Len, Alice C L; Starling, Shimona; Shivkumar, Maitreyi; Jolly, Clare

    2017-01-24

    HIV-1 spreads between CD4 T cells most efficiently through virus-induced cell-cell contacts. To test whether this process potentiates viral spread by activating signaling pathways, we developed an approach to analyze the phosphoproteome in infected and uninfected mixed-population T cells using differential metabolic labeling and mass spectrometry. We discovered HIV-1-induced activation of signaling networks during viral spread encompassing over 200 cellular proteins. Strikingly, pathways downstream of the T cell receptor were the most significantly activated, despite the absence of canonical antigen-dependent stimulation. The importance of this pathway was demonstrated by the depletion of proteins, and we show that HIV-1 Env-mediated cell-cell contact, the T cell receptor, and the Src kinase Lck were essential for signaling-dependent enhancement of viral dissemination. This study demonstrates that manipulation of signaling at immune cell contacts by HIV-1 is essential for promoting virus replication and defines a paradigm for antigen-independent T cell signaling. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  16. RAC1 activation drives pathologic interactions between the epidermis and immune cells.

    Science.gov (United States)

    Winge, Mårten C G; Ohyama, Bungo; Dey, Clara N; Boxer, Lisa M; Li, Wei; Ehsani-Chimeh, Nazanin; Truong, Allison K; Wu, Diane; Armstrong, April W; Makino, Teruhiko; Davidson, Matthew; Starcevic, Daniela; Kislat, Andreas; Nguyen, Ngon T; Hashimoto, Takashi; Homey, Bernard; Khavari, Paul A; Bradley, Maria; Waterman, Elizabeth A; Marinkovich, M Peter

    2016-07-01

    Interactions between the epidermis and the immune system govern epidermal tissue homeostasis. These epidermis-immune interactions are altered in the inflammatory disease psoriasis; however, the pathways that underlie this aberrant immune response are not well understood. Here, we determined that Ras-related C3 botulinum toxin substrate 1 (RAC1) is a key mediator of epidermal dysfunction. RAC1 activation was consistently elevated in psoriatic epidermis and primary psoriatic human keratinocytes (PHKCs) exposed to psoriasis-related stimuli, but not in skin from patients with basal or squamous cell carcinoma. Expression of a constitutively active form of RAC1 (RACV12) in mice resulted in the development of lesions similar to those of human psoriasis that required the presence of an intact immune system. RAC1V12-expressing mice and human psoriatic skin showed similar RAC1-dependent signaling as well as transcriptional overlap of differentially expressed epidermal and immune pathways. Coculture of PHKCs with immunocytes resulted in the upregulation of RAC1-dependent proinflammatory cytokines, an effect that was reproduced by overexpressing RAC1 in normal human keratinocytes. In keratinocytes, modulating RAC1 activity altered differentiation, proliferation, and inflammatory pathways, including STAT3, NFκB, and zinc finger protein 750 (ZNF750). Finally, RAC1 inhibition in xenografts composed of human PHKCs and immunocytes abolished psoriasiform hyperplasia and inflammation in vivo. These studies implicate RAC1 as a potential therapeutic target for psoriasis and as a key orchestrator of pathologic epidermis-immune interactions.

  17. Phasic dopamine release drives rapid activation of striatal D2-receptors

    Science.gov (United States)

    Marcott, Pamela F; Mamaligas, Aphroditi A; Ford, Christopher P

    2014-01-01

    Summary Striatal dopamine transmission underlies numerous goal-directed behaviors. Medium spiny neurons (MSNs) are a major target of dopamine in the striatum. However, as dopamine does not directly evoke a synaptic event in MSNs, the time course of dopamine signaling in these cells remains unclear. To examine how dopamine release activates D2-receptors on MSNs, G-protein activated inwardly rectifying potassium (GIRK2; Kir 3.2) channels were virally overexpressed in the striatum and the resulting outward currents were used as a sensor of D2-receptor activation. Electrical and optogenetic stimulation of dopamine terminals evoked robust D2-receptor inhibitory post-synaptic currents (IPSCs) in GIRK2-expressing MSNs that occurred in under a second. Evoked D2-IPSCs could be driven by repetitive stimulation and were not occluded by background dopamine tone. Together, the results indicate that D2-receptors on MSNs exhibit functional low affinity and suggest that striatal D2-receptors can encode both tonic and phasic dopamine signals. PMID:25242218

  18. Bax inhibitor 1, a modulator of calcium homeostasis, confers affective resilience

    OpenAIRE

    Hunsberger, Joshua G.; Machado-Vieira, Rodrigo; Austin, Daniel R.; Zarate, Carlos; Chuang, De-Maw; Chen, Guang; Reed, John C.; Manji, Husseini K.

    2011-01-01

    The endoplamic reticulum (ER) is a critical site for intracellular calcium storage as well as protein synthesis, folding, and trafficking. Disruption of these processes is gaining support for contributing to heritable vulnerability of certain diseases. Here, we investigated Bax inhibitor 1 (BI-1), an anti-apoptotic protein that primarily resides in the ER and associates with B-cell lymphoma 2 (Bcl-2) and Bcl-XL, as an affective resiliency factor through its modulation of calcium homeostasis. ...

  19. Interleukin-33 Drives Activation of Alveolar Macrophages and Airway Inflammation in a Mouse Model of Acute Exacerbation of Chronic Asthma

    Directory of Open Access Journals (Sweden)

    Melissa M. Bunting

    2013-01-01

    Full Text Available We investigated the role of interleukin-33 (IL-33 in airway inflammation in an experimental model of an acute exacerbation of chronic asthma, which reproduces many of the features of the human disease. Systemically sensitized female BALB/c mice were challenged with a low mass concentration of aerosolized ovalbumin for 4 weeks to induce chronic asthmatic inflammation and then received a single moderate-level challenge to trigger acute airway inflammation simulating an asthmatic exacerbation. The inflammatory response and expression of cytokines and activation markers by alveolar macrophages (AM were assessed, as was the effect of pretreatment with a neutralizing antibody to IL-33. Compared to chronically challenged mice, AM from an acute exacerbation exhibited significantly enhanced expression of markers of alternative activation, together with enhanced expression of proinflammatory cytokines and of cell surface proteins associated with antigen presentation. In parallel, there was markedly increased expression of both mRNA and immunoreactivity for IL-33 in the airways. Neutralization of IL-33 significantly decreased both airway inflammation and the expression of proinflammatory cytokines by AM. Collectively, these data indicate that in this model of an acute exacerbation of chronic asthma, IL-33 drives activation of AM and has an important role in the pathogenesis of airway inflammation.

  20. Autocrine CSF-1R signaling drives mesothelioma chemoresistance via AKT activation.

    Science.gov (United States)

    Cioce, M; Canino, C; Goparaju, C; Yang, H; Carbone, M; Pass, H I

    2014-04-10

    Clinical management of malignant pleural mesothelioma (MPM) is very challenging because of the uncommon resistance of this tumor to chemotherapy. We report here increased expression of macrophage colony-stimulating-factor-1-receptor (M-CSF/CSF-1R) mRNA in mesothelioma versus normal tissue specimens and demonstrate that CSF-1R expression identifies chemoresistant cells of mesothelial nature in both primary cultures and mesothelioma cell lines. By using RNAi or ligand trapping, we demonstrate that the chemoresistance properties of those cells depend on autocrine CSF-1R signaling. At the single-cell level, the isolated CSF-1R(pos) cells exhibit a complex repertoire of pluripotency, epithelial-mesenchymal transition and detoxifying factors, which define a clonogenic, chemoresistant, precursor-like cell sub-population. The simple activation of CSF-1R in untransformed mesothelial cells is sufficient to confer clonogenicity and resistance to pemetrexed, hallmarks of mesothelioma. In addition, this induced a gene expression profile highly mimicking that observed in the MPM cells endogenously expressing the receptor and the ligands, suggesting that CSF-1R expression is mainly responsible for the phenotype of the identified cell sub-populations. The survival of CSF1R(pos) cells requires active AKT (v-akt murine thymoma viral oncogene homolog 1) signaling, which contributed to increased levels of nuclear, transcriptionally competent β-catenin. Inhibition of AKT reduced the transcriptional activity of β-catenin-dependent reporters and sensitized the cells to senescence-induced clonogenic death after pemetrexed treatment. This work expands what is known on the non-macrophage functions of CSF-1R and its role in solid tumors, and suggests that CSF-1R signaling may have a critical pathogenic role in a prototypical, inflammation-related cancer such as MPM and therefore may represent a promising target for therapeutic intervention.

  1. Activated WNT signaling in postnatal SOX2-positive dental stem cells can drive odontoma formation

    Science.gov (United States)

    Xavier, Guilherme M.; Patist, Amanda L.; Healy, Chris; Pagrut, Ankita; Carreno, Gabriela; Sharpe, Paul T.; Pedro Martinez-Barbera, Juan; Thavaraj, Selvam; Cobourne, Martyn T.; Andoniadou, Cynthia L.

    2015-01-01

    In common with most mammals, humans form only two dentitions during their lifetime. Occasionally, supernumerary teeth develop in addition to the normal complement. Odontoma represent a small group of malformations containing calcified dental tissues of both epithelial and mesenchymal origin, with varying levels of organization, including tooth-like structures. The specific cell type responsible for the induction of odontoma, which retains the capacity to re-initiate de novo tooth development in postnatal tissues, is not known. Here we demonstrate that aberrant activation of WNT signaling by expression of a non-degradable form of β-catenin specifically in SOX2-positive postnatal dental epithelial stem cells is sufficient to generate odontoma containing multiple tooth-like structures complete with all dental tissue layers. Genetic lineage-tracing confirms that odontoma form in a similar manner to normal teeth, derived from both the mutation-sustaining epithelial stem cells and adjacent mesenchymal tissues. Activation of the WNT pathway in embryonic SOX2-positive progenitors results in ectopic expression of secreted signals that promote odontogenesis throughout the oral cavity. Significantly, the inductive potential of epithelial dental stem cells is retained in postnatal tissues, and up-regulation of WNT signaling specifically in these cells is sufficient to promote generation and growth of ectopic malformations faithfully resembling human odontoma. PMID:26411543

  2. Nucleotide-induced asymmetry within ATPase activator ring drives σ54-RNAP interaction and ATP hydrolysis

    Energy Technology Data Exchange (ETDEWEB)

    Sysoeva, Tatyana A.; Chowdhury, Saikat; Guo, Liang; Nixon, B. Tracy [IIT; (Penn)

    2013-12-10

    It is largely unknown how the typical homomeric ring geometry of ATPases associated with various cellular activities enables them to perform mechanical work. Small-angle solution X-ray scattering, crystallography, and electron microscopy (EM) reconstructions revealed that partial ATP occupancy caused the heptameric closed ring of the bacterial enhancer-binding protein (bEBP) NtrC1 to rearrange into a hexameric split ring of striking asymmetry. The highly conserved and functionally crucial GAFTGA loops responsible for interacting with σ54–RNA polymerase formed a spiral staircase. We propose that splitting of the ensemble directs ATP hydrolysis within the oligomer, and the ring's asymmetry guides interaction between ATPase and the complex of σ54 and promoter DNA. Similarity between the structure of the transcriptional activator NtrC1 and those of distantly related helicases Rho and E1 reveals a general mechanism in homomeric ATPases whereby complex allostery within the ring geometry forms asymmetric functional states that allow these biological motors to exert directional forces on their target macromolecules.

  3. Discoidin domain receptor 1 activity drives an aggressive phenotype in gastric carcinoma.

    Science.gov (United States)

    Hur, Hoon; Ham, In-Hye; Lee, Dakeun; Jin, Hyejin; Aguilera, Kristina Y; Oh, Hye Jeong; Han, Sang-Uk; Kwon, Ji Eun; Kim, Young-Bae; Ding, Ke; Brekken, Rolf A

    2017-01-31

    Discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase that utilizes collagen as a ligand, is a key molecule in the progression of solid tumors as it regulates the interaction of cancer cells with the tumor stroma. However, the clinical relevance of DDR1 expression in gastric carcinoma is yet to be investigated. Here, we assessed the role of DDR1 in mediating the aggressive phenotype of gastric carcinoma and its potential as a therapeutic target. We conducted DDR1 immunohistochemistry using a tissue microarray of 202 gastric carcinoma specimens. We examined the effect of collagen-induced activation of DDR1 on cell signaling, tumorigenesis, and cell migration in gastric cancer cell lines, and tumor growth in a xenograft animal model of gastric cancer. Our results showed that 50.5% of gastric cancer tissues are positive for DDR1 expression, and positive DDR1 expression was significantly correlated with a poor prognosis (P = 0.015). In a subgroup analysis, DDR1 expression was prognostically meaningful only in patients receiving adjuvant treatment (P = 0.013). We also demonstrated that collagen was able to activate DDR1 and increase the clonogenicity and migration of gastric cancer cells. We observed that a DDR1 inhibitor, 7rh benzamide, suppressed tumor growth in gastric cancer xenografts. Our findings suggest a key role for DDR1 signaling in mediating the aggressive phenotype of gastric carcinoma. Importantly, inhibition of DDR1 is an attractive strategy for gastric carcinoma therapy.

  4. High and low activity rats: elevated intrinsic physical activity drives resistance to diet-induced obesity in non-bred rats.

    Science.gov (United States)

    Perez-Leighton, Claudio E; Boland, Kelsey; Billington, Charles J; Kotz, Catherine M

    2013-02-01

    Humans and rodents show large variability in their individual sensitivity to diet-induced obesity (DIO), which has been associated with differences in intrinsic spontaneous physical activity (SPA). Evidence from genetic and out-bred rat obesity models shows that higher activity of the orexin peptides results in higher intrinsic SPA and protection against DIO. Based on this, we hypothesized that naturally occurring variation in SPA and orexin signaling is sufficient to drive differences in sensitivity to DIO. Orexin expression, behavioral responses to orexin-A, basal energy expenditure and sensitivity to DIO were measured in in non-manipulated male Sprague-Dawley rats selected for high and low intrinsic SPA. Male Sprague-Dawley rats were classified as high-activity or low-activity based on differences in intrinsic SPA. High-activity rats showed higher expression of prepro-orexin mRNA, higher sensitivity to behavioral effects of orexin injection, higher basal energy expenditure and were more resistant to obesity caused by high-fat diet consumption than low-activity rats. Our results define a new model of differential DIO sensitivity, the high-activity and low-activity rats, and suggest that naturally occurring variations in intrinsic SPA cause differences in energy expenditure that are mediated by orexin signaling and alter DIO sensitivity. Copyright © 2012 The Obesity Society.

  5. STAT3 signaling drives EZH2 transcriptional activation and mediates poor prognosis in gastric cancer.

    Science.gov (United States)

    Pan, Yuan-Ming; Wang, Cheng-Gang; Zhu, Min; Xing, Rui; Cui, Jian-Tao; Li, Wen-Mei; Yu, De-Dong; Wang, Shu-Bin; Zhu, Wei; Ye, Ying-Jiang; Wu, Yun; Wang, Shan; Lu, You-Yong

    2016-12-09

    STAT3 signaling plays the pivotal role in tumorigenesis through EZH2 epigenetic modification, which enhanced STAT3 activity by increased tyrosine phosphorylation of STAT3. Here, another possible feedback mechanism and clinical significance of EZH2 and STAT3 were investigated in gastric cancer (GC). STAT3, p-STAT3 (Tyr 705) and EZH2 expression were examined in 63 GC specimens with matched normal tissues by IHC staining. EZH2 and STAT3 were also identified in five GC cell lines using RT-PCR and western blot analyses. p-STAT3 protein was detected by western blotting. In order to investigate whether EZH2 expression was directly regulated by STAT3, EZH2 expression was further detected using siRNA for STAT3 or IL-6 stimulation, with dual luciferase reporter analyses, electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assays. The clinical significance of STAT3, p-STAT3 and EZH2 expression was evaluated by multi-factor COX regression and Kaplan-Meier analyses. Hyper-activation of STAT3, p-STAT3 and EZH2 expression were observed in GC cells and tissues. STAT3 signaling was correlated with EZH2 expression in GC (R = 0.373, P = 0.003), which was consistent with our data showing that STAT3 as the transcriptional factor enhanced EZH2 transcriptional activity by binding the relative promoter region (-214 ~ -206). STAT3 was an independent signature for poor survival (P = 0.002). Patients with STAT3(+)/EZH2(+) or p-STAT3(+)/EZH2(+) had a worse outcome than others (P EZH2 was associated with advanced TNM staging (P = 0.017). Moreover, treatment with a combination of siSTAT3 and EZH2-specific inhibitor, 3-deazaneplanocin A (DZNEP), increased the apoptotic ratio of cells. It is benefit for targeting STAT3-EZH2 interplay in GC treatment. Our results indicate that STAT3 status mediated EZH2 upregulation, associated with advanced TNM stage and poor prognosis, suggesting that combination with knockdown of STAT3 and EZH2 inhibitor

  6. Induction Motor Drive System Based on Linear Active Disturbance Rejection Controller

    Science.gov (United States)

    Liu, Liying; Zhang, Yongli; Yao, Qingmei

    It is difficult to establish an exact mathematical model for the induction motor and the robustness is poor of the vector control system using PI regulator. This paper adopts the linear active disturbance rejection controller (LADRC) to control inductor motor. LADRC doesn't need the exact mathematical model of motor and it can not only estimate but also compensate the general disturbance that includes the coupling items in model of motor and parameters perturbations by linear extended state observer (LESO), so the rotor flux and torque fully decouple. As a result, the performance is improved. To prove the above control scheme, the proposed control system has been simulated in MATLAB/SIMULINK, and the comparison was made with PID. Simulation results show that LADRC' has better performance and robustness than PID.

  7. Malignant T cells express lymphotoxin alpha and drive endothelial activation in cutaneous T cell lymphoma

    DEFF Research Database (Denmark)

    Lauenborg, Britt; Christensen, Louise; Ralfkiaer, Ulrik

    2015-01-01

    Lymphotoxin α (LTα) plays a key role in the formation of lymphatic vasculature and secondary lymphoid structures. Cutaneous T cell lymphoma (CTCL) is the most common primary lymphoma of the skin and in advanced stages, malignant T cells spreads through the lymphatic to regional lymph nodes...... to internal organs and blood. Yet, little is known about the mechanism of the CTCL dissemination. Here, we show that CTCL cells express LTα in situ and that LTα expression is driven by aberrantly activated JAK3/STAT5 pathway. Importantly, via TNF receptor 2, LTα functions as an autocrine factor by stimulating...... expression of IL-6 in the malignant cells. LTα and IL-6, together with VEGF promote angiogenesis by inducing endothelial cell sprouting and tube formation. Thus, we propose that LTα plays a role in malignant angiogenesis and disease progression in CTCL and may serve as a therapeutic target in this disease....

  8. Posterior Parietal Cortex Drives Inferotemporal Activations During Three-Dimensional Object Vision.

    Directory of Open Access Journals (Sweden)

    Ilse C Van Dromme

    2016-04-01

    Full Text Available The primate visual system consists of a ventral stream, specialized for object recognition, and a dorsal visual stream, which is crucial for spatial vision and actions. However, little is known about the interactions and information flow between these two streams. We investigated these interactions within the network processing three-dimensional (3D object information, comprising both the dorsal and ventral stream. Reversible inactivation of the macaque caudal intraparietal area (CIP during functional magnetic resonance imaging (fMRI reduced fMRI activations in posterior parietal cortex in the dorsal stream and, surprisingly, also in the inferotemporal cortex (ITC in the ventral visual stream. Moreover, CIP inactivation caused a perceptual deficit in a depth-structure categorization task. CIP-microstimulation during fMRI further suggests that CIP projects via posterior parietal areas to the ITC in the ventral stream. To our knowledge, these results provide the first causal evidence for the flow of visual 3D information from the dorsal stream to the ventral stream, and identify CIP as a key area for depth-structure processing. Thus, combining reversible inactivation and electrical microstimulation during fMRI provides a detailed view of the functional interactions between the two visual processing streams.

  9. Fluorescence Lifetime Imaging Microscopy reveals rerouting of SNARE trafficking driving dendritic cell activation

    Science.gov (United States)

    Verboogen, Daniëlle Rianne José; González Mancha, Natalia; ter Beest, Martin; van den Bogaart, Geert

    2017-01-01

    SNARE proteins play a crucial role in intracellular trafficking by catalyzing membrane fusion, but assigning SNAREs to specific intracellular transport routes is challenging with current techniques. We developed a novel Förster resonance energy transfer-fluorescence lifetime imaging microscopy (FRET-FLIM)-based technique allowing visualization of real-time local interactions of fluorescently tagged SNARE proteins in live cells. We used FRET-FLIM to delineate the trafficking steps underlying the release of the inflammatory cytokine interleukin-6 (IL-6) from human blood-derived dendritic cells. We found that activation of dendritic cells by bacterial lipopolysaccharide leads to increased FRET of fluorescently labeled syntaxin 4 with VAMP3 specifically at the plasma membrane, indicating increased SNARE complex formation, whereas FRET with other tested SNAREs was unaltered. Our results revealed that SNARE complexing is a key regulatory step for cytokine production by immune cells and prove the applicability of FRET-FLIM for visualizing SNARE complexes in live cells with subcellular spatial resolution. DOI: http://dx.doi.org/10.7554/eLife.23525.001 PMID:28524818

  10. Sensorless sliding mode torque control of an IPMSM drive based on active flux concept

    Directory of Open Access Journals (Sweden)

    A.A. Hassan

    2012-03-01

    Full Text Available This paper investigates a novel direct torque control of a sensorless interior permanent magnet synchronous motor based on a sliding mode technique. The speed and position of the interior permanent magnet synchronous motor are estimated online based on active flux concept. To overcome the large ripple content associated with the direct torque, a torque/flux sliding mode controller has been employed. Two integral surface functions are used to construct the sliding mode controller. The command voltage is estimated from the torque and flux errors based on the two switching functions. The idea of the total sliding mode is used to eliminate the problem of reaching phase stability. The space vector modulation is combined with the sliding mode controller to ensure minimum torque and flux ripples and provides high resolution voltage control. The proposed scheme has the advantages of simple implementation, and does not require an external signal injection. In addition, it combines the merits of the direct torque control, sliding mode controller, and space vector modulation besides to the sensorless control. Simulation works are carried out to demonstrate the ability of the proposed scheme at different operating conditions. The results confirm the high performance of the proposed scheme at standstill, low and high speeds including load disturbance and parameters variation.

  11. Antiosteoporotic Activity of Dioscorea alata L. cv. Phyto through Driving Mesenchymal Stem Cells Differentiation for Bone Formation

    Directory of Open Access Journals (Sweden)

    Kang-Yung Peng

    2011-01-01

    Full Text Available The aim of this study was to evaluate the effect of an ethanol extract of the rhizomes of Dioscorea alata L. cv. Phyto, Dispo85E, on bone formation and to investigate the mechanisms involved. Our results showed that Dispo85E increased the activity of alkaline phosphatase (ALP and bone nodule formation in primary bone marrow cultures. In addition, Dispo85E stimulated pluripotent C3H10T1/2 stem cells to differentiate into osteoblasts rather than adipocytes. Our in vivo data indicated that Dispo85E promotes osteoblastogenesis by increasing ALP activity and bone nodule formation in both intact and ovariectomized (OVX mice. Microcomputed tomography (μCT analysis also showed that Dispo85E ameliorates the deterioration of trabecular bone mineral density (tBMD, trabecular bone volume/total volume (BV/TV, and trabecular bone number (Tb.N in OVX mice. Our results suggested that Dispo85E is a botanical drug with a novel mechanism that drives the lineage-specific differentiation of bone marrow stromal cells and is a candidate drug for osteoporosis therapy.

  12. Allergen uptake, activation, and IL-23 production by pulmonary myeloid DCs drives airway hyperresponsiveness in asthma-susceptible mice.

    Directory of Open Access Journals (Sweden)

    Ian P Lewkowich

    Full Text Available Maladaptive, Th2-polarized inflammatory responses are integral to the pathogenesis of allergic asthma. As regulators of T cell activation, dendritic cells (DCs are important mediators of allergic asthma, yet the precise signals which render endogenous DCs "pro-asthmatic", and the extent to which these signals are regulated by the pulmonary environment and host genetics, remains unclear. Comparative phenotypic and functional analysis of pulmonary DC populations in mice susceptible (A/J, or resistant (C3H to experimental asthma, revealed that susceptibility to airway hyperresponsiveness is associated with preferential myeloid DC (mDC allergen uptake, and production of Th17-skewing cytokines (IL-6, IL-23, whereas resistance is associated with increased allergen uptake by plasmacytoid DCs. Surprisingly, adoptive transfer of syngeneic HDM-pulsed bone marrow derived mDCs (BMDCs to the lungs of C3H mice markedly enhanced lung IL-17A production, and rendered them susceptible to allergen-driven airway hyperresponsiveness. Characterization of these BMDCs revealed levels of antigen uptake, and Th17 promoting cytokine production similar to that observed in pulmonary mDCs from susceptible A/J mice. Collectively these data demonstrate that the lung environment present in asthma-resistant mice promotes robust pDC allergen uptake, activation, and limits Th17-skewing cytokine production responsible for driving pathologic T cell responses central to the development of allergen-induced airway hyperresponsiveness.

  13. miRNA-32 Drives Brown Fat Thermogenesis and Trans-activates Subcutaneous White Fat Browning in Mice.

    Science.gov (United States)

    Ng, Raymond; Hussain, Nurul Attiqah; Zhang, Qiongyi; Chang, Chengwei; Li, Hongyu; Fu, Yanyun; Cao, Lei; Han, Weiping; Stunkel, Walter; Xu, Feng

    2017-05-09

    Brown adipose tissue (BAT) activation and subcutaneous white fat browning are essential components of the thermogenic response to cold stimulus in mammals. microRNAs have been shown to regulate both processes in cis. Here, we identify miR-32 as a BAT-specific super-enhancer-associated miRNA in mice that is selectively expressed in BAT and further upregulated during cold exposure. Inhibiting miR-32 in vivo led to impaired cold tolerance, decreased BAT thermogenesis, and compromised white fat browning as a result of reduced serum FGF21 levels. Further examination showed that miR-32 directly represses its target gene Tob1, thereby activating p38 MAP kinase signaling to drive FGF21 expression and secretion from BAT. BAT-specific miR-32 overexpression led to increased BAT thermogenesis and serum FGF21 levels, which further promotes white fat browning in trans. Our results suggested miR-32 and Tob1 as modulators of FGF21 signaling that can be manipulated for therapeutic benefit against obesity and metabolic syndrome. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  14. uPA/uPAR system activation drives a glycolytic phenotype in melanoma cells.

    Science.gov (United States)

    Laurenzana, Anna; Chillà, Anastasia; Luciani, Cristina; Peppicelli, Silvia; Biagioni, Alessio; Bianchini, Francesca; Tenedini, Elena; Torre, Eugenio; Mocali, Alessandra; Calorini, Lido; Margheri, Francesca; Fibbi, Gabriella; Del Rosso, Mario

    2017-09-15

    In this manuscript, we show the involvement of the uPA/uPAR system in the regulation of aerobic glycolysis of melanoma cells. uPAR over-expression in human melanoma cells controls an invasive and glycolytic phenotype in normoxic conditions. uPAR down-regulation by siRNA or its uncoupling from integrins, and hence from integrin-linked tyrosine kinase receptors (IL-TKRs), by an antagonist peptide induced a striking inhibition of the PI3K/AKT/mTOR/HIF1α pathway, resulting into impairment of glucose uptake, decrease of several glycolytic enzymes and of PKM2, a checkpoint that controls metabolism of cancer cells. Further, binding of uPA to uPAR regulates expression of molecules that govern cell invasion, including extracellular matrix metallo-proteinases inducer (EMPPRIN) and enolase, a glycolytyc enzyme that also serves as a plasminogen receptor, thus providing a common denominator between tumor metabolism and phenotypic invasive features. Such effects depend on the α5β1-integrin-mediated uPAR connection with EGFR in melanoma cells with engagement of the PI3K-mTOR-HIFα pathway. HIF-1α trans-activates genes whose products mediate tumor invasion and glycolysis, thus providing the common denominator between melanoma metabolism and its invasive features. These findings unveil a unrecognized interaction between the invasion-related uPAR and IL-TKRs in the control of glycolysis and disclose a new pharmacological target (i.e., uPAR/IL-TKRs axis) for the therapy of melanoma. © 2017 UICC.

  15. Distracted Driving

    Science.gov (United States)

    ... about 5 seconds, long enough to cover a football field while driving at 55 mph. 4 How ... 8 On September 17, 2010, the Federal Railroad Administration banned cell phone and electronic device use of ...

  16. Higher-Order Sensory Cortex Drives Basolateral Amygdala Activity during the Recall of Remote, but Not Recently Learned Fearful Memories.

    Science.gov (United States)

    Cambiaghi, Marco; Grosso, Anna; Likhtik, Ekaterina; Mazziotti, Raffaele; Concina, Giulia; Renna, Annamaria; Sacco, Tiziana; Gordon, Joshua A; Sacchetti, Benedetto

    2016-02-03

    Negative experiences are quickly learned and long remembered. Key unresolved issues in the field of emotional memory include identifying the loci and dynamics of memory storage and retrieval. The present study examined neural activity in the higher-order auditory cortex Te2 and basolateral amygdala (BLA) and their crosstalk during the recall of recent and remote fear memories. To this end, we obtained local field potentials and multiunit activity recordings in Te2 and BLA of rats that underwent recall at 24 h and 30 d after the association of an acoustic conditioned (CS, tone) and an aversive unconditioned stimulus (US, electric shock). Here we show that, during the recall of remote auditory threat memories in rats, the activity of the Te2 and BLA is highly synchronized in the theta frequency range. This functional connectivity stems from memory consolidation processes because it is present during remote, but not recent, memory retrieval. Moreover, the observed increase in synchrony is cue and region specific. A preponderant Te2-to-BLA directionality characterizes this dialogue, and the percentage of time Te2 theta leads the BLA during remote memory recall correlates with a faster latency to freeze to the auditory conditioned stimulus. The blockade of this information transfer via Te2 inhibition with muscimol prevents any retrieval-evoked neuronal activity in the BLA and animals are unable to retrieve remote memories. We conclude that memories stored in higher-order sensory cortices drive BLA activity when distinguishing between learned threatening and neutral stimuli. How and where in the brain do we store the affective/motivational significance of sensory stimuli acquired through life experiences? Scientists have long investigated how "limbic" structures, such as the amygdala, process affective stimuli. Here we show that retrieval of well-established threat memories requires the functional interplay between higher-order components of the auditory cortex and the

  17. μ opioid receptor activation hyperpolarizes respiratory-controlling Kölliker-Fuse neurons and suppresses post-inspiratory drive.

    Science.gov (United States)

    Levitt, Erica S; Abdala, Ana P; Paton, Julian F R; Bissonnette, John M; Williams, John T

    2015-10-01

    In addition to reductions in respiratory rate, opioids also cause aspiration and difficulty swallowing, indicating impairment of the upper airways. The Kölliker-Fuse (KF) maintains upper airway patency and a normal respiratory pattern. In this study, activation of μ opioid receptors in the KF reduced respiratory frequency and tidal volume in anaesthetized rats. Nerve recordings in an in situ preparation showed that activation of μ opioid receptors in the KF eliminated the post-inspiration phase of the respiratory cycle. In brain slices, μ opioid agonists hyperpolarized a distinct population (61%) of KF neurons by activation of an inwardly rectifying potassium conductance. These results suggest that KF neurons that are hyperpolarized by opioids could contribute to opioid-induced respiratory disturbances, particularly the impairment of upper airways. Opioid-induced respiratory effects include aspiration and difficulty swallowing, suggesting impairment of the upper airways. The pontine Kölliker-Fuse nucleus (KF) controls upper airway patency and regulates respiration, in particular the inspiratory/expiratory phase transition. Given the importance of the KF in coordinating respiratory pattern, the mechanisms of μ opioid receptor activation in this nucleus were investigated at the systems and cellular level. In anaesthetized, vagi-intact rats, injection of opioid agonists DAMGO or [Met(5) ]enkephalin (ME) into the KF reduced respiratory frequency and amplitude. The μ opioid agonist DAMGO applied directly into the KF of the in situ arterially perfused working heart-brainstem preparation of rat resulted in robust apneusis (lengthened low amplitude inspiration due to loss of post-inspiratory drive) that was rapidly reversed by the opioid antagonist naloxone. In brain slice preparations, activation of μ opioid receptors on KF neurons hyperpolarized a distinct population (61%) of neurons. As expected, the opioid-induced hyperpolarization reduced the excitability of

  18. Tumor necrosis factor-alpha regulates plasminogen activator inhibitor-1 in rat testicular peritubular cells

    National Research Council Canada - National Science Library

    Le Magueresse-Battistoni, B; Pernod, G; Kolodié, L; Morera, A M; Benahmed, M

    1997-01-01

    ...) as well as immunoreactive (Western blots) and bioactive (Stachrom) PAI-1 protein. Induction of PAI-1 mRNA started 4 h after the addition of TNF alpha (2.5-fold increase) and peaked (7-fold increase...

  19. Hepatocyte growth factor activator inhibitor-1 has a complex subcellular itinerary

    DEFF Research Database (Denmark)

    Godiksen, Sine; Selzer-Plon, Joanna; Pedersen, Esben D K

    2008-01-01

    and then recycles between the basolateral plasma membrane and endosomes for hours until it is transcytosed to the apical plasma membrane. Minor amounts of HAI-1 present at the apical plasma membrane are proteolytically cleaved and released into the apical medium. Full-length membrane-bound HAI-1 has a half...

  20. Biochemical mechanism of action of a diketopiperazine inactivator of plasminogen activator inhibitor-1

    DEFF Research Database (Denmark)

    Einholm, Anja P; Pedersen, Katrine E; Wind, Troels

    2003-01-01

    , situated above beta-sheet A, and is in agreement with the hypothesis that XR5118 binds laterally to beta-sheet A. These results improve our understanding of the unique conformational flexibility of serpins and the biochemical basis for using PAI-1 as a therapeutic target. Udgivelsesdato: 2003-Aug-1...

  1. Plasminogen activator inhibitor-1 4G/5G polymorphism in infertile women with and without endometriosis.

    Science.gov (United States)

    Gonçalves-Filho, Rubens P; Brandes, Ariel; Christofolini, Denise M; Lerner, Tatiana G; Bianco, Bianca; Barbosa, Caio P

    2011-05-01

    To evaluate PAI-1 genotypes in a group of infertile women with or without endometriosis and control subjects. Case-control study. Human Reproduction Center of Medicina do ABC Faculty. One hundred and forty infertile women with endometriosis, 64 women with idiopathic infertility and 148 fertile women as control subjects. The PAI-1 4G/5G polymorphism was identified by restriction fragment length polymorphism-polymerase chain reaction. Genotype distribution and allele frequency of the 4G/5G polymorphism of the PAI-1 gene. The frequencies of genotypes 4G/4G, 4G/5G and 5G/5G of the PAI-1 gene in the infertile women with endometriosis were 38.6, 37.1 and 24.3%, respectively, and in the control group 24.3, 33.8 and 41.9%, respectively (p=0.003). When the infertile women with endometriosis were divided according to their endometriosis stage, genotypes 4G/4G, 4G/5G and 5G/5G were identified, respectively, in 36.7, 32.9 and 30.4% of the patients with minimal/mild endometriosis (p=0.102) and in 41.0, 42.6 and 16.4% of the patients with moderate/severe endometriosis (p=0.001); in the women with idiopathic infertility, these genotypes were found at a frequency of 29.7, 34.3 and 36%, respectively (p=0.637). The data suggest that, in Brazilian women, the PAI-1 4G/5G polymorphism may be associated with a risk of endometriosis-associated infertility. © 2011 The Authors Acta Obstetricia et Gynecologica Scandinavica© 2011 Nordic Federation of Societies of Obstetrics and Gynecology.

  2. Metastasis of transgenic breast cancer in plasminogen activator inhibitor-1 gene-deficient mice

    DEFF Research Database (Denmark)

    Almholt, Kasper; Nielsen, Boye Schnack; Frandsen, Thomas Leth

    2003-01-01

    of metastasizing breast cancer. In these tumors, the expression pattern of uPA and PAI-1 resembles that of human ductal breast cancer and plasminogen is required for efficient metastasis. In a cohort of 63 transgenic mice that were either PAI-1-deficient or wild-type sibling controls, primary tumor growth...... limiting for tumor vascularization and metastasis, or that there is a functional redundancy between PAI-1 and other inhibitors of the uPA/plasmin system, masking the effect of PAI-1 deficiency....

  3. NK-, NKT- and CD8-Derived IFNγ Drives Myeloid Cell Activation and Erythrophagocytosis, Resulting in Trypanosomosis-Associated Acute Anemia.

    Directory of Open Access Journals (Sweden)

    Jennifer Cnops

    2015-06-01

    Full Text Available African trypanosomes are the causative agents of Human African Trypanosomosis (HAT/Sleeping Sickness and Animal African Trypanosomosis (AAT/Nagana. A common hallmark of African trypanosome infections is inflammation. In murine trypanosomosis, the onset of inflammation occurs rapidly after infection and is manifested by an influx of myeloid cells in both liver and spleen, accompanied by a burst of serum pro-inflammatory cytokines. Within 48 hours after reaching peak parasitemia, acute anemia develops and the percentage of red blood cells drops by 50%. Using a newly developed in vivo erythrophagocytosis assay, we recently demonstrated that activated cells of the myeloid phagocytic system display enhanced erythrophagocytosis causing acute anemia. Here, we aimed to elucidate the mechanism and immune pathway behind this phenomenon in a murine model for trypanosomosis. Results indicate that IFNγ plays a crucial role in the recruitment and activation of erythrophagocytic myeloid cells, as mice lacking the IFNγ receptor were partially protected against trypanosomosis-associated inflammation and acute anemia. NK and NKT cells were the earliest source of IFNγ during T. b. brucei infection. Later in infection, CD8+ and to a lesser extent CD4+ T cells become the main IFNγ producers. Cell depletion and transfer experiments indicated that during infection the absence of NK, NKT and CD8+ T cells, but not CD4+ T cells, resulted in a reduced anemic phenotype similar to trypanosome infected IFNγR-/- mice. Collectively, this study shows that NK, NKT and CD8+ T cell-derived IFNγ is a critical mediator in trypanosomosis-associated pathology, driving enhanced erythrophagocytosis by myeloid phagocytic cells and the induction of acute inflammation-associated anemia.

  4. Microbiota-activated CD103(+) DCs stemming from microbiota adaptation specifically drive γδT17 proliferation and activation.

    Science.gov (United States)

    Fleming, Chris; Cai, Yihua; Sun, Xuan; Jala, Venkatakrishna R; Xue, Feng; Morrissey, Samantha; Wei, Yu-Ling; Chien, Yueh-Hsiu; Zhang, Huang-Ge; Haribabu, Bodduluri; Huang, Jian; Yan, Jun

    2017-04-24

    IL-17-producing γδT cells (γδT17) promote autoinflammatory diseases and cancers. Yet, γδT17 peripheral regulation has not been thoroughly explored especially in the context of microbiota-host interaction. The potent antigen-presenting CD103(+) dendritic cell (DC) is a key immune player in close contact with both γδT17 cells and microbiota. This study presents a novel cellular network among microbiota, CD103(+) DCs, and γδT17 cells. Immunophenotyping of IL-17r(-/-) mice and IL-17r(-/-) IRF8(-/-) mice were performed by ex vivo immunostaining and flow cytometric analysis. We observed striking microbiome differences in the oral cavity and gut of IL-17r(-/-) mice by sequencing 16S rRNA gene (v1-v3 region) and analyzed using QIIME 1.9.0 software platform. Principal coordinate analysis of unweighted UniFrac distance matrix showed differential clustering for WT and IL-17r(-/-) mice. We found drastic homeostatic expansion of γδT17 in all major tissues, most prominently in cervical lymph nodes (cLNs) with monoclonal expansion of Vγ6 γδT17 in IL-17r(-/-) mice. Ki-67 staining and in vitro CFSE assays showed cellular proliferation due to cell-to-cell contact stimulation with microbiota-activated CD103(+) DCs. A newly developed double knockout mice model for IL-17r and CD103(+) DCs (IL-17r(-/-)IRF8(-/-)) showed a specific reduction in Vγ6 γδT17. Vγ6 γδT17 expansion is inhibited in germ-free mice and antibiotic-treated specific pathogen-free (SPF) mice. Microbiota transfer using cohousing of IL-17r(-/-) mice with wildtype mice induces γδT17 expansion in the wildtype mice with increased activated CD103(+) DCs in cLNs. However, microbiota transfer using fecal transplant through oral gavage to bypass the oral cavity showed no difference in colon or systemic γδT17 expansion. These findings reveal for the first time that γδT17 cells are regulated by microbiota dysbiosis through cell-to-cell contact with activated CD103(+) DCs leading to drastic systemic

  5. AKT activation drives the nuclear localization of CSE1L and a pro-oncogenic transcriptional activation in ovarian cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Lorenzato, Annalisa; Biolatti, Marta [Department of Oncology, University of Torino School of Medicine, Torino (Italy); Institute for Cancer Research at Candiolo, Candiolo, Torino (Italy); Delogu, Giuseppe [Department of Biomedical Sciences-Histology, University of Sassari, Sassari (Italy); Capobianco, Giampiero [Department of Surgical, Microsurgical and Medical Sciences, University of Sassari, Sassari (Italy); Farace, Cristiano [Department of Biomedical Sciences-Histology, University of Sassari, Sassari (Italy); Dessole, Salvatore; Cossu, Antonio; Tanda, Francesco [Department of Surgical, Microsurgical and Medical Sciences, University of Sassari, Sassari (Italy); Madeddu, Roberto [Department of Biomedical Sciences-Histology, University of Sassari, Sassari (Italy); National Institute of Biostructures and Biosystems, Rome (Italy); Olivero, Martina [Department of Oncology, University of Torino School of Medicine, Torino (Italy); Institute for Cancer Research at Candiolo, Candiolo, Torino (Italy); Di Renzo, Maria Flavia, E-mail: mariaflavia.direnzo@unito.it [Department of Oncology, University of Torino School of Medicine, Torino (Italy); Institute for Cancer Research at Candiolo, Candiolo, Torino (Italy)

    2013-10-15

    The human homolog of the yeast cse1 gene (CSE1L) is over-expressed in ovarian cancer. CSE1L forms complex with Ran and importin-α and has roles in nucleocytoplasmic traffic and gene expression. CSE1L accumulated in the nucleus of ovarian cancer cell lines, while it was localized also in the cytoplasm of other cancer cell lines. Nuclear localization depended on AKT, which was constitutively active in ovarian cancer cells, as the CSE1L protein translocated to the cytoplasm when AKT was inactivated. Moreover, the expression of a constitutively active AKT forced the translocation of CSE1L from the cytoplasm to the nucleus in other cancer cells. Nuclear accrual of CSE1L was associated to the nuclear accumulation of the phosphorylated Ran Binding protein 3 (RanBP3), which depended on AKT as well. Also in samples of human ovarian cancer, AKT activation was associated to nuclear accumulation of CSE1L and phosphorylation of RanBP3. Expression profiling of ovarian cancer cells after CSE1L silencing showed that CSE1L was required for the expression of genes promoting invasion and metastasis. In agreement, CSE1L silencing impaired motility and invasiveness of ovarian cancer cells. Altogether these data show that in ovarian cancer cells activated AKT by affecting RanBP3 phosphorylation determines the nuclear accumulation of CSE1L and likely the nuclear concentration of transcription factors conveying pro-oncogenic signals. - highlights: • CSE1L is a key player in nucleocytoplasmic traffic by forming complex with Ran. • AKT phosphorylates RanBP3 that regulates the nucleocytoplasmic gradient of Ran. • The activated oncogenic AKT drives the nuclear accumulation of CSE1L. • CSE1L in the nucleus up-regulates genes conveying pro-oncogenic signals. • CSE1L might contribute to tumor progression driven by the activated oncogenic AKT.

  6. Electric field-induced suppression of PTEN drives epithelial-to-mesenchymal transition via mTORC1 activation.

    Science.gov (United States)

    Yan, Tiantian; Jiang, Xupin; Guo, Xiaowei; Chen, Wen; Tang, Di; Zhang, Junhui; Zhang, Xingyue; Zhang, Dongxia; Zhang, Qiong; Jia, Jiezhi; Huang, Yuesheng

    2017-02-01

    suppression and the EMT, as mTORC1 inhibition reversed the EMT induced by PTEN downregulation. Our data demonstrate that the EF-induced suppression of PTEN drives the EMT via mTORC1 activation, thereby revealing a new and promising role of EFs in facilitating wound reepithelialization. These results provide a novel perspective regarding the significance of EFs in wound healing; therefore, electrical stimulation offers a new avenue of wound management for improved and accelerated wound healing. Copyright © 2016 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.

  7. A Modular Active Front-End Rectifier with Electronic Phase-Shifting for Harmonic Mitigation in Motor Drive Applications

    DEFF Research Database (Denmark)

    Zare, Firuz; Davari, Pooya; Blaabjerg, Frede

    2017-01-01

    In this paper, an electronic phase-shifting strategy has been optimized for a multi-parallel configuration of line-commutated rectifiers with a common dc-bus voltage used in motor drive application. This feature makes the performance of the system independent of the load profile and maximizes its...

  8. The Drive to Influence

    Science.gov (United States)

    Rodriguez, Diego

    2017-01-01

    At the heart of the educational vocation is a drive to influence, to meaningfully affect the learning and development of others. For adult educators working in higher education, daily activities--from teaching classes to supervising student research to attending faculty meetings to sitting on advisory boards--are full of opportunities to…

  9. CSI: Hard Drive

    Science.gov (United States)

    Sturgeon, Julie

    2008-01-01

    Acting on information from students who reported seeing a classmate looking at inappropriate material on a school computer, school officials used forensics software to plunge the depths of the PC's hard drive, searching for evidence of improper activity. Images were found in a deleted Internet Explorer cache as well as deleted file space.…

  10. The Drive-Wise Project: Driving Simulator Training increases real driving performance in healthy older drivers

    Directory of Open Access Journals (Sweden)

    Gianclaudio eCasutt

    2014-05-01

    Full Text Available Background: Age-related cognitive decline is often associated with unsafe driving behavior. We hypothesized that 10 active training sessions in a driving simulator increase cognitive and on-road driving performance. In addition, driving simulator training should outperform cognitive training.Methods: Ninety-one healthy active drivers (62 – 87 years were randomly assigned to either (1 a driving simulator training group, (2 an attention training group (vigilance and selective attention, or (3 a control group. The main outcome variables were on-road driving and cognitive performance. Seventy-seven participants (85% completed the training and were included in the analyses. Training gains were analyzed using a multiple regression analysis with planned comparisons.Results: The driving simulator training group showed an improvement in on-road driving performance compared to the attention training group. In addition, both training groups increased cognitive performance compared to the control group. Conclusion: Driving simulator training offers the potential to enhance driving skills in older drivers. Compared to the attention training, the simulator training seems to be a more powerful program for increasing older drivers’ safety on the road.

  11. The drive-wise project: driving simulator training increases real driving performance in healthy older drivers.

    Science.gov (United States)

    Casutt, Gianclaudio; Theill, Nathan; Martin, Mike; Keller, Martin; Jäncke, Lutz

    2014-01-01

    Age-related cognitive decline is often associated with unsafe driving behavior. We hypothesized that 10 active training sessions in a driving simulator increase cognitive and on-road driving performance. In addition, driving simulator training should outperform cognitive training. Ninety-one healthy active drivers (62-87 years) were randomly assigned to one of three groups: (1) a driving simulator training group, (2) an attention training group (vigilance and selective attention), or (3) a control group. The main outcome variables were on-road driving and cognitive performance. Seventy-seven participants (85%) completed the training and were included in the analyses. Training gains were analyzed using a multiple regression analysis with planned orthogonal comparisons. The driving simulator-training group showed an improvement in on-road driving performance compared to the attention-training group. In addition, both training groups increased cognitive performance compared to the control group. Driving simulator training offers the potential to enhance driving skills in older drivers. Compared to the attention training, the simulator training seems to be a more powerful program for increasing older drivers' safety on the road.

  12. [Psychotropic substances and driving].

    Science.gov (United States)

    Bordini, L; Riboldi, L; Ferrario, M M

    2012-01-01

    Consumption of psychotropic substances (alcohol, drugs, medication) has a major impact on complex activity performance such as driving. This issue is of relevant social interest for the high number of potentially involved subjects and the often fatale outcomes, and affects also occupational physicians because of the high number of people whose job is driving. There are still few studies trying to assess the presence of a possible association between increased risk of accident/injury at work and consumption of psychotropic substances and results are not always in agreement. In spite of such uncertainties and some Italian regulations still worth being amended by Legislator, the possible impact of consumption of psychoactive substances on driving is an issue to be still better defined for which occupational physicians may play a basic role in the field of prevention, clinics and rehabilitation.

  13. Toxoplasma gondii protease inhibitor-1 (TgPI-1) is a novel vaccine candidate against toxoplasmosis.

    Science.gov (United States)

    Cuppari, Anahi Fernandez; Sanchez, Vanesa; Ledesma, Bibiana; Frank, Fernanda M; Goldman, Alejandra; Angel, Sergio O; Martin, Valentina

    2008-09-15

    The Toxoplasma gondii serin protease inhibitor-1 (TgPI-1) is a dense granule antigen that showed to specifically inhibit trypsin, chymotrypsin and neutrophil elastase, suggesting a possible modulatory role during the parasite invasion process and on the development of the innate immune response. To study the immune-protective value of TgPI-1, C3H/HeN mice were immunized with a recombinant form of the antigen rTgPI-1 combined with alum. All immunized mice produced specific anti-rTgPI-1 immunoglobulins, with high IgG antibody titers and a mixed IgG(1)/IgG(2a) response, with predominance of IgG(1) production. The cellular immune response was associated with the production of IFN-gamma and IL-10 cytokines. Vaccinated mice displayed significant protection against an oral challenge either after a lethal infection with Me49 cysts (90% survival vs. 50%) and also after a non-lethal infection (58% reduction in brain parasite load) compared to the non-vaccinated control group. In conclusion, rTgPI-1 elicits a strong specific immune response providing partial protection against both T. gondii acute and chronic infection, so it would be a good candidate in a vaccine against toxoplasmosis, which could be combined with other relevant parasite antigens.

  14. Bax inhibitor 1, a modulator of calcium homeostasis, confers affective resilience.

    Science.gov (United States)

    Hunsberger, Joshua G; Machado-Vieira, Rodrigo; Austin, Daniel R; Zarate, Carlos; Chuang, De-Maw; Chen, Guang; Reed, John C; Manji, Husseini K

    2011-07-27

    The endoplasmic reticulum (ER) is a critical site for intracellular calcium storage as well as protein synthesis, folding, and trafficking. Disruption of these processes is gaining support for contributing to heritable vulnerability of certain diseases. Here, we investigated Bax inhibitor 1 (BI-1), an anti-apoptotic protein that primarily resides in the ER and associates with B-cell lymphoma 2 (Bcl-2) and Bcl-XL, as an affective resiliency factor through its modulation of calcium homeostasis. We found that transgenic (TG) mice with BI-1 reinforced expression, via the neuronal specific enolase promoter, showed protection against the learned helplessness (LH) paradigm, an animal model to test stress coping. TG mice were also protected against anhedonia following both serotonin and catecholamine depletion as measured in two different models, the female urine sniffing test and the saccharine preference test. In addition, we used primary mouse cortical cultures to explore the ability of BI-1 to influence calcium homeostasis under basal conditions and also following challenge with thapsigargin (THPS), an inhibitor of sarco/endoplasmic reticulum Ca(2+) ATPase (SERCA) that disrupts calcium homeostasis. TG neurons showed decreased basal cytosolic calcium levels and decreased Ca(2+) cytosolic accumulation following challenge with THPS as compared to WT neuronal cultures. Together, these data suggest that BI-1, through its actions on calcium homeostasis, may confer affective resiliency in multiple animal models of depression and anhedonia. Published by Elsevier B.V.

  15. Risk-Taking Behavior in a Computerized Driving Task: Brain Activation Correlates of Decision-Making, Outcome, and Peer Influence in Male Adolescents.

    Directory of Open Access Journals (Sweden)

    Victor Vorobyev

    Full Text Available Increased propensity for risky behavior in adolescents, particularly in peer groups, is thought to reflect maturational imbalance between reward processing and cognitive control systems that affect decision-making. We used functional magnetic resonance imaging (fMRI to investigate brain functional correlates of risk-taking behavior and effects of peer influence in 18-19-year-old male adolescents. The subjects were divided into low and high risk-taking groups using either personality tests or risk-taking rates in a simulated driving task. The fMRI data were analyzed for decision-making (whether to take a risk at intersections and outcome (pass or crash phases, and for the influence of peer competition. Personality test-based groups showed no difference in the amount of risk-taking (similarly increased during peer competition and brain activation. When groups were defined by actual task performance, risk-taking activated two areas in the left medial prefrontal cortex (PFC significantly more in low than in high risk-takers. In the entire sample, risky decision-specific activation was found in the anterior and dorsal cingulate, superior parietal cortex, basal ganglia (including the nucleus accumbens, midbrain, thalamus, and hypothalamus. Peer competition increased outcome-related activation in the right caudate head and cerebellar vermis in the entire sample. Our results suggest that the activation of the medial (rather than lateral PFC and striatum is most specific to risk-taking behavior of male adolescents in a simulated driving situation, and reflect a stronger conflict and thus increased cognitive effort to take risks in low risk-takers, and reward anticipation for risky decisions, respectively. The activation of the caudate nucleus, particularly for the positive outcome (pass during peer competition, further suggests enhanced reward processing of risk-taking under peer influence.

  16. Multiple Conformations of Gal3 Protein Drive the Galactose-Induced Allosteric Activation of the GAL Genetic Switch of Saccharomyces cerevisiae.

    Science.gov (United States)

    Kar, Rajesh Kumar; Kharerin, Hungyo; Padinhateeri, Ranjith; Bhat, Paike Jayadeva

    2017-01-06

    Gal3p is an allosteric monomeric protein that activates the GAL genetic switch of Saccharomyces cerevisiae in response to galactose. Expression of constitutive mutant of Gal3p or overexpression of wild-type Gal3p activates the GAL switch in the absence of galactose. These data suggest that Gal3p exists as an ensemble of active and inactive conformations. Structural data have indicated that Gal3p exists in open (inactive) and closed (active) conformations. However, a mutant of Gal3p that predominantly exists in inactive conformation and is yet capable of responding to galactose has not been isolated. To understand the mechanism of allosteric transition, we have isolated a triple mutant of Gal3p with V273I, T404A, and N450D substitutions, which, upon overexpression, fails to activate the GAL switch on its own but activates the switch in response to galactose. Overexpression of Gal3p mutants with single or double mutations in any of the three combinations failed to exhibit the behavior of the triple mutant. Molecular dynamics analysis of the wild-type and the triple mutant along with two previously reported constitutive mutants suggests that the wild-type Gal3p may also exist in super-open conformation. Furthermore, our results suggest that the dynamics of residue F237 situated in the hydrophobic pocket located in the hinge region drives the transition between different conformations. Based on this study, we suggest that conformational selection mechanism is the driving force in the allosteric transition of Gal3p, which may have implications in other signaling pathways involving monomeric proteins. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. Risk-Taking Behavior in a Computerized Driving Task: Brain Activation Correlates of Decision-Making, Outcome, and Peer Influence in Male Adolescents.

    Science.gov (United States)

    Vorobyev, Victor; Kwon, Myoung Soo; Moe, Dagfinn; Parkkola, Riitta; Hämäläinen, Heikki

    2015-01-01

    Increased propensity for risky behavior in adolescents, particularly in peer groups, is thought to reflect maturational imbalance between reward processing and cognitive control systems that affect decision-making. We used functional magnetic resonance imaging (fMRI) to investigate brain functional correlates of risk-taking behavior and effects of peer influence in 18-19-year-old male adolescents. The subjects were divided into low and high risk-taking groups using either personality tests or risk-taking rates in a simulated driving task. The fMRI data were analyzed for decision-making (whether to take a risk at intersections) and outcome (pass or crash) phases, and for the influence of peer competition. Personality test-based groups showed no difference in the amount of risk-taking (similarly increased during peer competition) and brain activation. When groups were defined by actual task performance, risk-taking activated two areas in the left medial prefrontal cortex (PFC) significantly more in low than in high risk-takers. In the entire sample, risky decision-specific activation was found in the anterior and dorsal cingulate, superior parietal cortex, basal ganglia (including the nucleus accumbens), midbrain, thalamus, and hypothalamus. Peer competition increased outcome-related activation in the right caudate head and cerebellar vermis in the entire sample. Our results suggest that the activation of the medial (rather than lateral) PFC and striatum is most specific to risk-taking behavior of male adolescents in a simulated driving situation, and reflect a stronger conflict and thus increased cognitive effort to take risks in low risk-takers, and reward anticipation for risky decisions, respectively. The activation of the caudate nucleus, particularly for the positive outcome (pass) during peer competition, further suggests enhanced reward processing of risk-taking under peer influence.

  18. Smartphone Based Approach For Monitoring Inefficient And Unsafe Driving Behavior And Recognizing Drink And Drive Conditions.

    Directory of Open Access Journals (Sweden)

    G. V. Mane

    2015-08-01

    Full Text Available Many automobile drivers having knowledge of the driving behaviours and habits that can lead to inefficient and unsafe driving. However it is often the case that these same drivers unknowingly manifest these inefficient and unsafe driving behaviours in their everyday driving activity. The proposed system proposes a practical and economical way to capture measure and alert drives of inefficient and unsafe driving as well as highly efficient system aimed at early detection and alert of dangerous vehicle maneuvers typically related to drunk driving. The upcoming solution consists of a mobile application running on a modern smartphone device paired with a compatible OBDII On-board diagnostics II reader.

  19. Protein Phosphatase Inhibitor-1 Gene Therapy in a Swine Model of Nonischemic Heart Failure.

    Science.gov (United States)

    Watanabe, Shin; Ishikawa, Kiyotake; Fish, Kenneth; Oh, Jae Gyun; Motloch, Lukas J; Kohlbrenner, Erik; Lee, Philyoung; Xie, Chaoqin; Lee, Ahyoung; Liang, Lifan; Kho, Changwon; Leonardson, Lauren; McIntyre, Maritza; Wilson, Scott; Samulski, R Jude; Kranias, Evangelia G; Weber, Thomas; Akar, Fadi G; Hajjar, Roger J

    2017-10-03

    Increased protein phosphatase-1 in heart failure (HF) induces molecular changes deleterious to the cardiac cell. Inhibiting protein phosphatase-1 through the overexpression of a constitutively active inhibitor-1 (I-1c) has been shown to reverse cardiac dysfunction in a model of ischemic HF. This study sought to determine the therapeutic efficacy of a re-engineered adenoassociated viral vector carrying I-1c (BNP116.I-1c) in a preclinical model of nonischemic HF, and to assess thoroughly the safety of BNP116.I-1c gene therapy. Volume-overload HF was created in Yorkshire swine by inducing severe mitral regurgitation. One month after mitral regurgitation induction, pigs were randomized to intracoronary delivery of either BNP116.I-1c (n = 6) or saline (n = 7). Therapeutic efficacy and safety were evaluated 2 months after gene delivery. Additionally, 24 naive pigs received different doses of BNP116.I-1c for safety evaluation. At 1 month after mitral regurgitation induction, pigs developed HF as evidenced by increased left ventricular end-diastolic pressure and left ventricular volume indexes. Treatment with BNP116.I-1c resulted in improved left ventricular ejection fraction (-5.9 ± 4.2% vs. 5.5 ± 4.0%; p pigs also exhibited a significant increase in left atrial ejection fraction at 2 months after gene delivery (-4.3 ± 3.1% vs. 7.5 ± 3.1%; p = 0.02). In vitro I-1c gene transfer in isolated left atrial myocytes from both pigs and rats increased calcium transient amplitude, consistent with its positive impact on left atrial contraction. We found no evidence of adverse electrical remodeling, arrhythmogenicity, activation of a cellular immune response, or off-target organ damage by BNP116.I-1c gene therapy in pigs. Intracoronary delivery of BNP116.I-1c was safe and improved contractility of the left ventricle and atrium in a large animal model of nonischemic HF. Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights

  20. Comparison of activities of daily living (ADLs) in two different one arm drive wheelchairs: a study of individuals/participants with hemiplegia.

    Science.gov (United States)

    Mandy, Anne; Walton, Claire; Michaelis, Jon

    2015-03-01

    This pilot study measured activities of daily living performance in individuals/participants with hemiplegia propelling both a standard dual handrim Action 3 wheelchair and a standard Action 3 wheelchair with a Neater Uni-Wheelchair kit attachment. The kit consists of a steerable front. Does the use of the NUW affect the performance quality of activities of daily living in individuals/participants with hemiplegia. Is there a difference in the motor and process skills during activities of daily living performance, and in the time taken to complete the activities. Four individuals/participants with hemiplegia were used in a cross over, repeated measures trial. Assessment of Motor and Process Skills of users undertaking making a bed and laying a table "Swedish style", tasks were measured and time taken to complete each task were recorded. Bed making completion time was quicker in the Neater Uni-wheelchair (p < 0.03). Motor skills were significantly higher than the process ability skills (p < 0.05). Activities of daily living tasks in the Neater Uni-wheelchair were completed more efficiently with no loss in quality of motor and process skills performance. This suggests that the Neater Uni-wheelchair is a viable alternative to current one arm drive provision. Implications for Rehabilitation Inappropriate wheelchair provision can result in capacity limitation and poorer quality of ADL motor skill as well-lowered process performance skill. AMPS can help to explain motor and process skill differences in complex activities.

  1. Proactive vs. reactive car driving: EEG evidence for different driving strategies of older drivers.

    Science.gov (United States)

    Karthaus, Melanie; Wascher, Edmund; Getzmann, Stephan

    2018-01-01

    Aging is associated with a large heterogeneity in the extent of age-related changes in sensory, motor, and cognitive functions. All these functions can influence the performance in complex tasks like car driving. The present study aims to identify potential differences in underlying cognitive processes that may explain inter-individual variability in driving performance. Younger and older participants performed a one-hour monotonous driving task in a driving simulator under varying crosswind conditions, while behavioral and electrophysiological data were recorded. Overall, younger and older drivers showed comparable driving performance (lane keeping). However, there was a large difference in driving lane variability within the older group. Dividing the older group in two subgroups with low vs. high driving lane variability revealed differences between the two groups in electrophysiological correlates of mental workload, consumption of mental resources, and activation and sustaining of attention: Older drivers with high driving lane variability showed higher frontal Alpha and Theta activity than older drivers with low driving lane variability and-with increasing crosswind-a more pronounced decrease in Beta activity. These results suggest differences in driving strategies of older and younger drivers, with the older drivers using either a rather proactive and alert driving strategy (indicated by low driving lane variability and lower Alpha and Beta activity), or a rather reactive strategy (indicated by high driving lane variability and higher Alpha activity).

  2. Human U6 promoter drives stronger shRNA activity than its schistosome orthologue in Schistosoma mansoni and human fibrosarcoma cells

    Science.gov (United States)

    Duvoisin, Raphaël; Ayuk, Mary A.; Rinaldi, Gabriel; Suttiprapa, Sutas; Mann, Victoria H.; Lee, Clarence M.; Harris, Nicola; Brindley, Paul J.

    2011-01-01

    Blood flukes or schistosomes are the causative agents of human schistosomiasis, one of the major neglected tropical diseases. Draft genome sequences have been reported for schistosomes, but functional genomics tools are needed to investigate the role and essentiality of the newly reported genes. Vector based RNA interference can contribute to functional genomics analysis for schistosomes. Using mRNA encoding reporter firefly luciferase as a model target, we compared the performance of a schistosome and a human promoter from the U6 gene in driving shRNA in human fibrosarcoma cells and in cultured schistosomes. Further, both a retroviral (Murine leukemia virus [MLV]) and plasmid (piggyBac, pXL-Bac II) vector were utilized. The schistosome U6 gene promoter was 270 bp in length, the human U6 gene promoter was 264 bp; they shared 41% identity. Following transduction of both HT1080 fibrosarcoma cells and schistosomules of Schistosoma mansoni with pseudotyped MLV virions, stronger knockdown of luciferase activity was seen with the virions encoding the human U6 promoter driven shRNA than the schistosome U6 promoter. A similar trend was seen after transfection of HT1080 cells and schistosomules with the pXL-Bac-II constructs – stronger knockdown of luciferase activity was seen with constructs encoding the human compared to schistosome U6 promoter. The findings indicate that a human U6 gene promoter drives stronger shRNA activity than its schistosome orthologue, not only in a human cancer cell line but also in larval schistosomes. This RNA polymerase III promoter represents a potentially valuable component for vector based RNA interference studies in schistosomes and related platyhelminth parasites. PMID:21953124

  3. Inactivity-induced respiratory plasticity: protecting the drive to breathe in disorders that reduce respiratory neural activity.

    Science.gov (United States)

    Strey, K A; Baertsch, N A; Baker-Herman, T L

    2013-11-01

    Multiple forms of plasticity are activated following reduced respiratory neural activity. For example, in ventilated rats, a central neural apnea elicits a rebound increase in phrenic and hypoglossal burst amplitude upon resumption of respiratory neural activity, forms of plasticity called inactivity-induced phrenic and hypoglossal motor facilitation (iPMF and iHMF), respectively. Here, we provide a conceptual framework for plasticity following reduced respiratory neural activity to guide future investigations. We review mechanisms giving rise to iPMF and iHMF, present new data suggesting that inactivity-induced plasticity is observed in inspiratory intercostals (iIMF) and point out gaps in our knowledge. We then survey conditions relevant to human health characterized by reduced respiratory neural activity and discuss evidence that inactivity-induced plasticity is elicited during these conditions. Understanding the physiological impact and circumstances in which inactivity-induced respiratory plasticity is elicited may yield novel insights into the treatment of disorders characterized by reductions in respiratory neural activity. Copyright © 2013 Elsevier B.V. All rights reserved.

  4. The active microbial diversity drives ecosystem multifunctionality and is physiologically related to carbon availability in Mediterranean semi-arid soils.

    Science.gov (United States)

    Bastida, Felipe; Torres, Irene F; Moreno, José L; Baldrian, Petr; Ondoño, Sara; Ruiz-Navarro, Antonio; Hernández, Teresa; Richnow, Hans H; Starke, Robert; García, Carlos; Jehmlich, Nico

    2016-09-01

    Biogeochemical processes and ecosystemic functions are mostly driven by soil microbial communities. However, most methods focus on evaluating the total microbial community and fail to discriminate its active fraction which is linked to soil functionality. Precisely, the activity of the microbial community is strongly limited by the availability of organic carbon (C) in soils under arid and semi-arid climate. Here, we provide a complementary genomic and metaproteomic approach to investigate the relationships between the diversity of the total community, the active diversity and ecosystem functionality across a dissolved organic carbon (DOC) gradient in southeast Spain. DOC correlated with the ecosystem multifunctionality index composed by soil respiration, enzyme activities (urease, alkaline phosphatase and β-glucosidase) and microbial biomass (phospholipid fatty acids, PLFA). This study highlights that the active diversity (determined by metaprotoemics) but not the diversity of the whole microbial community (evaluated by amplicon gene sequencing) is related to the availability of organic C and it is also connected to the ecosystem multifunctionality index. We reveal that DOC shapes the activities of bacterial and fungal populations in Mediterranean semi-arid soils and determines the compartmentalization of functional niches. For instance, Rhizobales thrived at high-DOC sites probably fuelled by metabolism of one-C compounds. Moreover, the analysis of proteins involved in the transport and metabolism of carbohydrates revealed that Ascomycota and Basidiomycota occupied different nutritional niches. The functional mechanisms for niche specialization were not constant across the DOC gradient. © 2016 John Wiley & Sons Ltd.

  5. PARP1 expression drives the synergistic antitumor activity of trabectedin and PARP1 inhibitors in sarcoma preclinical models.

    Science.gov (United States)

    Pignochino, Ymera; Capozzi, Federica; D'Ambrosio, Lorenzo; Dell'Aglio, Carmine; Basiricò, Marco; Canta, Marta; Lorenzato, Annalisa; Vignolo Lutati, Francesca; Aliberti, Sandra; Palesandro, Erica; Boccone, Paola; Galizia, Danilo; Miano, Sara; Chiabotto, Giulia; Napione, Lucia; Gammaitoni, Loretta; Sangiolo, Dario; Benassi, Maria Serena; Pasini, Barbara; Chiorino, Giovanna; Aglietta, Massimo; Grignani, Giovanni

    2017-04-28

    Enhancing the antitumor activity of the DNA-damaging drugs is an attractive strategy to improve current treatment options. Trabectedin is an isoquinoline alkylating agent with a peculiar mechanism of action. It binds to minor groove of DNA inducing single- and double-strand-breaks. These kinds of damage lead to the activation of PARP1, a first-line enzyme in DNA-damage response pathways. We hypothesized that PARP1 targeting could perpetuate trabectedin-induced DNA damage in tumor cells leading finally to cell death. We investigated trabectedin and PARP1 inhibitor synergism in several tumor histotypes both in vitro and in vivo (subcutaneous and orthotopic tumor xenografts in mice). We searched for key determinants of drug synergism by comparative genomic hybridization (aCGH) and gene expression profiling (GEP) and validated their functional role. Trabectedin activated PARP1 enzyme and the combination with PARP1 inhibitors potentiated DNA damage, cell cycle arrest at G2/M checkpoint and apoptosis, if compared to single agents. Olaparib was the most active PARP1 inhibitor to combine with trabectedin and we confirmed the antitumor and antimetastatic activity of trabectedin/olaparib combination in mice models. However, we observed different degree of trabectedin/olaparib synergism among different cell lines. Namely, in DMR leiomyosarcoma models the combination was significantly more active than single agents, while in SJSA-1 osteosarcoma models no further advantage was obtained if compared to trabectedin alone. aCGH and GEP revealed that key components of DNA-repair pathways were involved in trabectedin/olaparib synergism. In particular, PARP1 expression dictated the degree of the synergism. Indeed, trabectedin/olaparib synergism was increased after PARP1 overexpression and reduced after PARP1 silencing. PARP1 inhibition potentiated trabectedin activity in a PARP1-dependent manner and PARP1 expression in tumor cells might be a useful predictive biomarker that deserves

  6. DMXL2 drives epithelial to mesenchymal transition in hormonal therapy resistant breast cancer through Notch hyper-activation.

    Science.gov (United States)

    Faronato, Monica; Nguyen, Van T M; Patten, Darren K; Lombardo, Ylenia; Steel, Jennifer H; Patel, Naina; Woodley, Laura; Shousha, Sami; Pruneri, Giancarlo; Coombes, R Charles; Magnani, Luca

    2015-09-08

    The acquisition of endocrine therapy resistance in estrogen receptor α (ERα) breast cancer patients represents a major clinical problem. Notch signalling has been extensively linked to breast cancer especially in patients who fail to respond to endocrine therapy. Following activation, Notch intracellular domain is released and enters the nucleus where activates transcription of target genes. The numerous steps that cascade after activation of the receptor complicate using Notch as biomarker. Hence, this warrants the development of reliable indicators of Notch activity. DMXL2 is a novel regulator of Notch signalling not yet investigated in breast cancer. Here, we demonstrate that DMXL2 is overexpressed in a subset of endocrine therapy resistant breast cancer cell lines where it promotes epithelial to mesenchymal transition through hyper-activation of Notch signalling via V-ATPase dependent acidification. Following DMXL2 depletion or treatment with Bafilomycin A1, both EMT targets and Notch signalling pathway significantly decrease. We show for the first time that DMXL2 protein levels are significantly increased in ERα positive breast cancer patients that progress after endocrine therapy. Finally, we demonstrate that DMXL2 is a transmembrane protein with a potential extra-cellular domain. These findings identify DMXL2 as a novel, functional biomarker for ERα positive breast cancer.

  7. Constitutive Activity of the Arabidopsis MAP Kinase 3 Confers Resistance to Pseudomonas syringae and Drives Robust Immune Responses

    KAUST Repository

    Lang, Julien

    2017-08-02

    Mitogen Activated Protein Kinases (MAPKs) are known to be important mediators of plant responses to biotic and abiotic stresses. In a recent report, we enlarged the understanding of the Arabidopsis thaliana MPK3 functions showing that the expression of a constitutively active (CA) form of the protein led to auto-immune phenotypes. CA-MPK3 plants are dwarf and display defense responses that are characterized by the accumulation of salicylic acid and phytoalexins as well as by the upregulation of several defense genes. Consistently with these data, we present here results demonstrating that, compared to wild type controls, CA-MPK3 plants are more resistant to the hemibiotrophic pathogen Pseudomonas syringae DC3000. Based on our previous work, we also discuss the mechanisms of robust plant immunity controlled by sustained MPK3 activity, focusing especially on the roles of disease resistance proteins.

  8. Improved Control of an Active-Front-End Adjustable Speed Drive with a Small dc-link Capacitor under Real Grid Conditions

    DEFF Research Database (Denmark)

    Klumpner, Christian; Liserre, Marco; Blaabjerg, Frede

    2004-01-01

    Active front-end topologies will be widely used in the future and among them especially the two-level PWM rectifier, due to the need to improve the quality of the input currents and the robustness against grid disturbances of Adjustable Speed Drives (ASDs). Another expectation is that electrolytic...... capacitors will be replaced by film capacitors in order to increase the ASD lifetime, but as this has lower energy density, the dc-link capacitance is expected to decrease. In these circumstances, operation under unbalanced and distorted supply voltage as well as high dynamic operation of the ASD makes...... the control task more challenging. This paper discusses problems related to the ASD dc-link both in respect to its stability (under regeneration as well as in the case of constant power absorbed by the inverter stage) both also in respect to the dc voltage ripple generated by the grid unbalance and made more...

  9. Extended driving impairs nocturnal driving performances.

    Science.gov (United States)

    Sagaspe, Patricia; Taillard, Jacques; Akerstedt, Torbjorn; Bayon, Virginie; Espié, Stéphane; Chaumet, Guillaume; Bioulac, Bernard; Philip, Pierre

    2008-01-01

    Though fatigue and sleepiness at the wheel are well-known risk factors for traffic accidents, many drivers combine extended driving and sleep deprivation. Fatigue-related accidents occur mainly at night but there is no experimental data available to determine if the duration of prior driving affects driving performance at night. Participants drove in 3 nocturnal driving sessions (3-5 am, 1-5 am and 9 pm-5 am) on open highway. Fourteen young healthy men (mean age [+/-SD] = 23.4 [+/-1.7] years) participated Inappropriate line crossings (ILC) in the last hour of driving of each session, sleep variables, self-perceived fatigue and sleepiness were measured. Compared to the short (3-5 am) driving session, the incidence rate ratio of inappropriate line crossings increased by 2.6 (95% CI, 1.1 to 6.0; P<.05) for the intermediate (1-5 am) driving session and by 4.0 (CI, 1.7 to 9.4; P<.001) for the long (9 pm-5 am) driving session. Compared to the reference session (9-10 pm), the incidence rate ratio of inappropriate line crossings were 6.0 (95% CI, 2.3 to 15.5; P<.001), 15.4 (CI, 4.6 to 51.5; P<.001) and 24.3 (CI, 7.4 to 79.5; P<.001), respectively, for the three different durations of driving. Self-rated fatigue and sleepiness scores were both positively correlated to driving impairment in the intermediate and long duration sessions (P<.05) and increased significantly during the nocturnal driving sessions compared to the reference session (P<.01). At night, extended driving impairs driving performances and therefore should be limited.

  10. Extended driving impairs nocturnal driving performances.

    Directory of Open Access Journals (Sweden)

    Patricia Sagaspe

    Full Text Available Though fatigue and sleepiness at the wheel are well-known risk factors for traffic accidents, many drivers combine extended driving and sleep deprivation. Fatigue-related accidents occur mainly at night but there is no experimental data available to determine if the duration of prior driving affects driving performance at night. Participants drove in 3 nocturnal driving sessions (3-5 am, 1-5 am and 9 pm-5 am on open highway. Fourteen young healthy men (mean age [+/-SD] = 23.4 [+/-1.7] years participated Inappropriate line crossings (ILC in the last hour of driving of each session, sleep variables, self-perceived fatigue and sleepiness were measured. Compared to the short (3-5 am driving session, the incidence rate ratio of inappropriate line crossings increased by 2.6 (95% CI, 1.1 to 6.0; P<.05 for the intermediate (1-5 am driving session and by 4.0 (CI, 1.7 to 9.4; P<.001 for the long (9 pm-5 am driving session. Compared to the reference session (9-10 pm, the incidence rate ratio of inappropriate line crossings were 6.0 (95% CI, 2.3 to 15.5; P<.001, 15.4 (CI, 4.6 to 51.5; P<.001 and 24.3 (CI, 7.4 to 79.5; P<.001, respectively, for the three different durations of driving. Self-rated fatigue and sleepiness scores were both positively correlated to driving impairment in the intermediate and long duration sessions (P<.05 and increased significantly during the nocturnal driving sessions compared to the reference session (P<.01. At night, extended driving impairs driving performances and therefore should be limited.

  11. A high voltage DC-DC converter driving a Dielectric Electro Active Polymer actuator for wind turbine flaps

    DEFF Research Database (Denmark)

    Thummala, Prasanth; Zhang, Zhe; Andersen, Michael A. E.

    2012-01-01

    The Dielectric Electro Active Polymer (DEAP) material is a very thin (~80 μm) silicone elastomer film with a compliant metallic electrode layer on both sides. The DEAP is fundamentally a capacitor that is capable of very high strain. The property that the polymer changes its shape, as a result...

  12. Differential pathway coupling efficiency of the activated insulin receptor drives signaling selectivity by xmeta, an allosteric partial agonist antibody

    Science.gov (United States)

    XMetA, an anti-insulin receptor (IR) monoclonal antibody, is an allosteric partial agonist of the IR. We have previously reported that XMetA activates the “metabolic-biased” Akt kinase signaling pathway while having little or no effect on the “mitogenic” MAPK signaling pathwayof ERK 1/2. To inves...

  13. Complexity of the Microglial Activation Pathways that Drive Innate Host Responses During Lethal Alphavirus Encephalitis in Mice

    Directory of Open Access Journals (Sweden)

    Nilufer Esen

    2012-04-01

    Full Text Available Microglia express multiple TLRs (Toll-like receptors and provide important host defence against viruses that invade the CNS (central nervous system. Although prior studies show these cells become activated during experimental alphavirus encephalitis in mice to generate cytokines and chemokines that influence virus replication, tissue inflammation and neuronal survival, the specific PRRs (pattern recognition receptors and signalling intermediates controlling microglial activation in this setting remain unknown. To investigate these questions directly in vivo, mice ablated of specific TLR signalling molecules were challenged with NSV (neuroadapted Sindbis virus and CNS viral titres, inflammatory responses and clinical outcomes followed over time. To approach this problem specifically in microglia, the effects of NSV on primary cells derived from the brains of wild-type and mutant animals were characterized in vitro. From the standpoint of the virus, microglial activation required viral uncoating and an intact viral genome; inactivated virus particles did not elicit measurable microglial responses. At the level of the target cell, NSV triggered multiple PRRs in microglia to produce a broad range of inflammatory mediators via non-overlapping signalling pathways. In vivo, disease survival was surprisingly independent of TLR-driven responses, but still required production of type-I IFN (interferon to control CNS virus replication. Interestingly, the ER (endoplasmic reticulum protein UNC93b1 facilitated host survival independent of its known effects on endosomal TLR signalling. Taken together, these data show that alphaviruses activate microglia via multiple PRRs, highlighting the complexity of the signalling networks by which CNS host responses are elicited by these infections.

  14. HARMONIC DRIVE SELECTION

    Directory of Open Access Journals (Sweden)

    Piotr FOLĘGA

    2014-03-01

    Full Text Available The variety of types and sizes currently in production harmonic drive is a problem in their rational choice. Properly selected harmonic drive must meet certain requirements during operation, and achieve the anticipated service life. The paper discusses the problems associated with the selection of the harmonic drive. It also presents the algorithm correct choice of harmonic drive. The main objective of this study was to develop a computer program that allows the correct choice of harmonic drive by developed algorithm.

  15. The Pelargonium sidoides Extract EPs 7630 Drives the Innate Immune Defense by Activating Selected MAP Kinase Pathways in Human Monocytes.

    Science.gov (United States)

    Witte, Katrin; Koch, Egon; Volk, Hans-Dieter; Wolk, Kerstin; Sabat, Robert

    2015-01-01

    Pelargonium sidoides is a medical herb and respective extracts are used very frequently for the treatment of respiratory tract infections. However, the effects of Pelargonium sidoides and a special extract prepared from its roots (EPs 7630) on human immune cells are not fully understood. Here we demonstrate that EPs 7630 induced a rapid and dose-dependent production of TNF-α, IL-6, and IL-10 by human blood immune cells. This EPs 7630-induced cytokine profile was more pro-inflammatory in comparison with the profile induced by viral or bacterial infection-mimicking agents. The search for EPs 7630 target cells revealed that T-cells did not respond to EPs 7630 stimulation by production of TNF-α, IL-6, or IL-10. Furthermore, pretreatment of T-cells with EPs 7630 did not modulate their TNF-α, IL-6, and IL-10 secretion during subsequent activation. In contrast to lymphocytes, monocytes showed clear intracellular TNF-α staining after EPs 7630 treatment. Accordingly, EPs 7630 predominantly provoked activation of MAP kinases and inhibition of p38 strongly reduced the monocyte TNF-α production. The pretreatment of blood immune cells with EPs 7630 lowered their secretion of TNF-α and IL-10 and caused an IL-6 dominant response during second stimulation with viral or bacterial infection-mimicking agents. In summary, we demonstrate that EPs 7630 activates human monocytes, induces MAP kinase-dependent pro-inflammatory cytokines in these cells, and specifically modulates their production capacity of mediators known to lead to an increase of acute phase protein production in the liver, neutrophil generation in the bone marrow, and the generation of adaptive Th17 and Th22 cells.

  16. Activation of NF-κB drives the enhanced survival of adipose tissue macrophages in an obesogenic environment.

    Science.gov (United States)

    Hill, Andrea A; Anderson-Baucum, Emily K; Kennedy, Arion J; Webb, Corey D; Yull, Fiona E; Hasty, Alyssa H

    2015-10-01

    Macrophage accumulation in adipose tissue (AT) during obesity contributes to inflammation and insulin resistance. Recruitment of monocytes to obese AT has been the most studied mechanism explaining this accumulation. However, recent evidence suggests that recruitment-independent mechanisms may also regulate pro-inflammatory AT macrophage (ATM) numbers. The role of increased ATM survival during obesity has yet to be explored. We demonstrate that activation of apoptotic pathways is significantly reduced in ATMs from diet-induced and genetically obese mice. Concurrently, pro-survival Bcl-2 family member protein levels and localization to the mitochondria is elevated in ATMs from obese mice. This increased pro-survival signaling was associated with elevated activation of the transcription factor, NF-κB, and increased expression of its pro-survival target genes. Finally, an obesogenic milieu increased ATM viability only when NF-κB signaling pathways were functional. Our data demonstrate that obesity promotes survival of inflammatory ATMs, possibly through an NF-κB-regulated mechanism.

  17. Driving Care Quality: Aligning Trainee Assessment and Supervision Through Practical Application of Entrustable Professional Activities, Competencies, and Milestones.

    Science.gov (United States)

    Carraccio, Carol; Englander, Robert; Holmboe, Eric S; Kogan, Jennifer R

    2016-02-01

    To address the long-standing challenge of meaningful trainee assessment, the authors reviewed and expanded on the Accountable Assessment for Quality Care and Supervision (AAQCS) equation. The equation proposes that care quality is the product of the interaction between trainee performance (measured by workplace assessment) and supervision (required level of intervention to ensure care quality) in the context of the environment where the care occurs: Trainee performance × Appropriate supervision = Safe, effective patient-centered care. Assessing trainee performance and matching that performance to "appropriate" supervision, however, is fraught with challenges. The authors suggest a unifying framework that integrates entrustable professional activities (EPAs), competencies, and milestones to inform trainee assessment and supervision, thereby enabling the practical application of the AAQCS equation in the workplace. Because the unit of measure for an EPA is the outcome of whether the trainee can safely and effectively perform the professional activity without supervision, the proposed unifying framework directly aligns with the dependent variable in the AAQCS equation: care quality.The value of applying a unifying framework that integrates EPAs, competencies, and milestones to the AAQCS equation in the clinical learning environment lies in its ability to provide supervisors with a shared mental model of performance expectations for trainees, reducing unwanted variability and improving assessment accuracy; guidance for aligning performance milestones of trainees with the needed level of supervisor intervention to ensure care quality; and substrate for specific feedback to improve the trainee's professional development as a way to ensure future care quality.

  18. Perturbation of ribosome biogenesis drives cells into senescence through 5S RNP-mediated p53 activation.

    Science.gov (United States)

    Nishimura, Kazuho; Kumazawa, Takuya; Kuroda, Takao; Katagiri, Naohiro; Tsuchiya, Mai; Goto, Natsuka; Furumai, Ryohei; Murayama, Akiko; Yanagisawa, Junn; Kimura, Keiji

    2015-03-03

    The 5S ribonucleoprotein particle (RNP) complex, consisting of RPL11, RPL5, and 5S rRNA, is implicated in p53 regulation under ribotoxic stress. Here, we show that the 5S RNP contributes to p53 activation and promotes cellular senescence in response to oncogenic or replicative stress. Oncogenic stress accelerates rRNA transcription and replicative stress delays rRNA processing, resulting in RPL11 and RPL5 accumulation in the ribosome-free fraction, where they bind MDM2. Experimental upregulation of rRNA transcription or downregulation of rRNA processing, mimicking the nucleolus under oncogenic or replicative stress, respectively, also induces RPL11-mediated p53 activation and cellular senescence. We demonstrate that exogenous expression of certain rRNA-processing factors rescues the processing defect, attenuates p53 accumulation, and increases replicative lifespan. To summarize, the nucleolar-5S RNP-p53 pathway functions as a senescence inducer in response to oncogenic and replicative stresses. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  19. Perturbation of Ribosome Biogenesis Drives Cells into Senescence through 5S RNP-Mediated p53 Activation

    Directory of Open Access Journals (Sweden)

    Kazuho Nishimura

    2015-03-01

    Full Text Available The 5S ribonucleoprotein particle (RNP complex, consisting of RPL11, RPL5, and 5S rRNA, is implicated in p53 regulation under ribotoxic stress. Here, we show that the 5S RNP contributes to p53 activation and promotes cellular senescence in response to oncogenic or replicative stress. Oncogenic stress accelerates rRNA transcription and replicative stress delays rRNA processing, resulting in RPL11 and RPL5 accumulation in the ribosome-free fraction, where they bind MDM2. Experimental upregulation of rRNA transcription or downregulation of rRNA processing, mimicking the nucleolus under oncogenic or replicative stress, respectively, also induces RPL11-mediated p53 activation and cellular senescence. We demonstrate that exogenous expression of certain rRNA-processing factors rescues the processing defect, attenuates p53 accumulation, and increases replicative lifespan. To summarize, the nucleolar-5S RNP-p53 pathway functions as a senescence inducer in response to oncogenic and replicative stresses.

  20. Fear of feces? Trade-offs between disease risk and foraging drive animal activity around raccoon latrines

    Science.gov (United States)

    Weinstein, Sara B.; Moura, Chad W.; Mendez, Jon Francis; Lafferty, Kevin D.

    2017-01-01

    Fear of predation alters prey behavior, which can indirectly alter entire landscapes. A parasite-induced ecology of fear might also exist if animals avoid parasite-contaminated resources when infection costs outweigh foraging benefits. To investigate whether animals avoid parasite contaminated sites, and if such avoidance balances disease costs and foraging gains, we monitored animal behavior at raccoon latrines – sites that concentrate both seeds and pathogenic parasite eggs. Using wildlife cameras, we documented over 40 potentially susceptible vertebrate species in latrines and adjacent habitat. Latrine contact rates reflected background activity, diet preferences and disease risk. Disease-tolerant raccoons and rats displayed significant site attraction, while susceptible birds and small mammals avoided these high-risk sites. This suggests that parasites, like predators, might create a landscape of fear for vulnerable hosts. Such non-consumptive parasite effects could alter disease transmission, population dynamics, and even ecosystem structure.

  1. Monocyte activation drives preservation of membrane thiols by promoting release of oxidised membrane moieties via extracellular vesicles.

    Science.gov (United States)

    Szabó-Taylor, K É; Tóth, E Á; Balogh, A M; Sódar, B W; Kádár, L; Pálóczi, K; Fekete, N; Németh, A; Osteikoetxea, X; Vukman, K V; Holub, M; Pállinger, É; Nagy, Gy; Winyard, P G; Buzás, E I

    2017-07-01

    The redox state of cellular exofacial molecules is reflected by the amount of available thiols. Furthermore, surface thiols can be considered as indicators of immune cell activation. One group of thiol containing proteins, peroxiredoxins, in particular, have been associated with inflammation. In this study, we assessed surface thiols of the U937 and Thp1 monocyte cell lines and primary monocytes in vitro upon inflammatory stimulation by irreversibly labelling the cells with a fluorescent derivative of maleimide. We also investigated exofacial thiols on circulating blood mononuclear cells in patients with rheumatoid arthritis and healthy controls. When analysing extracellular vesicles, we combined thiol labelling with the use of antibodies to specific CD markers to exclude extracellular vesicle mimicking signals from thiol containing protein aggregates. Furthermore, differential detergent lysis was applied to confirm the vesicular nature of the detected extracellular events in blood plasma. We found an increase in exofacial thiols on monocytes upon in vitro stimulation by LPS or TNF, both in primary monocytes and monocytic cell lines (pextracellular vesicles showed a decrease in their exofacial thiols compared with those from unstimulated cells (pextracellular vesicles of isolated CD14 + cells from rheumatoid arthritis patients had decreased thiol levels compared with healthy subjects (pextracellular vesicles was increased in rheumatoid arthritis blood plasma (pextracellular vesicle-enriched preparations from blood plasma. Our data show that cell surface thiols play a protective role and reflect oxidative stress resistance state in activated immune cells. Furthermore, they support a role of extracellular vesicles in the redox regulation of human monocytes, possibly representing an antioxidant mechanism. Copyright © 2017. Published by Elsevier Inc.

  2. Bacterial community dynamics in full-scale activated sludge bioreactors: operational and ecological factors driving community assembly and performance.

    Science.gov (United States)

    Valentín-Vargas, Alexis; Toro-Labrador, Gladys; Massol-Deyá, Arturo A

    2012-01-01

    The assembling of bacterial communities in conventional activated sludge (CAS) bioreactors was thought, until recently, to be chaotic and mostly unpredictable. Studies done over the last decade have shown that specific, and often, predictable random and non-random factors could be responsible for that process. These studies have also motivated a "structure-function" paradigm that is yet to be resolved. Thus, elucidating the factors that affect community assembly in the bioreactors is necessary for predicting fluctuations in community structure and function. For this study activated sludge samples were collected during a one-year period from two geographically distant CAS bioreactors of different size. Combining community fingerprinting analysis and operational parameters data with a robust statistical analysis, we aimed to identify relevant links between system performance and bacterial community diversity and dynamics. In addition to revealing a significant β-diversity between the bioreactors' communities, results showed that the largest bioreactor had a less dynamic but more efficient and diverse bacterial community throughout the study. The statistical analysis also suggests that deterministic factors, as opposed to stochastic factors, may have a bigger impact on the community structure in the largest bioreactor. Furthermore, the community seems to rely mainly on mechanisms of resistance and functional redundancy to maintain functional stability. We suggest that the ecological theories behind the Island Biogeography model and the species-area relationship were appropriate to predict the assembly of bacterial communities in these CAS bioreactors. These results are of great importance for engineers and ecologists as they reveal critical aspects of CAS systems that could be applied towards improving bioreactor design and operation.

  3. Inducible nitric oxide synthase (iNOS) drives mTOR pathway activation and proliferation of human melanoma by reversible nitrosylation of TSC2

    Science.gov (United States)

    Lopez-Rivera, Esther; Jayaraman, Padmini; Parikh, Falguni; Davies, Michael A.; Ekmekcioglu, Suhendan; Izadmehr, Sudeh; Milton, Denái R.; Chipuk, Jerry E.; Grimm, Elizabeth A.; Estrada, Yeriel; Aguirre-Ghiso, Julio; Sikora, Andrew G.

    2014-01-01

    Melanoma is one of the cancers of fastest-rising incidence in the world. iNOS is overexpressed in melanoma and other cancers, and previous data suggest that iNOS and nitric oxide (NO) drive survival and proliferation of human melanoma cells. However, specific mechanisms through which this occurs are poorly defined. One candidate is the PI3K/AKT/mTOR pathway, which plays a major role in proliferation, angiogenesis, and metastasis of melanoma and other cancers. We used the chick embryo chorioallantoic membrane (CAM) assay to test the hypothesis that melanoma growth is regulated by iNOS-dependent mTOR pathway activation. Both pharmacologic inhibition and siRNA-mediated gene silencing of iNOS suppressed melanoma proliferation and in vivo growth on the CAM in human melanoma models. This was associated with strong downregulation of mTOR pathway activation by Western blot analysis of p-mTOR, p-P70S6K, p-S6RP, and p-4EBP1. iNOS expression and NO were associated with reversible nitrosylation of TSC2, and inhibited dimerization of TSC2 with its inhibitory partner TSC1, enhancing GTPase activity of its target Rheb, a critical activator of mTOR signaling. Immunohistochemical analysis of tumor specimens from stage III melanoma patients showed a significant correlation between iNOS expression levels and expression of mTOR pathway members. Exogenously-supplied NO was also sufficient to reverse mTOR pathway inhibition by the B-Raf inhibitor Vemurafenib. In summary, covalent modification of TSC2 by iNOS-derived NO is associated with impaired TSC2/TSC1 dimerization, mTOR pathway activation, and proliferation of human melanoma. This model is consistent with the known association of iNOS overexpression and poor prognosis in melanoma and other cancers. PMID:24398473

  4. Vegetation dynamics and its driving forces from climate change and human activities in the Three-River Source Region, China from 1982 to 2012.

    Science.gov (United States)

    Zhang, Ying; Zhang, Chaobin; Wang, Zhaoqi; Chen, Yizhao; Gang, Chengcheng; An, Ru; Li, Jianlong

    2016-09-01

    The Three-River Source Region (TRSR), a region with key importance to the ecological security of China, has undergone climate changes and a shift in human activities driven by a series of ecological restoration projects in recent decades. To reveal the spatiotemporal dynamics of vegetation dynamics and calculate the contributions of driving factors in the TRSR across different periods from 1982 to 2012, net primary productivity (NPP) estimated using the Carnegie-Ames-Stanford approach model was used to assess the status of vegetation. The actual effects of different climatic variation trends on interannual variation in NPP were analyzed. Furthermore, the relationships of NPP with different climate factors and human activities were analyzed quantitatively. Results showed the following: from 1982 to 2012, the average NPP in the study area was 187.37gcm(-2)yr(-1). The average NPP exhibited a fluctuation but presented a generally increasing trend over the 31-year study period, with an increase rate of 1.31gcm(-2)yr(-2). During the entire study period, the average contributions of temperature, precipitation, and solar radiation to NPP interannual variation over the entire region were 0.58, 0.73, and 0.09gcm(-2)yr(-2), respectively. Radiation was the climate factor with the greatest influence on NPP interannual variation. The factor that restricted NPP increase changed from temperature and radiation to precipitation. The average contributions of climate change and human activities to NPP interannual variation were 1.40gcm(-2)yr(-2) and -0.08gcm(-2)yr(-2), respectively. From 1982 to 2000, the general climate conditions were favorable to vegetation recovery, whereas human activities had a weaker negative impact on vegetation growth. From 2001 to 2012, climate conditions began to have a negative impact on vegetation growth, whereas human activities made a favorable impact on vegetation recovery. Copyright © 2016 Elsevier B.V. All rights reserved.

  5. Naturalistic driving : observing everyday driving behaviour.

    NARCIS (Netherlands)

    2010-01-01

    Naturalistic Driving is a relatively new research method for the observation of everyday driving behaviour of road users. For this purpose, systems are installed in subjects’ own vehicles that unobtrusively register vehicle manoeuvres, driver behaviour (such as eye, head and hand manoeuvres) and

  6. Driving While Non-White: Exploring Traffic Stops and Post-Stop Activities in North Carolina, 2005-2009

    Directory of Open Access Journals (Sweden)

    Cameron D. Lippard

    2011-11-01

    Full Text Available Research has established that Blacks face disproportionate amounts of traffic stops, searches, and arrests by police compared to Whites. However, few studies have ventured past the Black-White dichotomy and considered how Hispanics or other minorities may face the same disparities, especially in places where the Hispanic population has dramatically increased in recent years. Using traffic stop and post-stop data compiled by the North Carolina Department of Justice from 2005 to 2009, this study explored whether Hispanics, Blacks, as well as other racial minorities experienced a higher likelihood of traffic stops, citations, searches, and arrests compared to Whites within sample of city, county, and state law enforcement agencies. We found that generally all racial and ethnic minority groups face higher rates of traffic stops than Whites by almost every law enforcement agency sampled. We also found that rates of post-stop activities including searches, citations, and arrests are higher for all racial and ethnic minority groups examined compared to Whites, especially for Hispanics. Hispanic and non-White disparities in traffic stops also cannot be explained away when controlling for population size, type of law enforcement agency, or the reason stated for the traffic stop (e.g., DWI, speeding, or investigation. More important, however, is that the rate of searches for racial and ethnic minorities did not necessarily match the rates of citations and arrests minorities receive, suggesting that some stops could be racially or ethnically motivated.

  7. Alcohol drives S-nitrosylation and redox activation of protein phosphatase 1, causing bovine airway cilia dysfunction.

    Science.gov (United States)

    Price, Michael E; Pavlik, Jacqueline A; Liu, Miao; Ding, Shi-Jian; Wyatt, Todd A; Sisson, Joseph H

    2017-03-01

    Individuals with alcohol (ethanol)-use disorders are at increased risk for lung infections, in part, due to defective mucociliary clearance driven by motile cilia in the airways. We recently reported that isolated, demembranated bovine cilia (axonemes) are capable of producing nitric oxide (∙NO) when exposed to biologically relevant concentrations of alcohol. This increased presence of ∙NO can lead to protein S-nitrosylation, a posttranslational modification signaling mechanism involving reversible adduction of nitrosonium cations or ∙NO to thiolate or thiyl radicals, respectively, of proteins forming S-nitrosothiols (SNOs). We quantified and compared SNO content between isolated, demembranated axonemes extracted from bovine tracheae, with or without in situ alcohol exposure (100 mM × 24 h). We demonstrate that relevant concentrations of alcohol exposure shift the S-nitrosylation status of key cilia regulatory proteins, including 20-fold increases in S-nitrosylation of proteins that include protein phosphatase 1 (PP1). With the use of an ATP-reactivated axoneme motility system, we demonstrate that alcohol-driven S-nitrosylation of PP1 is associated with PP1 activation and dysfunction of axoneme motility. These new data demonstrate that alcohol can shift the S-nitrothiol balance at the level of the cilia organelle and highlight S-nitrosylation as a novel signaling mechanism to regulate PP1 and cilia motility.

  8. Enzyme-ligand interactions that drive active site rearrangements in the Helicobacter pylori 5´-methylthioadenosine/S-adenosylhomocysteine nucleosidase

    Energy Technology Data Exchange (ETDEWEB)

    Ronning, Donald R; Iacopelli, Natalie M; Mishra, Vidhi [Toledo

    2012-03-15

    The bacterial enzyme 5'-methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTAN) plays a central role in three essential metabolic pathways in bacteria: methionine salvage, purine salvage, and polyamine biosynthesis. Recently, its role in the pathway that leads to the production of autoinducer II, an important component in quorum-sensing, has garnered much interest. Because of this variety of roles, MTAN is an attractive target for developing new classes of inhibitors that influence bacterial virulence and biofilm formation. To gain insight toward the development of new classes of MTAN inhibitors, the interactions between the Helicobacter pylori-encoded MTAN and its substrates and substrate analogs were probed using X-ray crystallography. The structures of MTAN, an MTAN-Formycin A complex, and an adenine bound form were solved by molecular replacement and refined to 1.7, 1.8, and 1.6 Å, respectively. The ribose-binding site in the MTAN and MTAN-adenine cocrystal structures contain a tris[hydroxymethyl]aminomethane molecule that stabilizes the closed form of the enzyme and displaces a nucleophilic water molecule necessary for catalysis. This research gives insight to the interactions between MTAN and bound ligands that promote closing of the enzyme active site and highlights the potential for designing new classes of MTAN inhibitors using a link/grow or ligand assembly development strategy based on the described H. pylori MTAN crystal structures.

  9. Transient microbiota exposures activate dormant Escherichia coli infection in the bladder and drive severe outcomes of recurrent disease.

    Directory of Open Access Journals (Sweden)

    Nicole M Gilbert

    2017-03-01

    Full Text Available Pathogens often inhabit the body asymptomatically, emerging to cause disease in response to unknown triggers. In the bladder, latent intracellular Escherichia coli reservoirs are regarded as likely origins of recurrent urinary tract infection (rUTI, a problem affecting millions of women worldwide. However, clinically plausible triggers that activate these reservoirs are unknown. Clinical studies suggest that the composition of a woman's vaginal microbiota influences her susceptibility to rUTI, but the mechanisms behind these associations are unclear. Several lines of evidence suggest that the urinary tract is routinely exposed to vaginal bacteria, including Gardnerella vaginalis, a dominant member of the vaginal microbiota in some women. Using a mouse model, we show that bladder exposure to G. vaginalis triggers E. coli egress from latent bladder reservoirs and enhances the potential for life-threatening outcomes of the resulting E. coli rUTI. Transient G. vaginalis exposures were sufficient to cause bladder epithelial apoptosis and exfoliation and interleukin-1-receptor-mediated kidney injury, which persisted after G. vaginalis clearance from the urinary tract. These results support a broader view of UTI pathogenesis in which disease can be driven by short-lived but powerful urinary tract exposures to vaginal bacteria that are themselves not "uropathogenic" in the classic sense. This "covert pathogenesis" paradigm may apply to other latent infections, (e.g., tuberculosis, or for diseases currently defined as noninfectious because routine culture fails to detect microbes of recognized significance.

  10. Levamisole promotes murine bone marrow derived dendritic cell activation and drives Th1 immune response in vitro and in vivo.

    Science.gov (United States)

    Fu, Yubing; Wang, Ting; Xiu, Lei; Shi, Xiaojie; Bian, Ziyao; Zhang, Yongli; Ruhan, A; Wang, Xiao

    2016-02-01

    Our lab previously found that levamisole (LMS) as an adjuvant enhanced the efficacy of vaccine against infectious pathogens. However, the cellular and molecular mechanisms remain to be defined. In this study, we showed that BALB/c bone marrow-derived DC stimulated with LMS resulted in enhanced cell-surface expression of CD80, CD86, CD40 and MHC class II, as well as enhanced production of IL-12p70, TNF-α and IL-1β. Interestingly, the LMS activated DCs were able to stimulate CD4(+) T cell proliferation and facilitated Th1 differentiation by increasing the secretion of IFN-γ in an allogeneic mixed leukocyte reaction. Furthermore, to confirm the in vitro data, we investigated the effect of LMS on antigen-specific antibody and cytokine production in BALB/c mice. Immunization with LMS plus OVA showed that anti-OVA IgG2a and IFN-γ were increased significantly compared with OVA alone in BALB/c mice. In conclusion, our results suggested that murine bone marrow-derived DC, played a crucial role in the effect of LMS on the induction of Th1 responses, which probably was due to its ability to promote DC maturation and secrete proinflammatory cytokines. Copyright © 2015 Elsevier B.V. All rights reserved.

  11. A Neoglycoconjugate Containing the Human Milk Sugar LNFPIII Drives Anti-Inflammatory Activation of Antigen Presenting Cells in a CD14 Dependent Pathway.

    Directory of Open Access Journals (Sweden)

    Smanla Tundup

    Full Text Available The milk pentasaccharide LNFPIII has therapeutic action for metabolic and autoimmune diseases and prolongs transplant survival in mice when presented as a neoglycoconjugate. Within LNFPIII is the Lewisx trisaccharide, expressed by many helminth parasites. In humans, LNFPIII is found in human milk and also known as stage-specific embryonic antigen-1. LNFPIII-NGC drives alternative activation of macrophages and dendritic cells via NFκB activation in a TLR4 dependent mechanism. However, the connection between LNFPIII-NGC activation of APCs, TLR4 signaling and subsequent MAP kinase signaling leading to anti-inflammatory activation of APCs remains unknown. In this study we determined that the innate receptor CD14 was essential for LNFPIII-NGC induction of both ERK and NFkB activation in APCs. Induction of ERK activation by LNFPIII-NGC was completely dependent on CD14/TLR4-Ras-Raf1/TPL2-MEK axis in bone marrow derived dendritic cells (BMDCs. In addition, LNFPIII-NGC preferentially induced the production of Th2 "favoring" chemokines CCL22 and matrix metalloprotease protein-9 in a CD14 dependent manner in BMDCs. In contrast, LNFPIII-NGC induces significantly lower levels of Th1 "favoring" chemokines, MIP1α, MIP1β and MIP-2 compared to levels in LPS stimulated cells. Interestingly, NGC of the identical human milk sugar LNnT, minus the alpha 1-3 linked fucose, failed to activate APCs via TLR4/MD2/CD14 receptor complex, suggesting that the alpha 1-3 linked fucose in LNFPIII and not on LNnT, is required for this process. Using specific chemical inhibitors of the MAPK pathway, we found that LNFPIII-NGC induction of CCL22, MMP9 and IL-10 production was dependent on ERK activation. Over all, this study suggests that LNFPIII-NGC utilizes CD14/TLR4-MAPK (ERK axis in modulating APC activation to produce anti-inflammatory chemokines and cytokines in a manner distinct from that seen for the pro-inflammatory PAMP LPS. These pathways may explain the in vivo

  12. Brain stem activity changes associated with restored sympathetic drive following CPAP treatment in OSA subjects: a longitudinal investigation.

    Science.gov (United States)

    Lundblad, Linda C; Fatouleh, Rania H; McKenzie, David K; Macefield, Vaughan G; Henderson, Luke A

    2015-08-01

    Obstructive sleep apnea (OSA) is associated with significantly elevated muscle sympathetic nerve activity (MSNA), leading to hypertension and increased cardiovascular morbidity. Although little is known about the mechanisms responsible for the sympathoexcitation, we have recently shown that the elevated MSNA in OSA is associated with altered neural processing in various brain stem sites, including the dorsolateral pons, rostral ventrolateral medulla, medullary raphe, and midbrain. Given the risk associated with elevated MSNA, we aimed to determine if treatment of OSA with continuous positive airway pressure (CPAP) would reduce the elevated MSNA and reverse the brain stem functional changes associated with the elevated MSNA. We performed concurrent recordings of MSNA and blood oxygen level-dependent (BOLD) signal intensity of the brain stem, using high-resolution functional magnetic resonance imaging, in 15 controls and 13 subjects with OSA, before and after 6 mo CPAP treatment. As expected, 6 mo of CPAP treatment significantly reduced MSNA in subjects with OSA, from 54 ± 4 to 23 ± 3 bursts/min and from 77 ± 7 to 36 ± 3 bursts/100 heart beats. Importantly, we found that MSNA-coupled changes in BOLD signal intensity within the dorsolateral pons, medullary raphe, and rostral ventrolateral medulla returned to control levels. That is, CPAP treatment completely reversed brain stem functional changes associated with elevated MSNA in untreated OSA subjects. These data highlight the effectiveness of CPAP treatment in reducing one of the most significant health issues associated with OSA, that is, elevated MSNA and its associated elevated morbidity. Copyright © 2015 the American Physiological Society.

  13. What drives slow wave activity during early non-REM sleep: Learning during prior wake or effort?

    Directory of Open Access Journals (Sweden)

    Ziyang Li

    Full Text Available What is the function of sleep in humans? One claim is that sleep consolidates learning. Slow wave activity (SWA, i.e. slow oscillations of frequency < 4 Hz, has been observed in electroencephalograms (EEG during sleep; it increases with prior wakefulness and decreases with sleep. Studies have claimed that increase in SWA in specific regions of the sleeping brain is correlated with overnight improved performance, i.e. overnight consolidation, on a demanding motor learning task. We wondered if SWA change during sleep is attributable to overnight consolidation or to metabolic demand. Participants executed out-and-back movements to a target using a pen-like cursor with their dominant hand while the target and cursor position were displayed on a screen. They trained on three different conditions on separate nights, differing in the amount and degree of rotation between the actual hand movement direction and displayed cursor movement direction. In the no-rotation (NR condition, there was no rotation. In the single rotation (SR condition, the amount of rotation remained the same throughout, and performance improved both across pre-sleep training and after sleep, i.e. overnight consolidation occurred; in the random rotation (RR condition, the amount of rotation varied randomly from trial to trial, and no overnight consolidation occurred; SR and RR were cognitively demanding. The average EEG power density of SWA for the first 30 min. of non-rapid eye movement sleep after training was computed. Both SR and RR elicited increase in SWA in the parietal region; furthermore, the topographic distribution of SWA in each was remarkably similar. No correlation was found between the overnight performance improvement on SR and the SWA change in the parietal region on measures of learning. Our results argue that regulation of SWA in early sleep is associated with high levels of cognitive effort during prior wakefulness, and not just overnight consolidation.

  14. Human activities and climate variability drive fast-paced change across the world's estuarine-coastal ecosystems

    Science.gov (United States)

    Cloern, James E.; Abreu, Paulo C.; Carstensen, Jacob; Chauvaud, Laurent; Elmgren, Ragnar; Grall, Jacques; Greening, Holly; Johansson, John O.R.; Kahru, Mati; Sherwood, Edward T.; Xu, Jie; Yin, Kedong

    2016-01-01

    Time series of environmental measurements are essential for detecting, measuring and understanding changes in the Earth system and its biological communities. Observational series have accumulated over the past 2–5 decades from measurements across the world's estuaries, bays, lagoons, inland seas and shelf waters influenced by runoff. We synthesize information contained in these time series to develop a global view of changes occurring in marine systems influenced by connectivity to land. Our review is organized around four themes: (i) human activities as drivers of change; (ii) variability of the climate system as a driver of change; (iii) successes, disappointments and challenges of managing change at the sea-land interface; and (iv) discoveries made from observations over time. Multidecadal time series reveal that many of the world's estuarine–coastal ecosystems are in a continuing state of change, and the pace of change is faster than we could have imagined a decade ago. Some have been transformed into novel ecosystems with habitats, biogeochemistry and biological communities outside the natural range of variability. Change takes many forms including linear and nonlinear trends, abrupt state changes and oscillations. The challenge of managing change is daunting in the coastal zone where diverse human pressures are concentrated and intersect with different responses to climate variability over land and over ocean basins. The pace of change in estuarine–coastal ecosystems will likely accelerate as the human population and economies continue to grow and as global climate change accelerates. Wise stewardship of the resources upon which we depend is critically dependent upon a continuing flow of information from observations to measure, understand and anticipate future changes along the world's coastlines.

  15. Human activities and climate variability drive fast-paced change across the world's estuarine-coastal ecosystems.

    Science.gov (United States)

    Cloern, James E; Abreu, Paulo C; Carstensen, Jacob; Chauvaud, Laurent; Elmgren, Ragnar; Grall, Jacques; Greening, Holly; Johansson, John Olov Roger; Kahru, Mati; Sherwood, Edward T; Xu, Jie; Yin, Kedong

    2016-02-01

    Time series of environmental measurements are essential for detecting, measuring and understanding changes in the Earth system and its biological communities. Observational series have accumulated over the past 2-5 decades from measurements across the world's estuaries, bays, lagoons, inland seas and shelf waters influenced by runoff. We synthesize information contained in these time series to develop a global view of changes occurring in marine systems influenced by connectivity to land. Our review is organized around four themes: (i) human activities as drivers of change; (ii) variability of the climate system as a driver of change; (iii) successes, disappointments and challenges of managing change at the sea-land interface; and (iv) discoveries made from observations over time. Multidecadal time series reveal that many of the world's estuarine-coastal ecosystems are in a continuing state of change, and the pace of change is faster than we could have imagined a decade ago. Some have been transformed into novel ecosystems with habitats, biogeochemistry and biological communities outside the natural range of variability. Change takes many forms including linear and nonlinear trends, abrupt state changes and oscillations. The challenge of managing change is daunting in the coastal zone where diverse human pressures are concentrated and intersect with different responses to climate variability over land and over ocean basins. The pace of change in estuarine-coastal ecosystems will likely accelerate as the human population and economies continue to grow and as global climate change accelerates. Wise stewardship of the resources upon which we depend is critically dependent upon a continuing flow of information from observations to measure, understand and anticipate future changes along the world's coastlines. © 2015 The Authors. Global Change Biology Published by John Wiley & Sons Ltd.

  16. N-acetyl lysyltyrosylcysteine amide inhibits myeloperoxidase, a novel tripeptide inhibitor1[S

    Science.gov (United States)

    Zhang, Hao; Jing, Xigang; Shi, Yang; Xu, Hao; Du, Jianhai; Guan, Tongju; Weihrauch, Dorothee; Jones, Deron W.; Wang, Weiling; Gourlay, David; Oldham, Keith T.; Hillery, Cheryl A.; Pritchard, Kirkwood A.

    2013-01-01

    Myeloperoxidase (MPO) plays important roles in disease by increasing oxidative and nitrosative stress and oxidizing lipoproteins. Here we report N-acetyl lysyltyrosylcysteine amide (KYC) is an effective inhibitor of MPO activity. We show KYC inhibits MPO-mediated hypochlorous acid (HOCl) formation and nitration/oxidation of LDL. Disulfide is the major product of MPO-mediated KYC oxidation. KYC (⩽4,000 μM) does not induce cytotoxicity in bovine aortic endothelial cells (BAECs). KYC inhibits HOCl generation by phorbol myristate acetate (PMA)-stimulated neutrophils and human promyelocytic leukemia (HL-60) cells but not superoxide generation by PMA-stimulated HL-60 cells. KYC inhibits MPO-mediated HOCl formation in BAEC culture and protects BAECs from MPO-induced injury. KYC inhibits MPO-mediated lipid peroxidation of LDL whereas tyrosine (Tyr) and tryptophan (Trp) enhance oxidation. KYC is unique as its isomers do not inhibit MPO activity, or are much less effective. Ultraviolet-visible spectral studies indicate KYC binds to the active site of MPO and reacts with compounds I and II. Docking studies show the Tyr of KYC rests just above the heme of MPO. Interestingly, KYC increases MPO-dependent H2O2 consumption. These data indicate KYC is a novel and specific inhibitor of MPO activity that is nontoxic to endothelial cell cultures. Accordingly, KYC may be useful for treating MPO-mediated vascular disease. PMID:23883583

  17. Vegetation dynamics and its driving forces from climate change and human activities in the Three-River Source Region, China from 1982 to 2012

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Ying; Zhang, Chaobin; Wang, Zhaoqi; Chen, Yizhao; Gang, Chengcheng [School of Life Science, Nanjing University, Xianlin Road 163, Qixia District, Nanjing, 210046 (China); An, Ru [School of Earth Science and Engineering, Hohai University, Xikang Road 129, Nanjing, 210098 (China); Li, Jianlong, E-mail: lijianlongnju@163.com [School of Life Science, Nanjing University, Xianlin Road 163, Qixia District, Nanjing, 210046 (China)

    2016-09-01

    The Three-River Source Region (TRSR), a region with key importance to the ecological security of China, has undergone climate changes and a shift in human activities driven by a series of ecological restoration projects in recent decades. To reveal the spatiotemporal dynamics of vegetation dynamics and calculate the contributions of driving factors in the TRSR across different periods from 1982 to 2012, net primary productivity (NPP) estimated using the Carnegie–Ames–Stanford approach model was used to assess the status of vegetation. The actual effects of different climatic variation trends on interannual variation in NPP were analyzed. Furthermore, the relationships of NPP with different climate factors and human activities were analyzed quantitatively. Results showed the following: from 1982 to 2012, the average NPP in the study area was 187.37 g cm{sup −2} yr{sup −1}. The average NPP exhibited a fluctuation but presented a generally increasing trend over the 31-year study period, with an increase rate of 1.31 g cm{sup −2} yr{sup −2}. During the entire study period, the average contributions of temperature, precipitation, and solar radiation to NPP interannual variation over the entire region were 0.58, 0.73, and 0.09 g cm{sup −2} yr{sup −2}, respectively. Radiation was the climate factor with the greatest influence on NPP interannual variation. The factor that restricted NPP increase changed from temperature and radiation to precipitation. The average contributions of climate change and human activities to NPP interannual variation were 1.40 g cm{sup −2} yr{sup −2} and − 0.08 g cm{sup −2} yr{sup −2}, respectively. From 1982 to 2000, the general climate conditions were favorable to vegetation recovery, whereas human activities had a weaker negative impact on vegetation growth. From 2001 to 2012, climate conditions began to have a negative impact on vegetation growth, whereas human activities made a favorable impact on vegetation

  18. Electric Vehicle - Economical driving

    DEFF Research Database (Denmark)

    Jensen, VCE, Steen V.; Schøn, Henriette

    1999-01-01

    Instruct the reader in getting most satisfaction out of an EV, especially concerning driving and loading.......Instruct the reader in getting most satisfaction out of an EV, especially concerning driving and loading....

  19. A wasp manipulates neuronal activity in the sub-esophageal ganglion to decrease the drive for walking in its cockroach prey.

    Directory of Open Access Journals (Sweden)

    Ram Gal

    Full Text Available BACKGROUND: The parasitoid Jewel Wasp hunts cockroaches to serve as a live food supply for its offspring. The wasp stings the cockroach in the head and delivers a cocktail of neurotoxins directly inside the prey's cerebral ganglia. Although not paralyzed, the stung cockroach becomes a living yet docile 'zombie', incapable of self-initiating spontaneous or evoked walking. We show here that such neuro-chemical manipulation can be attributed to decreased neuronal activity in a small region of the cockroach cerebral nervous system, the sub-esophageal ganglion (SEG. A decrease in descending permissive inputs from this ganglion to thoracic central pattern generators decreases the propensity for walking-related behaviors. METHODOLOGY AND PRINCIPAL FINDINGS: We have used behavioral, neuro-pharmacological and electrophysiological methods to show that: (1 Surgically removing the cockroach SEG prior to wasp stinging prolongs the duration of the sting 5-fold, suggesting that the wasp actively targets the SEG during the stinging sequence; (2 injecting a sodium channel blocker, procaine, into the SEG of non-stung cockroaches reversibly decreases spontaneous and evoked walking, suggesting that the SEG plays an important role in the up-regulation of locomotion; (3 artificial focal injection of crude milked venom into the SEG of non-stung cockroaches decreases spontaneous and evoked walking, as seen with naturally-stung cockroaches; and (4 spontaneous and evoked neuronal spiking activity in the SEG, recorded with an extracellular bipolar microelectrode, is markedly decreased in stung cockroaches versus non-stung controls. CONCLUSIONS AND SIGNIFICANCE: We have identified the neuronal substrate responsible for the venom-induced manipulation of the cockroach's drive for walking. Our data strongly support previous findings suggesting a critical and permissive role for the SEG in the regulation of locomotion in insects. By injecting a venom cocktail directly into the

  20. Gear bearing drive

    Science.gov (United States)

    Weinberg, Brian (Inventor); Mavroidis, Constantinos (Inventor); Vranish, John M. (Inventor)

    2011-01-01

    A gear bearing drive provides a compact mechanism that operates as an actuator providing torque and as a joint providing support. The drive includes a gear arrangement integrating an external rotor DC motor within a sun gear. Locking surfaces maintain the components of the drive in alignment and provide support for axial loads and moments. The gear bearing drive has a variety of applications, including as a joint in robotic arms and prosthetic limbs.

  1. Regulation of the Action of Early Mitotic Inhibitor 1 on the Anaphase-promoting Complex/Cyclosome by Cyclin-dependent Kinases*

    Science.gov (United States)

    Moshe, Yakir; Bar-On, Ortal; Ganoth, Dvora; Hershko, Avram

    2011-01-01

    Cell cycle regulation is characterized by alternating activities of cyclin-dependent kinases (CDKs) and of the ubiquitin ligase anaphase promoting complex/cyclosome (APC/C). During S-phase APC/C is inhibited by early mitotic inhibitor 1 (Emi1) to allow the accumulation of cyclins A and B and to prevent re-replication. Emi1 is degraded at prophase by a Plk1-dependent pathway. Recent studies in which the degradation pathway of Emi1 was disrupted have shown that APC/C is activated at mitotic entry despite stabilization of Emi1. These results suggested the possibility of additional mechanisms other than degradation of Emi1, which release APC/C from inhibition by Emi1 upon entry into mitosis. In this study we report one such mechanism, by which the ability of Emi1 to inhibit APC/C is negatively regulated by CDKs. We show that in Plk1-inhibited cells Emi1 is stabilized and phosphorylated, that Emi1 is phosphorylated by CDKs in mitotic but not S-phase cell extracts, and that Emi1 phosphorylation by mitotic cell extracts or purified CDKs markedly reduces the ability of Emi1 to bind and to inhibit APC/C. Finally, we show that the addition of extracts from S-phase cells to extracts from mitotic cells protects Emi1 from CDK-mediated inactivation. PMID:21454540

  2. Firearms, alcohol and crime: convictions for driving under the influence (DUI) and other alcohol-related crimes and risk for future criminal activity among authorised purchasers of handguns.

    Science.gov (United States)

    Wintemute, Garen J; Wright, Mona A; Castillo-Carniglia, Alvaro; Shev, Aaron; Cerdá, Magdalena

    2018-02-01

    Firearm violence frequently involves alcohol, but there are no studies of misuse of alcohol and risk for future violence among firearm owners. We examined the association between prior convictions for alcohol-related crimes, chiefly driving under the influence (DUI), and risk of subsequent arrest among 4066 individuals who purchased handguns in California in 1977. During follow-up through 1991, 32.8% of those with prior alcohol-related convictions and 5.7% of those with no prior criminal history were arrested for a violent or firearm-related crime; 15.9% and 2.7%, respectively, were arrested for murder, rape, robbery or aggravated assault. Prior alcohol-related convictions were associated with a fourfold to fivefold increase in risk of incident arrest for a violent or firearm-related crime, a relative increase greater than that seen for age, sex or prior violence. Prior convictions for alcohol-related crime may be an important predictor of risk for future criminal activity among purchasers of firearms. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  3. What drives "fibrinolysis"?

    Science.gov (United States)

    Medcalf, R L

    2015-01-01

    The timely removal of blood clots and fibrin deposits is essential in the regulation of haemostasis. This is achieved by the fibrinolytic system, an enzymatic process that regulates the activation of plasminogen into its proteolytic form, plasmin. This is a self-regulated event as the very presence of fibrin initiates plasminogen activation on the fibrin surface due to the presentation of exposed C-terminal lysine residues in fibrin that allow plasminogen to position itself via its lysine binding sites and to be more efficiently cleaved by tissue-type plasminogen activator (t-PA). Hence fibrin, the ultimate substrate of plasmin during fibrinolysis, is indeed an essential cofactor in the cascade. What has now come to light is that the fibrinolytic system is not solely designed to eliminate fibrin. Indeed, it is a broad acting system that processes a variety of proteins, including many in the brain where there is no fibrin. So what drives t-PA-mediated plasminogen activation when fibrin is not available? This review will describe the broadening role of the fibrinolytic system highlighting the importance of fibrin and other key proteins as facilitators during t-PA-mediated plasminogen activation.

  4. Generation of Domestic Hot Water, Space Heating and Driving Pattern Profiles for Integration Analysis of Active Loads in Low Voltage Grids

    DEFF Research Database (Denmark)

    Diaz de Cerio Mendaza, Iker; Pigazo, Alberto; Bak-Jensen, Birgitte

    2013-01-01

    at household level. Despite of the well-known flexible service that this kind of loads can provide, their flexibility is highly dependent of the domestic hot water and space heating demand and the driving habits of each user. This paper presents two methodologies employed to randomly generate thermal power...... demand and electric vehicle driving profiles, to be used for power grid calculations. The generated thermal profiles relied on a statistical analysis made from real domestic hot water and space heating data from 25 households of a typical Danish residential area. The driving profiles instead were formed...

  5. Temporal profile of prolonged, night‐time driving performance: breaks from driving temporarily reduce time‐on‐task fatigue but not sleepiness

    National Research Council Canada - National Science Library

    PHIPPS‐NELSON, JO; REDMAN, JENNIFER R; RAJARATNAM, SHANTHA M. W

    2011-01-01

    .... We examined the temporal profile of changes in driving performance, electroencephalogram (EEG) activity and subjective measures of sleepiness and fatigue during prolonged nocturnal driving in a car simulator...

  6. Naturalistic drive cycle synthesis for pickup trucks.

    Science.gov (United States)

    Liu, Zifan; Ivanco, Andrej; Filipi, Zoran

    2015-09-01

    Future pick-up trucks are meeting much stricter fuel economy and exhaust emission standards. Design tradeoffs will have to be carefully evaluated to satisfy consumer expectations within the regulatory and cost constraints. Boundary conditions will obviously be critical for decision making: thus, the understanding of how customers are driving in naturalistic settings is indispensable. Federal driving schedules, while critical for certification, do not capture the richness of naturalistic cycles, particularly the aggressive maneuvers that often shape consumer perception of performance. While there are databases with large number of drive cycles, applying all of them directly in the design process is impractical. Therefore, representative drive cycles that capture the essence of the naturalistic driving should be synthesized from naturalistic driving data. Naturalistic drive cycles are firstly categorized by investigating their micro-trip components, defined as driving activities between successive stops. Micro-trips are expected to characterize underlying local traffic conditions, and separate different driving patterns. Next, the transitions from one vehicle state to another vehicle state in each cycle category are captured with Transition Probability Matrix (TPM). Candidate drive cycles can subsequently be synthesized using Markov Chain based on TPMs for each category. Finally, representative synthetic drive cycles are selected through assessment of significant cycle metrics to identify the ones with smallest errors. This paper provides a framework for synthesis of representative drive cycles from naturalistic driving data, which can subsequently be used for efficient optimization of design or control of pick-up truck powertrains. Manufacturers will benefit from representative drive cycles in several aspects, including quick assessments of vehicle performance and energy consumption in simulations, component sizing and design, optimization of control strategies, and

  7. Are We Driving Our Kids to Unhealthy Habits? Results of the Active Healthy Kids Canada 2013 Report Card on Physical Activity for Children and Youth

    Directory of Open Access Journals (Sweden)

    Casey E. Gray

    2014-06-01

    Full Text Available This article examines the time trends in patterns of school travel mode among Canadian children and youth to inform the Active Transportation (AT indicator of the 2013 Active Healthy Kids Canada Report Card on Physical Activity for Children and Youth. The AT grade was assigned based on a comprehensive synthesis of the 2000 and 2010 Physical Activity Monitor studies from the Canadian Fitness and Lifestyle Research Institute and the 1992, 1998, 2005, and 2010 General Social Survey from Statistics Canada. The results showed that in 2013, AT was graded a D, because less than half of Canadian children and youth used only active modes of transportation to get to and from school. The proportion of Canadian children and youth who used only inactive modes of transportation for school travel increased significantly from 51% to 62% over the last decade. Children and youth from larger communities and those with lower household income levels were significantly more likely to use AT than those living in smaller communities and those in higher income households, respectively. In conclusion, motorized transport for school travel has increased steadily over the last decade across Canada. Regional and socio-demographic disparities should be considered in efforts to increase the number of children using AT.

  8. Protection from High Fat Diet-induced Increase in Ceramide in Mice Lacking Plasminogen Activator Inhibitor 1*

    OpenAIRE

    Shah, Charmi; Yang, Guang; Lee, Ian; Bielawski, Jacek; Yusuf A Hannun; Samad, Fahumiya

    2008-01-01

    Obesity increases the risk for metabolic and cardiovascular disease, and adipose tissue plays a central role in this process. Ceramide, the key intermediate of sphingolipid metabolism, also contributes to obesity-related disorders. We show that a high fat diet increased ceramide levels in the adipose tissues and plasma in C57BL/6J mice via a mechanism that involves an increase in gene expression of enzymes mediating ceramide generation through the de novo pathway (e.g. serine palmitoyltransfe...

  9. Plasminogen Activator Inhibitor-1 in Cigarette Smoke Exposure and Influenza A Virus Infection-Induced Lung Injury

    Science.gov (United States)

    Bhandary, Yashodhar P.; Shetty, Shwetha K.; Marudamuthu, Amarnath S.; Midde, Krishna K.; Ji, Hong-Long; Shams, Homoyoun; Subramaniam, Renuka; Fu, Jian; Idell, Steven; Shetty, Sreerama

    2015-01-01

    Parenchymal lung inflammation and airway and alveolar epithelial cell apoptosis are associated with cigarette smoke exposure (CSE), which contributes to chronic obstructive pulmonary disease (COPD). Epidemiological studies indicate that people exposed to chronic cigarette smoke with or without COPD are more susceptible to influenza A virus (IAV) infection. We found increased p53, PAI-1 and apoptosis in AECs, with accumulation of macrophages and neutrophils in the lungs of patients with COPD. In Wild-type (WT) mice with passive CSE (PCSE), p53 and PAI-1 expression and apoptosis were increased in AECs as was lung inflammation, while those lacking p53 or PAI-1 resisted AEC apoptosis and lung inflammation. Further, inhibition of p53-mediated induction of PAI-1 by treatment of WT mice with caveolin-1 scaffolding domain peptide (CSP) reduced PCSE-induced lung inflammation and reversed PCSE-induced suppression of eosinophil-associated RNase1 (EAR1). Competitive inhibition of the p53-PAI-1 mRNA interaction by expressing p53-binding 3’UTR sequences of PAI-1 mRNA likewise suppressed CS-induced PAI-1 and AEC apoptosis and restored EAR1 expression. Consistent with PCSE-induced lung injury, IAV infection increased p53, PAI-1 and apoptosis in AECs in association with pulmonary inflammation. Lung inflammation induced by PCSE was worsened by subsequent exposure to IAV. Mice lacking PAI-1 that were exposed to IAV showed minimal viral burden based on M2 antigen and hemagglutination analyses, whereas transgenic mice that overexpress PAI-1 without PCSE showed increased M2 antigen and inflammation after IAV infection. These observations indicate that increased PAI-1 expression promotes AEC apoptosis and exacerbates lung inflammation induced by IAV following PCSE. PMID:25932922

  10. Lack of association between level of Plasminogen Activator Inhibitor-1 and estimates of tumor angiogenesis in early breast cancer

    DEFF Research Database (Denmark)

    Offersen, Birgitte Vrou; Riisbro, Rikke; Knoop, Ann

    2007-01-01

    we studied the relationship between PAI-1 and estimates of angiogenesis in breast cancer. Tumor tissue specimens from 438 breast cancer patients were included. Median follow-up was 10.3 years. Protein levels of PAI-1 were measured using an ELISA. Angiogenesis scores were performed using a Chalkley...... counts were significantly associated with poor disease-specific survival (p=0.004). Combining low/low versus high/high tertiles of Chalkley counts and PAI-1 showed actuarial 10-year survival rates of 82% versus 52% (p=0.004). High N-stage (p....009) were independent markers of death from breast cancer. This study confirms high PAI-1 or high Chalkley counts as markers of poor prognosis in breast cancer patients, and suggests that the prognostic impact of PAI-1 is independent of its supposed involvement in tumor angiogenesis. Udgivelsesdato: 2007...

  11. Plasminogen activator inhibitor-1 4G/5G polymorphism is associated with coronary artery disease risk: a meta-analysis.

    Science.gov (United States)

    Zhang, Huifeng; Dong, Pingshuan; Yang, Xuming; Liu, Zhenghao

    2014-01-01

    The aim of the current study was to evaluate the association of PAI-1 4G/5G polymorphism with coronary artery disease (CAD) risk using a meta-analysis. All eligible studies were identified through a search of PubMed, EMBASE, China National Knowledge Infrastructure (CNKI), Database of Chinese Scientific and Technical Periodicals, and China Biology Medical literature database (CBM) before June 2014. The association between the PAI-1 4G/5G polymorphism and CAD risk was estimated by odds ratio (OR) and 95% confidence interval (CI). A total of 72 studies including 23557 cases and 21526 controls were eventually collected. The PAI-1 4G/5G polymorphism was significant associated with CAD risk in overall population (OR=1.19, 95% CI 1.10-1.28, P 5G polymorphism was a risk factor for CAD.

  12. Plasminogen activator inhibitor-1 is a critical downstream target of p53 in the induction of replicative senescence

    NARCIS (Netherlands)

    Kortlever, R.M.; Higgins, P.J.; Bernards, R.A.

    2006-01-01

    genesPAI-1PI(3)KPKBGSK3cyclin D1p19ARFp21CIP1uPAp16INK4Acyclin EPCNAp53 limits the proliferation of primary diploid fibroblasts by inducing a state of growth arrest named replicative senescence — a process which protects against oncogenic transformation and requires integrity of the p53 tumour

  13. Simple Driving Techniques

    DEFF Research Database (Denmark)

    Rosendahl, Mads

    2002-01-01

    Driving was introduced as a program transformation technique by Valentin Turchin in some papers around 1980. It was intended for the programming language REFAL and used in metasystem transitions based on super compilation. In this paper we present one version of driving for a more conventional lisp......-like language. Our aim is to extract a simple notion of driving and show that even in this tamed form it has much of the power of more general notions of driving. Our driving technique may be used to simplify functional programs which use function composition and will often be able to remove intermediate data...

  14. High performance AC drives

    CERN Document Server

    Ahmad, Mukhtar

    2010-01-01

    This book presents a comprehensive view of high performance ac drives. It may be considered as both a text book for graduate students and as an up-to-date monograph. It may also be used by R & D professionals involved in the improvement of performance of drives in the industries. The book will also be beneficial to the researchers pursuing work on multiphase drives as well as sensorless and direct torque control of electric drives since up-to date references in these topics are provided. It will also provide few examples of modeling, analysis and control of electric drives using MATLAB/SIMULIN

  15. Driving Fast Flows with Volumetric Current Drive

    Science.gov (United States)

    Milhone, Jason; Endrizzi, D.; Flanagan, K.; Nornberg, M. D.; Peterson, E. E.; Forest, C. B.

    2017-10-01

    Volumetric current drive has been shown to be an efficient method for driving fast flows with high Rm for studying the onset of flow-driven plasma instabilities. High performance plasmas are produced with 20 kW of electron cyclotron heating (ECH) and thermally emissive lanthanum hexaboride cathodes. Plasma flow is achieved by injecting current through the plasma across an externally applied weak magnetic field setting up a J × B body force on the plasma volume. Two scenarios for volumetric current drive have been demonstrated. The first injects current across a weak uniform axial magnetic field driving a Keplerian-like flow for magneto-rotational instability (MRI) studies. The second injects current across a weak quadrupole magnetic field for driving a von Karman-like flow for dynamo studies. First results measuring velocity and ion temperature profiles measured by a Fabry-Perot interferometer are shown. Detailed mach probe flow measurements show stronger flow shear in volumetric current drive compared to previous edge-driven plasma flow experiments. Worked funded by NSF and DOE.

  16. Switched reluctance drives - New aspects

    Science.gov (United States)

    Philips, D. A.

    A 1-kW switched reluctance drive is presented. The author introduces an efficient power converter requiring a small number of switches. An analytical model of the interactive behavior of the motor and the power converter is developed, which shows the drive to be essentially torque controlled. In order to improve the efficiency of the power converter, the author applies premagnetization. The necessity of time-leading activation of the power switches at higher speeds is demonstrated, and the optimal time lead is calculated. The controllability of torque, the premagnetization principle, and the time lead are studied experimentally, and the results agree quite well with the theoretical model.

  17. CD16+ monocyte subset was enriched and functionally exacerbated in driving T-cell activation and B-cell response in systemic lupus erythematosus

    Directory of Open Access Journals (Sweden)

    Huaqun Zhu

    2016-11-01

    Full Text Available Background: The roles that CD16+ monocyte subset plays in T-cell activation and B-cell response have not been well studied in systemic lupus erythematosus (SLE. Objective: The present study aimed to investigate the distribution of CD16+ monocyte subsets in SLE and explore their possible roles in T-cell activation and B-cell differentiation. Methods: The frequencies of monocyte subsets in the peripheral blood of healthy controls (HCs and patients with SLE were determined by flow cytometry. Monocyte subsets were sorted and co-cultured with CD4+ T cells and CD19+ B cells. Then, T and B cells were collected for different subset detection, while the supernatants were collected for immunoglobulin G (IgG, IgA, and IgM or interferon (IFN-γ and interleukin (IL-17A detection by enzyme-linked immunosorbent assay. Results: Our results showed that CD16+ monocytes exhibited a pro-inflammatory phenotype with elevated CD80, CD86, HLA-DR, and CX3CR1 expression on the cell surface. It’s further demonstrated that CD16+ monocytes from patients and HCs shared different cell-surface marker profiles. The CD16+ subset was enriched in SLE and had an exacerbated capacity to promote CD4+ T cell polarization into a Th17 phenotype. Also, CD16+ monocytes had enhanced impacts on CD19+ B cells to differentiate into plasma B cells and regulatory B cells with more Ig production. Conclusions: This study demonstrated that CD16+ monocytes, characterized by different cell-surface marker profiles, were enriched and played a critical role in driving the pathogenic T- and B-cell responses in patients with SLE.

  18. Alertness maintaining tasks (AMTs) while driving.

    Science.gov (United States)

    Oron-Gilad, Tal; Ronen, Adi; Shinar, David

    2008-05-01

    We evaluated the effectiveness of alertness maintaining tasks (AMTs) on driver performance, subjective feelings, and psychophysiological state in monotonous simulated driving in two experiments. In the first experiment, 12 professional truck drivers participated in five sessions of simulated driving: driving only, driving with one of three AMTs (counterbalanced), and driving while listening to music. AMTs were not equally effective in maintaining alertness. The trivia AMT prevented driving performance deterioration, and increased alertness (measured by standardized HRV). The choice reaction time AMT was least demanding but also increased subjective sleepiness and reduced arousal (measured by alpha/beta ratio). The working memory AMT caused a significant decrement in driving speed, increased subjective fatigue, and was regarded by the participants as detrimental to driving. Trivia was preferred by the majority of the drivers over the other two AMTs. Experiment 2 further examined the utility of the trivia AMT. When the drivers engaged in the trivia AMT they maintained better driving performance and perceived the driving duration as shorter than the control condition. The two experiments demonstrated that AMTs can have a positive effect on alertness. The effect is localized in the sense that it does not persist beyond the period of the AMT activation.

  19. 脑心通胶囊对老年人2型糖尿病颈动脉内膜中层厚度和血浆β血小板球蛋白P选择素及纤溶酶原激活物抑制剂1的影响%The effect of Naoxintong capsule treatment on carotid artery intima-media thickness, serum beta thromboglobulin,P-selectin and plasminogen activator inhibitor-1 in elderly type 2 diabetic patients with subclinical atherosclerotic vascular disease

    Institute of Scientific and Technical Information of China (English)

    王俊; 程森华; 杨晓翠; 孙国香; 徐更华; 王益波

    2017-01-01

    目的 探讨脑心通胶囊治疗老年2型糖尿病血管病变患者对其颈动脉内膜中层厚度(IMT)、血浆β-血小板球蛋白(β-TG)、P-选择素(CD62p)和纤溶酶原激活物抑制剂-1(PAI-1)的影响.方法 回顾性研究,选择医院2014年6月至2015年5月收治的110例老年2型糖尿病血管病变患者为研究对象.数字抽签随机分为观察组和对照组(各55例),入选患者均给予常规治疗,观察组患者同时给予脑心通胶囊治疗.对比分析两组患者血浆β-TG、CD62p和PAI-1水平变化. 结果 治疗前,两组患者颈动脉IMT、PAI-1、β-TG和CD62p水平比较,差异无统计学意义(均P>0.05).治疗后,观察组与对照组患者比较,颈动脉IMT(1.31±0.26)mm比(1.44±0.26)mm,差异有统计学意义(t=4.058,P<0.05);观察组患者血浆PAI-1、β-TG和CD62p水平与对照组比较,PAI-1(2.23±0.48)μg/L比(2.56±0.61)μg/L、β TG(29.76±10.24) μg/L比(35.98±10.35)μg/L,CD62p(162.3±21.5)ng/L比(176.96±20.3)ng/L,差异有统计学意义(t值分别为3.965、11.293、14.624,均P<0.05). 结论 脑心通胶囊治疗2型糖尿病亚临床血管病变患者有利于减少颈动脉内膜中层厚度,降低血小板释放活性,减轻患者机体氧化应激反应,从而减轻老年2型糖尿病患者血管病变.%Objective To investigate the effects of Naoxintong Capsule treatment on the carotid artery intima media thickness(IMT),plasma beta thromboglobulin(beta TG),P-selectin(CD62p)and plasminogen activator inhibitor 1 (PAI 1)in elderly patients with type 2 diabetes mellitus and subclinical atherosclerotic vascular disease.Methods In retrospective study,110 cases of elderly patients with type 2 diabetic vascular diseases were selected and admitted as study subjects from June 2014 to May 2015.They were randomized into observation group and control group(n=55,each).All patients were given routine treatment.The patients in the observation group were treated with Naoxintong Capsule.The levels of

  20. Signal transducer and activator of transcription 5 activation is sufficient to drive transcriptional induction of cyclin D2 gene and proliferation of rat pancreatic beta-cells

    DEFF Research Database (Denmark)

    Friedrichsen, Birgitte N; Richter, Henrijette E; Hansen, Johnny A

    2003-01-01

    Signal transducer and activator of transcription 5 (STAT5) activation plays a central role in GH- and prolactin-mediated signal transduction in the pancreatic beta-cells. In previous experiments we demonstrated that STAT5 activation is necessary for human (h)GH-stimulated proliferation of INS-1...... cells and hGH-induced increase of mRNA-levels of the cell cycle regulator cyclin D2. In this study we have further characterized the role of STAT5 in the regulation of cyclin D expression and beta-cell proliferation by hGH. Cyclin D2 mRNA and protein levels (but not cyclin D1 and D3) were induced...... in a time-dependent manner by hGH in INS-1 cells. Inhibition of protein synthesis by coincubation with cycloheximide did not affect the hGH-induced increase of cyclin D2 mRNA levels at 4 h. Expression of a dominant negative STAT5 mutant, STAT5aDelta749, partially inhibited cyclin D2 protein levels. INS-1...

  1. The proto-oncogene Myc drives expression of the NK cell-activating NKp30 ligand B7-H6 in tumor cells.

    Science.gov (United States)

    Textor, Sonja; Bossler, Felicitas; Henrich, Kai-Oliver; Gartlgruber, Moritz; Pollmann, Julia; Fiegler, Nathalie; Arnold, Annette; Westermann, Frank; Waldburger, Nina; Breuhahn, Kai; Golfier, Sven; Witzens-Harig, Mathias; Cerwenka, Adelheid

    2016-07-01

    Natural Killer (NK) cells are innate effector cells that are able to recognize and eliminate tumor cells through engagement of their surface receptors. NKp30 is a potent activating NK cell receptor that elicits efficient NK cell-mediated target cell killing. Recently, B7-H6 was identified as tumor cell surface expressed ligand for NKp30. Enhanced B7-H6 mRNA levels are frequently detected in tumor compared to healthy tissues. To gain insight in the regulation of expression of B7-H6 in tumors, we investigated transcriptional mechanisms driving B7-H6 expression by promoter analyses. Using luciferase reporter assays and chromatin immunoprecipitation we mapped a functional binding site for Myc, a proto-oncogene overexpressed in certain tumors, in the B7-H6 promoter. Pharmacological inhibition or siRNA/shRNA-mediated knock-down of c-Myc or N-Myc significantly decreased B7-H6 expression on a variety of tumor cells including melanoma, pancreatic carcinoma and neuroblastoma cell lines. In tumor cell lines from different origin and primary tumor tissues of hepatocellular carcinoma (HCC), lymphoma and neuroblastoma, mRNA levels of c-Myc positively correlated with B7-H6 expression. Most importantly, upon inhibition or knock-down of c-Myc in tumor cells impaired NKp30-mediated degranulation of NK cells was observed. Thus, our data imply that Myc driven tumors could be targets for cancer immunotherapy exploiting the NKp30/B7-H6 axis.

  2. The relationship between impaired driving crashes and beliefs about impaired driving: do residents in high crash rate counties have greater concerns about impaired driving?

    Science.gov (United States)

    Beck, Kenneth H; Yan, Alice F; Wang, Min Qi; Kerns, Timothy J; Burch, Cynthia A

    2009-04-01

    The purpose of this investigation was to examine the relationship between impaired driving crashes and public beliefs and concerns about impaired driving across each of Maryland's twenty-four counties (including Baltimore City). It was hypothesized that residents of counties that experience higher impaired driving crashes would express more concerns about impaired driving and perceive more risks about driving impaired than residents of counties that have lower rates of impaired driving. Data for alcohol impaired driving crashes were obtained for the years 2004-2006. These data were compared to public opinion data that was obtained annually by random-digit-dial telephone surveys from 2004 to 2007. Concerns about drunk driving as well as perceptions of the likelihood of being stopped by the police if one were to drive after having too much to drink were related to counties with higher serious impaired driving crash rates, as were perceptions that the police and the legal system were too lenient. Perceptions about the likelihood of being stopped by the police were higher in those counties with more impaired driving enforcement activity. Perceptions of concern appear to be shaped more by crash exposure than enforcement activity. Campaigns that address impaired driving prevention should substantially increase enforcement, strengthen the adjudication process of impaired drivers, and emphasize the potential seriousness of drinking-driving crashes in their promotional activities.

  3. Superluminal warp drive

    Energy Technology Data Exchange (ETDEWEB)

    Gonzalez-Diaz, Pedro F. [Colina de los Chopos, Centro de Fisica ' Miguel A. Catalan' , Instituto de Matematicas y Fisica Fundamental, Consejo Superior de Investigaciones Cientificas, Serrano 121, 28006 Madrid (Spain)], E-mail: p.gonzalezdiaz@imaff.cfmac.csic.es

    2007-09-20

    In this Letter we consider a warp drive spacetime resulting from that suggested by Alcubierre when the spaceship can only travel faster than light. Restricting to the two dimensions that retains most of the physics, we derive the thermodynamic properties of the warp drive and show that the temperature of the spaceship rises up as its apparent velocity increases. We also find that the warp drive spacetime can be exhibited in a manifestly cosmological form.

  4. Universal Drive Train Facility

    Data.gov (United States)

    Federal Laboratory Consortium — This vehicle drive train research facility is capable of evaluating helicopter and ground vehicle power transmission technologies in a system level environment. The...

  5. Drives for electric vehicles

    Energy Technology Data Exchange (ETDEWEB)

    Dustmann, C.H.

    1989-01-01

    Internal combustion and electricity as engine driving forces are compared with regard to their specific weight, engine characteristics, efficiency in converting the primary energy and trends of development. Electric drives show a number of advantages especially in cities where frequent stop-and-go traffic is the rule: low emissions, low noise and good utilization of the primary energy are the main advantages here. Technically one needs to have suitable batteries and driving systems. With the Na-S-heavy duty battery coming on to the market a wave of innovations on the area of high-efficiency electric drives is expected in the following years. (orig.).

  6. Oxidative stress drives CD8+ T-cell skin trafficking in patients with vitiligo through CXCL16 upregulation by activating the unfolded protein response in keratinocytes.

    Science.gov (United States)

    Li, Shuli; Zhu, Guannan; Yang, Yuqi; Jian, Zhe; Guo, Sen; Dai, Wei; Shi, Qiong; Ge, Rui; Ma, Jingjing; Liu, Ling; Li, Kai; Luan, Qi; Wang, Gang; Gao, Tianwen; Li, Chunying

    2017-07-01

    In patients with vitiligo, an increased reactive oxygen species (ROS) level has been proved to be a key player during disease initiation and progression in melanocytes. Nevertheless, little is known about the effects of ROS on other cells involved in the aberrant microenvironment, such as keratinocytes and the following immune events. CXCL16 is constitutively expressed in keratinocytes and was recently found to mediate homing of CD8+ T cells in human skin. We sought to explicate the effect of oxidative stress on human keratinocytes and its capacity to drive CD8+ T-cell trafficking through CXCL16 regulation. We first detected putative T-cell skin-homing chemokines and ROS in serum and lesions of patients with vitiligo. The production of candidate chemokines was detected by using quantitative real-time PCR and ELISA in keratinocytes exposed to H2O2. Furthermore, the involved mediators were analyzed by using quantitative real-time PCR, Western blotting, ELISA, and immunofluorescence. Next, we tested the chemotactic migration of CD8+ T cells from patients with vitiligo mediated by the CXCL16-CXCR6 pair using the transwell assay. CXCL16 expression increased and showed a positive correlation with oxidative stress levels in serum and lesions of patients with vitiligo. The H2O2-induced CXCL16 expression was due to the activation of 2 unfolded protein response pathways: kinase RNA (PKR)-like ER kinase-eukaryotic initiation factor 2α and inositol-requiring enzyme 1α-X-box binding protein 1. CXCL16 produced by stressed keratinocytes induced migration of CXCR6+CD8+ T cells derived from patients with vitiligo. CXCR6+CD8+ T-cell skin infiltration is accompanied by melanocyte loss in lesions of patients with vitiligo. Our study demonstrated that CXCL16-CXCR6 mediates CD8+ T-cell skin trafficking under oxidative stress in patients with vitiligo. The CXCL16 expression in human keratinocytes induced by ROS is, at least in part, caused by unfolded protein response activation

  7. Electric Vehicle - Economical driving

    DEFF Research Database (Denmark)

    Jensen, VCE, Steen V.; Schøn, Henriette

    1999-01-01

    How do you reduce the energy-wast when driving and loading EV's - or rather: How do I get more km/l out of an EV......How do you reduce the energy-wast when driving and loading EV's - or rather: How do I get more km/l out of an EV...

  8. Piezoelectric drive circuit

    Science.gov (United States)

    Treu, Jr., Charles A.

    1999-08-31

    A piezoelectric motor drive circuit is provided which utilizes the piezoelectric elements as oscillators and a Meacham half-bridge approach to develop feedback from the motor ground circuit to produce a signal to drive amplifiers to power the motor. The circuit automatically compensates for shifts in harmonic frequency of the piezoelectric elements due to pressure and temperature changes.

  9. Wrong-way driving.

    NARCIS (Netherlands)

    2006-01-01

    Wrong-way driving is a phenomenon that mainly happens on motorways. Although the number of wrong-way crashes is relatively limited, their consequences are much more severe than the consequences of other motorway injury crashes. The groups most often causing wrong-way driving accidents are young,

  10. Self-driving carsickness.

    NARCIS (Netherlands)

    Diels, C.; Bos, J.E.

    2016-01-01

    This paper discusses the predicted increase in the occurrence and severity of motion sickness in self-driving cars. Self-driving cars have the potential to lead to significant benefits. From the driver's perspective, the direct benefits of this technology are considered increased comfort and

  11. Switched reluctance motor drives

    Indian Academy of Sciences (India)

    Davis RM, Ray WF, Blake RJ 1981 Inverter drive for switched reluctance: circuits and component ratings. Inst. Elec. Eng. Proc. B128: 126-136. Ehsani M. 1991 Position Sensor elimination technique for the switched reluctance motor drive. US Patent No. 5,072,166. Ehsani M, Ramani K R 1993 Direct control strategies based ...

  12. Fundamentals of electrical drives

    CERN Document Server

    Veltman, André; De Doncker, Rik W

    2007-01-01

    Provides a comprehensive introduction to various aspects of electrical drive systems. This volume provides a presentation of dynamic generic models that cover all major electrical machine types and modulation/control components of a drive as well as dynamic and steady state analysis of transformers and electrical machines.

  13. Self-driving carsickness

    NARCIS (Netherlands)

    Diels, C.; Bos, J.E.

    2016-01-01

    This paper discusses the predicted increase in the occurrence and severity of motion sickness in self-driving cars. Self-driving cars have the potential to lead to significant benefits. From the driver's perspective, the direct benefits of this technology are considered increased comfort and

  14. Electric vehicles: Driving range

    Science.gov (United States)

    Kempton, Willett

    2016-09-01

    For uptake of electric vehicles to increase, consumers' driving-range needs must be fulfilled. Analysis of the driving patterns of personal vehicles in the US now shows that today's electric vehicles can meet all travel needs on almost 90% of days from a single overnight charge.

  15. Association Between Alcohol-Impaired Driving Enforcement-Related Strategies and Alcohol-Impaired Driving

    OpenAIRE

    Sanem, Julia R.; Erickson, Darin J.; Rutledge, Patricia C.; Lenk, Kathleen M.; Nelson, Toben F.; Jones-Webb, Rhonda; Toomey, Traci L.

    2015-01-01

    All states in the U.S. prohibit alcohol-impaired driving but active law enforcement is necessary for effectively reducing this behavior. Sobriety checkpoints, saturation patrols, open container laws, and media campaigns related to enforcement efforts are all enforcement-related strategies for reducing alcohol-impaired driving. We conducted surveys of all state patrol agencies and a representative sample of local law enforcement agencies to assess their use of alcohol-impaired driving enforcem...

  16. Mitochondrial division inhibitor 1 (mdivi-1) enhances death receptor-mediated apoptosis in human ovarian cancer cells

    Science.gov (United States)

    Wang, Jingnan; Hansen, Karyn; Edwards, Robert; Van Houten, Bennett; Qian, Wei

    2014-01-01

    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) based strategy is a promising targeted therapeutic approach for the treatment of a variety of cancers including ovarian cancer. However, the inherent or acquired resistance of tumor cells to TRAIL limits the potential application of TRAIL-mediated therapy. In this study, we identified that mitochondrial division inhibitor-1 (mdivi-1) is able to enhance the sensitivity of human ovarian cancer cells to death receptor ligands including TRAIL, FAS ligands, and TNF-α. Importantly, the combination of TRAIL and mdivi-1 has no apparent cytotoxic effect on non-transformed human cells, indicating a significant therapeutic window. We identified that caspase-8 and not the modulation of TRAIL receptors is required for the combination effect of TRAIL and mdivi-1. We further demonstrated that the enhanced efficacy of combination of mdivi-1 and death ligands is not dependent on the originally reported target of mdivi-1, Drp1, and is also not dependent on the two important pro-apoptotic Bcl-2 family proteins Bax and Bak. Thus, our study presents a novel strategy in enhancing the apoptotic effect of death receptor ligands and provides a new effective TRAIL-based combination approach for treating human ovarian cancer. PMID:25446129

  17. Soluble epoxide hydrolase inhibitor 1-trifluoromethoxyphenyl-3- (1-propionylpiperidin-4-yl) urea attenuates bleomycin-induced pulmonary fibrosis in mice.

    Science.gov (United States)

    Zhou, Yong; Yang, Jun; Sun, Guo-Ying; Liu, Tian; Duan, Jia-Xi; Zhou, Hui-Fang; Lee, Kin Sing; Hammock, Bruce D; Fang, Xiang; Jiang, Jian-Xin; Guan, Cha-Xiang

    2016-02-01

    Epoxyeicosatrienoic acids (EETs), the metabolites of arachidonic acid derived from the cytochrome P450 (CYP450) epoxygenases, are mainly metabolized by soluble epoxide hydrolase (sEH) to their corresponding diols. EETs but not their diols, have anti-inflammatory properties and inhibition of sEH might provide protective effects against inflammatory fibrosis. We test the effects of a selected sEH inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), on bleomycin-induced pulmonary fibrosis (PF) in mice. A mouse model of PF was established by intratracheal injection of bleomycin and TPPU was administered for 21 days after bleomycin injection. We found TPPU treatment improved the body weight loss and survival rate of bleomycin-stimulated mice. Histological examination showed that TPPU treatment alleviated bleomycin-induced inflammation and maintained the alveolar structure of the pulmonary tissues. TPPU also decreased the bleomycin-induced deposition of collagen and the expression of procollagen I mRNA in lung tissues of mice. TPPU decreased the transforming growth factor-β1 (TGF-β1), interleukin-1β (IL-1β) and IL-6 levels in the serum of bleomycin-stimulated mice. Furthermore, TPPU inhibited the proliferation and collagen synthesis of mouse fibroblasts and partially reversed TGF-β1-induced α-smooth muscle actin expression. Our results indicate that the inhibition of sEH attenuates bleomycin-induced inflammation and collagen deposition and therefore prevents bleomycin-induced PF in a mouse model.

  18. DriveID: safety innovation through individuation.

    Science.gov (United States)

    Sawyer, Ben; Teo, Grace; Mouloua, Mustapha

    2012-01-01

    The driving task is highly complex and places considerable perceptual, physical and cognitive demands on the driver. As driving is fundamentally an information processing activity, distracted or impaired drivers have diminished safety margins compared with non- distracted drivers (Hancock and Parasuraman, 1992; TRB 1998 a & b). This competition for sensory and decision making capacities can lead to failures that cost lives. Some groups, teens and elderly drivers for example, have patterns of systematically poor perceptual, physical and cognitive performance while driving. Although there are technologies developed to aid these different drivers, these systems are often misused and underutilized. The DriveID project aims to design and develop a passive, automated face identification system capable of robustly identifying the driver of the vehicle, retrieve a stored profile, and intelligently prescribing specific accident prevention systems and driving environment customizations.

  19. The influence of music on mood and performance while driving

    NARCIS (Netherlands)

    van der Zwaag, Marjolein D.; Dijksterhuis, Chris; de Waard, Dick; Mulder, Ben L. J. M.; Westerink, Joyce H. D. M.; Brookhuis, Karel A.

    2012-01-01

    Mood can influence our everyday behaviour and people often seek to reinforce, or to alter their mood, for example by turning on music. Music listening while driving is a popular activity. However, little is known about the impact of music listening while driving on physiological state and driving

  20. α-Amylase inhibitor-1 gene from Phaseolus vulgaris expressed in Coffea arabica plants inhibits α-amylases from the coffee berry borer pest

    Directory of Open Access Journals (Sweden)

    Oliveira-Neto Osmundo B

    2010-06-01

    Full Text Available Abstract Background Coffee is an important crop and is crucial to the economy of many developing countries, generating around US$70 billion per year. There are 115 species in the Coffea genus, but only two, C. arabica and C. canephora, are commercially cultivated. Coffee plants are attacked by many pathogens and insect-pests, which affect not only the production of coffee but also its grain quality, reducing the commercial value of the product. The main insect-pest, the coffee berry borer (Hypotheneumus hampei, is responsible for worldwide annual losses of around US$500 million. The coffee berry borer exclusively damages the coffee berries, and it is mainly controlled by organochlorine insecticides that are both toxic and carcinogenic. Unfortunately, natural resistance in the genus Coffea to H. hampei has not been documented. To overcome these problems, biotechnological strategies can be used to introduce an α-amylase inhibitor gene (α-AI1, which confers resistance against the coffee berry borer insect-pest, into C. arabica plants. Results We transformed C. arabica with the α-amylase inhibitor-1 gene (α-AI1 from the common bean, Phaseolus vulgaris, under control of the seed-specific phytohemagglutinin promoter (PHA-L. The presence of the α-AI1 gene in six regenerated transgenic T1 coffee plants was identified by PCR and Southern blotting. Immunoblotting and ELISA experiments using antibodies against α-AI1 inhibitor showed a maximum α-AI1 concentration of 0.29% in crude seed extracts. Inhibitory in vitro assays of the α-AI1 protein against H. hampei α-amylases in transgenic seed extracts showed up to 88% inhibition of enzyme activity. Conclusions This is the first report showing the production of transgenic coffee plants with the biotechnological potential to control the coffee berry borer, the most important insect-pest of crop coffee.

  1. α-Amylase inhibitor-1 gene from Phaseolus vulgaris expressed in Coffea arabica plants inhibits α-amylases from the coffee berry borer pest

    Science.gov (United States)

    2010-01-01

    Background Coffee is an important crop and is crucial to the economy of many developing countries, generating around US$70 billion per year. There are 115 species in the Coffea genus, but only two, C. arabica and C. canephora, are commercially cultivated. Coffee plants are attacked by many pathogens and insect-pests, which affect not only the production of coffee but also its grain quality, reducing the commercial value of the product. The main insect-pest, the coffee berry borer (Hypotheneumus hampei), is responsible for worldwide annual losses of around US$500 million. The coffee berry borer exclusively damages the coffee berries, and it is mainly controlled by organochlorine insecticides that are both toxic and carcinogenic. Unfortunately, natural resistance in the genus Coffea to H. hampei has not been documented. To overcome these problems, biotechnological strategies can be used to introduce an α-amylase inhibitor gene (α-AI1), which confers resistance against the coffee berry borer insect-pest, into C. arabica plants. Results We transformed C. arabica with the α-amylase inhibitor-1 gene (α-AI1) from the common bean, Phaseolus vulgaris, under control of the seed-specific phytohemagglutinin promoter (PHA-L). The presence of the α-AI1 gene in six regenerated transgenic T1 coffee plants was identified by PCR and Southern blotting. Immunoblotting and ELISA experiments using antibodies against α-AI1 inhibitor showed a maximum α-AI1 concentration of 0.29% in crude seed extracts. Inhibitory in vitro assays of the α-AI1 protein against H. hampei α-amylases in transgenic seed extracts showed up to 88% inhibition of enzyme activity. Conclusions This is the first report showing the production of transgenic coffee plants with the biotechnological potential to control the coffee berry borer, the most important insect-pest of crop coffee. PMID:20565807

  2. Alpha-amylase inhibitor-1 gene from Phaseolus vulgaris expressed in Coffea arabica plants inhibits alpha-amylases from the coffee berry borer pest.

    Science.gov (United States)

    Barbosa, Aulus E A D; Albuquerque, Erika V S; Silva, Maria C M; Souza, Djair S L; Oliveira-Neto, Osmundo B; Valencia, Arnubio; Rocha, Thales L; Grossi-de-Sa, Maria F

    2010-06-17

    Coffee is an important crop and is crucial to the economy of many developing countries, generating around US$70 billion per year. There are 115 species in the Coffea genus, but only two, C. arabica and C. canephora, are commercially cultivated. Coffee plants are attacked by many pathogens and insect-pests, which affect not only the production of coffee but also its grain quality, reducing the commercial value of the product. The main insect-pest, the coffee berry borer (Hypotheneumus hampei), is responsible for worldwide annual losses of around US$500 million. The coffee berry borer exclusively damages the coffee berries, and it is mainly controlled by organochlorine insecticides that are both toxic and carcinogenic. Unfortunately, natural resistance in the genus Coffea to H. hampei has not been documented. To overcome these problems, biotechnological strategies can be used to introduce an alpha-amylase inhibitor gene (alpha-AI1), which confers resistance against the coffee berry borer insect-pest, into C. arabica plants. We transformed C. arabica with the alpha-amylase inhibitor-1 gene (alpha-AI1) from the common bean, Phaseolus vulgaris, under control of the seed-specific phytohemagglutinin promoter (PHA-L). The presence of the alpha-AI1 gene in six regenerated transgenic T1 coffee plants was identified by PCR and Southern blotting. Immunoblotting and ELISA experiments using antibodies against alpha-AI1 inhibitor showed a maximum alpha-AI1 concentration of 0.29% in crude seed extracts. Inhibitory in vitro assays of the alpha-AI1 protein against H. hampei alpha-amylases in transgenic seed extracts showed up to 88% inhibition of enzyme activity. This is the first report showing the production of transgenic coffee plants with the biotechnological potential to control the coffee berry borer, the most important insect-pest of crop coffee.

  3. A BAX inhibitor-1 gene in Capsicum annuum is induced under various abiotic stresses and endows multi-tolerance in transgenic tobacco.

    Science.gov (United States)

    Isbat, Mohammad; Zeba, Naheed; Kim, Seong Ryong; Hong, Choo Bong

    2009-10-15

    Programmed cell death (PCD) is a highly conserved cellular suicide process important in developmental processes and elimination of damaged cells upon environmental stresses. Among the important regulators of PCD, much interest has been centered on BCL2-associated x protein (BAX) as the pro-PCD factor. On the other hand, BAX inhibitor-1 (BI-1) has been implicated as an anti-PCD factor that balances out the activity of BAX in the developmental processes and responses to environment. A cDNA clone coding a BI-1 gene was isolated from a cDNA library of heat-stressed hot pepper (Capsicum annuum) and named as CaBI-1. This gene contains an open reading frame (ORF) of 248 amino acids encoding a BI-1 protein. Genomic DNA-blot analysis for CaBI-1 suggested one or two loci in the C. annuum genome. Transcription of CaBI-1 was induced in response to high or low temperatures, drought, high salinity, flooding and heavy metal stresses, and ABA. We introduced the ORF of CaBI-1 under the control of the CaMV 35S promoter (P(35S)) into tobacco (Nicotiana tabacum cv. Wisconsin 38) genome by Agrobacterium-mediated transformation. The P(35S):CaBI-1 transgenic plants displayed markedly improved tolerance to high temperature, water deficit, and high salinity in comparison to the control plants. The results indicate that CaBI-1 is a BI-1 gene of which expression induced under various abiotic stresses and endows tolerance to several types of environmental stresses.

  4. Docosahexaenoic acid increases the expression of oxidative stress-induced growth inhibitor 1 through the PI3K/Akt/Nrf2 signaling pathway in breast cancer cells.

    Science.gov (United States)

    Tsai, Chia-Han; Shen, You-Cheng; Chen, Haw-Wen; Liu, Kai-Li; Chang, Jer-Wei; Chen, Pei-Yin; Lin, Chen-Yu; Yao, Hsien-Tsung; Li, Chien-Chun

    2017-10-01

    Oxidative stress-induced growth inhibitor 1 (OSGIN1), a tumor suppressor, inhibits cell proliferation and induces cell death. N-6 and n-3 PUFAs protect against breast cancer, but the molecular mechanisms of this effect are not clear. We investigated the effect of n-6 and n-3 PUFAs on OSGIN1 expression and whether OSGIN1 is involved in PUFA-induced apoptosis in breast cancer cells. We used 100 μM of n-6 PUFAs including arachidonic acid, linoleic acid, and gamma-linolenic acid and n-3 PUFAs including alpha-linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid (DHA). Only DHA significantly induced OSGIN1 protein and mRNA expression. DHA triggered reactive oxygen species (ROS) generation and nuclear translocation of Nrf2. LY294002, a PI3K inhibitor, suppressed DHA-induced OSGIN1 protein expression and nuclear accumulation of Nrf2. Nrf2 knockdown attenuated DHA-induced OSGIN1 expression. N-Acetyl-l-cysteine, a ROS scavenger, abrogated the DHA-induced increases in Akt phosphorylation, Nrf2 nuclear accumulation, and OSGIN1 expression. DHA induced the Bax/Bcl-2 ratio, mitochondrial accumulation of OSGIN1 and p53, and cytochrome c release; knockdown of OSGIN1 diminished these effects. In conclusion, induction of OSGIN1 by DHA is at least partially associated with increased ROS production, which activates PI3K/Akt/Nrf2 signaling. Induction of OSGIN1 may be involved in DHA-induced apoptosis in breast cancer cells. Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. Effects of Physical Driving Experience on Body Movement and Motion Sickness During Virtual Driving.

    Science.gov (United States)

    Chang, Chih-Hui; Chen, Fu-Chen; Kung, Wei-Ching; Stoffregen, Thomas A

    2017-11-01

    In previous research on motion sickness in simulated and virtual vehicles, subjects' experience controlling the corresponding physical vehicles has been confounded with their age. During driving of virtual automobiles in a video game, we separated chronological age from experience driving physical automobiles. Subjects drove a virtual automobile in a driving video game. Drivers were young adults with several years of experience driving physical automobiles, while nondrivers were individuals in the same age group who did not have a driver's license and had never driven an automobile. During virtual driving, we monitored movement of the head and torso. We collected independent measures of the incidence and severity of motion sickness. After virtual driving, motion sickness incidence did not differ between drivers (65%) and nondrivers (60%). Game performance and the severity of symptoms also did not differ between drivers and nondrivers. However, movement differed between subjects who later became motion sick and those who did not. In addition, physical driving experience influenced patterns of postural activity that preceded motion sickness during virtual driving. The results are consistent with the postural instability theory of motion sickness, and help to illuminate relationships between the control of physical and virtual vehicles.Chang C-H, Chen F-C, Kung W-C, Stoffregen TA. Effects of physical driving experience on body movement and motion sickness during virtual driving. Aerosp Med Hum Perform. 2017; 88(11):985-992.

  6. Effects of decades of physical driving on body movement and motion sickness during virtual driving.

    Directory of Open Access Journals (Sweden)

    Thomas A Stoffregen

    Full Text Available We investigated relations between experience driving physical automobiles and motion sickness during the driving of virtual automobiles. Middle-aged individuals drove a virtual automobile in a driving video game. Drivers were individuals who had possessed a driver's license for approximately 30 years, and who drove regularly, while non-drivers were individuals who had never held a driver's license, or who had not driven for more than 15 years. During virtual driving, we monitored movement of the head and torso. During virtual driving, drivers became motion sick more rapidly than non-drivers, but the incidence and severity of motion sickness did not differ as a function of driving experience. Patterns of movement during virtual driving differed as a function of driving experience. Separately, movement differed between participants who later became motion sick and those who did not. Most importantly, physical driving experience influenced patterns of postural activity that preceded motion sickness during virtual driving. The results are consistent with the postural instability theory of motion sickness, and help to illuminate relations between the control of physical and virtual vehicles.

  7. Turbulent current drive mechanisms

    Science.gov (United States)

    McDevitt, Christopher J.; Tang, Xian-Zhu; Guo, Zehua

    2017-08-01

    Mechanisms through which plasma microturbulence can drive a mean electron plasma current are derived. The efficiency through which these turbulent contributions can drive deviations from neoclassical predictions of the electron current profile is computed by employing a linearized Coulomb collision operator. It is found that a non-diffusive contribution to the electron momentum flux as well as an anomalous electron-ion momentum exchange term provide the most efficient means through which turbulence can modify the mean electron current for the cases considered. Such turbulent contributions appear as an effective EMF within Ohm's law and hence provide an ideal means for driving deviations from neoclassical predictions.

  8. Antihistamines and driving ability: Evidence from 30 years Dutch on-road driving research

    NARCIS (Netherlands)

    Verster, J.C.|info:eu-repo/dai/nl/241442702; Van De Loo, A.J.A.E.|info:eu-repo/dai/nl/369403649; Garssen, J.|info:eu-repo/dai/nl/086369962

    2015-01-01

    Background: Since all antihistamines are capable of crossing the blood-brain barrier, they may also cause sedation which may impair daily activities such as driving a car. The purpose of this review was to examine the effects of antihistamines on driving ability. Method: A literature search revealed

  9. Heart rate variability (HRV and muscular system activity (EMG in cases of crash threat during simulated driving of a passenger car

    Directory of Open Access Journals (Sweden)

    Krystyna Zużewicz

    2013-10-01

    Full Text Available Objectives: The aim of the study was to verify whether simultaneous responses from the muscular and circulatory system occur in the driver's body under simulated conditions of a crash threat. Materials and Methods: The study was carried out in a passenger car driving simulator. The crash was included in the driving test scenario developed in an urban setting. In the group of 22 young male subjects, two physiological signals - ECG and EMG were continuously recorded. The length of the RR interval in the ECG signal was assessed. A HRV analysis was performed in the time and frequency domains for 1-minute record segments at rest (seated position, during undisturbed driving as well as during and several minutes after the crash. For the left and right side muscles: m. trapezius (TR and m. flexor digitorum superficialis (FDS, the EMG signal amplitude was determined. The percentage of maximal voluntary contraction (MVC was compared during driving and during the crash. Results: As for the ECG signal, it was found that in most of the drivers changes occurred in the parameter values reflecting HRV in the time domain. Significant changes were noted in the mean length of RR intervals (mRR. As for the EMG signal, the changes in the amplitude concerned the signal recorded from the FDS muscle. The changes in ECG and EMG were simultaneous in half of the cases. Conclusion: Such parameters as mRR (ECG signal and FDS-L amplitude (EMG signal were the responses to accident risk. Under simulated conditions, responses from the circulatory and musculoskeletal systems are not always simultaneous. The results indicate that a more complete driver's response to a crash in road traffic is obtained based on parallel recording of two physiological signals (ECG and EMG.

  10. Relationships between cognitive functions and driving behavior in Parkinson's disease

    OpenAIRE

    RANCHET, Maud; Broussolle, Emmanuel; Poisson, Alice; PAIRE-FICOUT, Laurence

    2012-01-01

    Alterations in cognitive functions in Parkinson's disease (PD) have been reported even in mild stages of the disease. These functions may play a role in complex daily activities, such as driving. This article provides an overview on the relationships between cognitive functions and driving behaviour in PD in driving simulator and on-road studies. The role of attention, executive functions, visual memory, visuospatial construction and information processing speed is discussed. In driving simul...

  11. The influence of music on mood and performance while driving

    OpenAIRE

    van der Zwaag, Marjolein D.; Dijksterhuis, Chris; de Waard, Dick; Mulder, Ben L. J. M.; Westerink, Joyce H. D. M.; Brookhuis, Karel A.

    2012-01-01

    Mood can influence our everyday behaviour and people often seek to reinforce, or to alter their mood, for example by turning on music. Music listening while driving is a popular activity. However, little is known about the impact of music listening while driving on physiological state and driving performance. In the present experiment, it was investigated whether individually selected music can induce mood and maintain moods during a simulated drive. In addition, effects of positive, negative...

  12. Plasma autoantibodies against heat shock protein 70, enolase 1 and ribonuclease/angiogenin inhibitor 1 as potential biomarkers for cholangiocarcinoma.

    Directory of Open Access Journals (Sweden)

    Rucksak Rucksaken

    Full Text Available The diagnosis of cholangiocarcinoma (CCA is often challenging, leading to poor prognosis. CCA arises via chronic inflammation which may be associated with autoantibodies production. This study aims to identify IgG antibodies directed at self-proteins and tumor-associated antigens. Proteins derived from immortalized cholangiocyte cell line (MMNK1 and CCA cell lines (M055, M214 and M139 were separated using 2-dimensional electrophoresis and incubated with pooled plasma of patients with CCA and non-neoplastic controls by immunoblotting. Twenty five immunoreactive spots against all cell lines-derived proteins were observed on stained gels and studied by LC-MS/MS. Among these, heat shock protein 70 (HSP70, enolase 1 (ENO1 and ribonuclease/angiogenin inhibitor 1 (RNH1 obtained the highest matching scores and were thus selected for further validation. Western blot revealed immunoreactivity against HSP70 and RNH1 in the majority of CCA cases and weakly in healthy individuals. Further, ELISA showed that plasma HSP70 autoantibody level in CCA was significantly capable to discriminate CCA from healthy individuals with an area under the receiver operating characteristic curve of 0.9158 (cut-off 0.2630, 93.55% sensitivity and 73.91% specificity. Plasma levels of IgG autoantibodies against HSP70 were correlated with progression from healthy individuals to cholangitis to CCA (r = 0.679, P<0.001. In addition, circulating ENO1 and RNH1 autoantibodies levels were also significantly higher in cholangitis and CCA compared to healthy controls (P<0.05. Moreover, the combinations of HSP70, ENO1 or RNH1 autoantibodies positivity rates improved specificity to over 78%. In conclusion, plasma IgG autoantibodies against HSP70, ENO1 and RNH1 may represent new diagnostic markers for CCA.

  13. Expression of the Theobroma cacao Bax-inhibitor-1 gene in tomato reduces infection by the hemibiotrophic pathogen Moniliophthora perniciosa.

    Science.gov (United States)

    Scotton, Danielle Camargo; Azevedo, Mariana Da Silva; Sestari, Ivan; Da Silva, Jamille Santos; Souza, Lucas Anjos; Peres, Lázaro Eustáquio Pereira; Leal, Gildemberg Amorim; Figueira, Antonio

    2017-10-01

    Programmed cell death (PCD) plays a key role in plant responses to pathogens, determining the success of infection depending on the pathogen lifestyle and on which participant of the interaction triggers cell death. The hemibiotrophic basidiomycete Moniliophthora perniciosa is the causal agent of witches' broom disease of Theobroma cacao L. (cacao), a serious constraint for production in South America and the Caribbean. It has been hypothesized that M. perniciosa pathogenesis involves PCD, initially as a plant defence mechanism, which is diverted by the fungus to induce necrosis during the dikaryotic phase of the mycelia. Here, we evaluated whether the expression of a cacao anti-apoptotic gene would affect the incidence and severity of M. perniciosa infection using the 'Micro-Tom' (MT) tomato as a model. The cacao Bax-inhibitor-1 (TcBI-1) gene, encoding a putative basal attenuator of PCD, was constitutively expressed in MT to evaluate function. Transformants expressing TcBI-1, when treated with tunicamycin, an inducer of endoplasmic reticulum stress, showed a decrease in cell peroxidation. When the same transformants were inoculated with the necrotrophic fungal pathogens Sclerotinia sclerotiorum, Sclerotium rolfsii and Botrytis cinerea, a significant reduction in infection severity was observed, confirming TcBI-1 function. After inoculation with M. perniciosa, TcBI-1 transformant lines showed a significant reduction in disease incidence compared with MT. The overexpression of TcBI-1 appears to affect the ability of germinating spores to penetrate susceptible tissues, restoring part of the non-host resistance in MT against the S-biotype of M. perniciosa. © 2016 BSPP AND JOHN WILEY & SONS LTD.

  14. Drugs and driving

    NARCIS (Netherlands)

    Walsh, J. Michael; De Gier, Johan J.; Christopherson, Asbjørg S.; Verstraete, Alain G.

    The authors present a global overview on the issue of drugs and driving covering four major areas: (1) Epidemiology and Prevalence-which reviews epidemiological research, summarizes available information, discusses the methodological shortcomings of extant studies, and makes recommendations for

  15. Safe driving for teens

    Science.gov (United States)

    ... a problem for all drivers. Do not use cell phones for talking, texting, or email when you are ... Disease Control and Prevention (CDC). Driving among high school students - United States, 2013. MMWR Morb Mortal Wkly ...

  16. Science of driving.

    Science.gov (United States)

    2016-08-01

    The Science of Driving project focused on developing a collaborative relationship to develop curriculum units for middle school and high school students to engage them in exciting real-world scenarios. This effort involved faculty, staff, and student...

  17. The IRE1/bZIP60 pathway and bax inhibitor 1 suppress systemic accumulation of potyviruses and potexviruses in Arabidopsis and Nicotiana benthamiana Plants

    DEFF Research Database (Denmark)

    Gaguancela, Omar Arias; Zúñiga, Lizbeth Peña; Arias, Alexis Vela

    2016-01-01

    The inositol requiring enzyme (IRE1) is an endoplasmic reticulum (ER) stress sensor. When activated, it splices the bZIP60 mRNA, producing a truncated transcription factor that upregulates genes involved in the unfolded protein response. Bax inhibitor 1 (BI-1) is another ER stress sensor....... benthamiana. PVX-GFP and PVY-GFP accumulation was significantly elevated in these silenced plants compared with control plants. This study demonstrates that two ER stress pathways, namely IRE1/bZIP60 and the BI-1 pathway, limit systemic accumulation of potyvirus and potexvirus infection. Silencing BI-1...... expression also resulted in systemic necrosis. These data suggest that ER stress-activated pathways, led by IRE1 and BI-1, respond to invading potyvirus and potexviruses to restrict virus infection and enable physiological changes enabling plants to tolerate virus assault....

  18. Driving risk and Accidents

    OpenAIRE

    Sagaspe, P; Philip, P.

    2007-01-01

    For many years fatigue has been associated with an increased risk of accidents, but the causes were unclear. Work or driving that is extensive or conducted during the night-time hours is associated with accidents but few reports have differentiated fatigue, which is usually seen as owing to driving time, from sleepiness, which is owing to reduced sleep extended time awake or being awake at the circadian trough, or drugs. Epidemiological studies from the1990s showed that sleep-related accident...

  19. Microlinear piezo drive experiments

    OpenAIRE

    Azin, A. V.; Bogdanov, Evgeny Petrovich; Rikkonen, S. V.; PONOMAREV S.V.; Khramtsov, A. M.

    2017-01-01

    The article embraces the experimental description of the micro linear piezo drive intended for the peripheral cord tensioner in the reflecting surface shape regulator system for large-sized transformable spacecraft antenna reflectors. The research target is the experimental investigation of the micro linear piezo drive to determine the stable oscillatory system operating modes which would include improved energy conversion parameters. The following points are briefly presented: test stand con...

  20. Wrong-way driving.

    OpenAIRE

    2006-01-01

    Wrong-way driving is a phenomenon that mainly happens on motorways. Although the number of wrong-way crashes is relatively limited, their consequences are much more severe than the consequences of other motorway injury crashes. The groups most often causing wrong-way driving accidents are young, inexperienced drivers and elderly drivers. Alcohol often plays a large role with the young; processing (visual) information is especially a problem with the elderly. Improved road signs and infrastruc...

  1. Instant Google Drive starter

    CERN Document Server

    Procopio, Mike

    2013-01-01

    This book is a Starter which teaches you how to use Google Drive practically. This book is perfect for people of all skill levels who want to enjoy the benefits of using Google Drive to safely store their files online and in the cloud. It's also great for anyone looking to learn more about cloud computing in general. Readers are expected to have an Internet connection and basic knowledge of using the internet.

  2. Driving Schools Buying Behavior

    OpenAIRE

    Mbewe, Kelvin

    2011-01-01

    The purpose of this thesis is to understand driving schools’ buying behavior when buying auto-mobiles from car dealers and to understand the motives of the people responsible for making such decisions and how driving schools prefer to acquire automobiles from car dealers. These were the main research problems that required quantitative research to conclude. The theoretical chapter of the thesis discusses the principles that influence an organization’s buying behavior, the buying center, m...

  3. Belt drive construction improvement

    Directory of Open Access Journals (Sweden)

    I.Yu. Khomenko

    2012-08-01

    Full Text Available The possibility of the traction capacity increase of the belt drive TRK is examined. This was done for the purpose of air conditioning system of passenger car with double-generator system energy supplying. Belts XPC (made by the German firm «Continental ContiTech» testing were conducted. The results confirmed the possibility of their usage in order to improve belt drive TRK characteristics.

  4. Inside Solid State Drives (SSDs)

    CERN Document Server

    Micheloni, Rino; Eshghi, Kam

    2013-01-01

    Solid State Drives (SSDs) are gaining momentum in enterprise and client applications, replacing Hard Disk Drives (HDDs) by offering higher performance and lower power. In the enterprise, developers of data center server and storage systems have seen CPU performance growing exponentially for the past two decades, while HDD performance has improved linearly for the same period. Additionally, multi-core CPU designs and virtualization have increased randomness of storage I/Os. These trends have shifted performance bottlenecks to enterprise storage systems. Business critical applications such as online transaction processing, financial data processing and database mining are increasingly limited by storage performance. In client applications, small mobile platforms are leaving little room for batteries while demanding long life out of them. Therefore, reducing both idle and active power consumption has become critical. Additionally, client storage systems are in need of significant performance improvement as well ...

  5. Epilepsy and driving

    Directory of Open Access Journals (Sweden)

    Moetamedi M

    2000-09-01

    Full Text Available Epilepsy is a disease with high prevalence, which interferes driving and may lead to car accident; This case-control study has been done on 100 epileptic patients and 100 persons as control group, who had history of driving. We gathered our patients with face to face interview and registering their information in special forms which were prepared for this study. There were three times more accidents among epileptic cases comparing with control group and this difference was more considerable in men and in patients under 35 years old. The cause of accident were not seizure attack in more than 60% of the patients and these ordinary accidents were also more in case group. Epileptic patients with history of car accidents during driving had poor drug compliance comparing with the epileptics without history of an accident so drug compliance may be valuable in predicting accident in these patients. We have also found poor drug compliance in whom seizure attacks caused accident for them. 58% of the epileptics had not consulted their physician about driving. 43.3% of seizures during driving were of generalized type and none of the patients had inform police about their disease during getting driving license.

  6. Association between alcohol-impaired driving enforcement-related strategies and alcohol-impaired driving.

    Science.gov (United States)

    Sanem, Julia R; Erickson, Darin J; Rutledge, Patricia C; Lenk, Kathleen M; Nelson, Toben F; Jones-Webb, Rhonda; Toomey, Traci L

    2015-05-01

    All states in the U.S. prohibit alcohol-impaired driving but active law enforcement is necessary for effectively reducing this behavior. Sobriety checkpoints, saturation patrols, open container laws, and media campaigns related to enforcement efforts are all enforcement-related strategies for reducing alcohol-impaired driving. We conducted surveys of all state patrol agencies and a representative sample of local law enforcement agencies to assess their use of alcohol-impaired driving enforcement-related strategies and to determine the relationship between these enforcement-related strategies and self-reported alcohol-impaired driving behavior obtained from the Behavioral Risk Factor Surveillance System. We found that sobriety checkpoints, saturation patrols, and enforcement of open container laws were associated with a lower prevalence of alcohol-impaired driving but, more importantly, a combination of enforcement-related strategies was associated with a greater decrease in alcohol-impaired driving than any individual enforcement-related activity. In addition, alcohol-impaired driving enforcement-related strategies were associated with decreased alcohol-impaired driving above and beyond their association with decreased binge drinking. Results suggest law enforcement agencies should give greater priority to using a combination of strategies rather than relying on any one individual enforcement activity. Copyright © 2015 Elsevier Ltd. All rights reserved.

  7. Driving systems of scraper conveyors

    Energy Technology Data Exchange (ETDEWEB)

    Kryukov, I.V.

    1980-02-01

    About 50 types of face scraper conveyors are used in coal mines of the USSR. Various types of driving systems of scraper conveyors are described, among others: the UV-DP thyristor controlled direct current drive, AD-EhMS asynchronous drive with electro-magnetic coupling, and the AD- EhMP asynchronous drive with electro-magnetic powder clutch. These three types of scraper conveyor drive are regarded as superior to other types of drive. From among the three, the UV-DP thyristor controlled drive is the most modern but more difficult to produce and use in mines than AD-EhMP drives. (In Russian)

  8. Stability and skill in driving.

    Science.gov (United States)

    Treffner, Paul; Barrett, Rod; Petersen, Andrew

    2002-12-01

    Two experiments addressed the relation between postural stability, perceptual sensitivity, and stability of driving performance. A vehicle was fitted with differential GPS for measuring position and speed, position sensors for measuring brake and accelerator depression, force transducers for measuring door, console and footrest bracing forces, and an accelerometer for measuring the 3D accelerations of the vehicle. In Experiment 1, we investigated whether the initiation of deceleration and the control of braking might be due to sensitivity to the perceptual variable tau, which specifies time-to-contact (TTC), and in particular, whether its first derivative, tau-dot, is used to maintain a constant deceleration profile. Using both untrained experienced drivers (EDs) and trained driving instructors from the Holden Performance Driving Centre (HPDC), results confirmed that, regardless of skill level, tau-dot was maintained at a value close to 0.5 and, as predicted by Lee [Perception 5 (1976) 437], braking was initiated when TTC approximately 5 s. In Experiment 2, we wished to quantify the purported differences in driving behaviour between EDs and HPDC instructors during a variety of everyday manoeuvres. Results indicated that instructors utilised a different cornering trajectory, a different emergency braking strategy, and were able to perform a high-speed swerve and recovery task more effectively than the EDs. In general, the instructors applied greater bracing forces using the door and console compared with EDs. The instructors also applied greater footrest forces during emergency braking than did the EDs. The greater use of bracing by instructor drivers to resist g-forces represents a strategy of active stabilisation that enhances both postural stability, as well as overall stability and consistency of driving performance. Results are discussed with regard to the dynamics of perceptual-motor coordination, and how increased stability might improve sensitivity to

  9. Improvement in Brightness Uniformity by Compensating for the Threshold Voltages of Both the Driving Thin-Film Transistor and the Organic Light-Emitting Diode for Active-Matrix Organic Light-Emitting Diode Displays

    Directory of Open Access Journals (Sweden)

    Ching-Lin Fan

    2014-01-01

    Full Text Available This paper proposes a novel pixel circuit design and driving method for active-matrix organic light-emitting diode (AM-OLED displays that use low-temperature polycrystalline-silicon thin-film transistors (LTPS-TFTs as driving element. The automatic integrated circuit modeling simulation program with integrated circuit emphasis (AIM-SPICE simulator was used to verify that the proposed pixel circuit, which comprises five transistors and one capacitor, can supply uniform output current. The voltage programming method of the proposed pixel circuit comprises three periods: reset, compensation with data input, and emission periods. The simulated results reflected excellent performance. For instance, when ΔVTH=±0.33 V, the average error rate of the OLED current variation was low (<0.8%, and when ΔVTH_OLED=+0.33 V, the error rate of the OLED current variation was 4.7%. Moreover, when the I×R (current × resistance drop voltage of a power line was 0.3 V, the error rate of the OLED current variation was 5.8%. The simulated results indicated that the proposed pixel circuit exhibits high immunity to the threshold voltage deviation of both the driving poly-Si TFTs and OLEDs, and simultaneously compensates for the I×R drop voltage of a power line.

  10. Allele-specific imbalance of oxidative stress-induced growth inhibitor 1 associates with progression of hepatocellular carcinoma.

    Science.gov (United States)

    Liu, Ming; Li, Yan; Chen, Leilei; Chan, Tim Hon Man; Song, Yangyang; Fu, Li; Zeng, Ting-Ting; Dai, Yong-Dong; Zhu, Ying-Hui; Li, Yan; Chen, Juan; Yuan, Yun-Fei; Guan, Xin-Yuan

    2014-04-01

    Although there are a few highly penetrant mutations that are linked directly to cancer initiation, more less-penetrant susceptibility alleles have been associated with cancer risk and progression. We used RNA sequence analysis to search for genetic variations associated with pathogenesis of hepatocellular carcinoma (HCC). We analyzed 400 paired HCC and adjacent nontumor tissues, along with clinical information, from patients who underwent surgery at Sun Yat-Sen University in Guangzhou, China. Total RNA was extracted from tissues and sequenced, and variations with allele imbalance were identified. Effects of variants on cell functions were investigated in HCC cell lines and tumor xenografts in mice. Variants were associated with patient outcomes. We found a high proportion of allele imbalance in genes related to cellular stress. A nucleotide variation in the Oxidative Stress-Induced Growth Inhibitor 1 (OSGIN1) gene (nt 1494: G-A) resulted in an amino acid substitution (codon 438: Arg-His). The variant form of OSGIN1 was specifically retained in the tumor tissues. Functional assays showed that the common form of OSGIN1 functioned as a tumor suppressor, sensitizing HCC cells to chemotherapeutic agents by inducing apoptosis. However, the variant form of OSGIN1 was less effective. It appeared to affect the translocation of OSGIN1 from the nucleus to mitochondria, which is important for its apoptotic function. The expression pattern and localization of OSGIN1 was altered in HCC specimens, compared with adjacent liver tissue. Levels of OSGIN1 messenger RNA were reduced in 24.7% of HCC specimens, and down-regulation was associated with shorter overall and disease-free survival times of patients. Patients with the OSGIN1 1494A variant had the shortest mean survival time (32.68 mo) among patient subgroups, and their tumor samples had the lowest apoptotic index. We identified OSGIN1 as a tumor suppressor that is down-regulated or altered in human HCCs. Variants of OSGIN1

  11. Longitudinal Analysis of Undergraduate E-book Use Finds that Knowledge of Local Communities Drives Format Selection and Collection Development Activities

    Directory of Open Access Journals (Sweden)

    Melissa Goertzen

    2017-03-01

    , digital rights management (DRM restrictions created extreme frustration and were said to impede work. In some cases, students created workarounds for the purpose of accessing information in a usable form. This included visiting file sharing sites like Pirate Bay in order to locate DRM free content. Findings demonstrated a significant increase in student e-book use over the course of four years. However, this trend did not correspond to increased levels of sophistication in e-book use or facility with build-in functions on e-book platforms. The researchers discovered that students create workarounds instead of seeking out menu options that save time in the long run. This behaviour was consistent across the study group regardless of individual levels of experience working with e-books. Students commented that additional features slow down work rather than creating efficiency. For instance, when keyboard shortcuts used to copy and paste text did not function, students preferred to type out a passage rather than spend time searching for copy functions available on the e-book platform. Conclusion – Academic e-books continue to evolve in a fluid and dynamic environment. While the researchers saw improvements over the course of four years (e.g., fewer DRM restrictions access barriers remain, such as required authentication to access platform content. They also identified areas where training sessions lead by librarians could demonstrate how e-books support student research and learning activities. The researchers also found that user experiences are local in nature and specific to campus cultures and expectations. They concluded that knowledge of local user communities should drive book format selection. Whenever possible, libraries should provide access to multiple formats to support a variety of learning needs and research behaviours.

  12. Social Participation in Later Years: The Role of Driving Mobility.

    Science.gov (United States)

    Pristavec, Teja

    2016-05-12

    I investigate the role of driving mobility for older adults' formal and informal social participation. I expand the common driving status dichotomy using gradated driving frequency, driving change, and ride receipt to account for the complexity of driving behaviors in later years. I estimate logistic regression models using the 2011 and 2013 waves of the National Health and Aging Trends Study on a nationally representative sample of 4,359 community-dwelling older adults. I adjust models for demographic, socioeconomic, health, and social activity factors. Frequent drivers are most likely to visit friends and family, go out for enjoyment, attend religious services, and participate in organized activities compared with occasional drivers, those who ceased driving, and those who never drove. Driving frequency decrease lowers social participation. Participation does not differ between those who ceased driving and those who never drove. Persons with consistent ride access participate more than those never receiving rides. Models using a measure of driving mobility fit data better than models using dichotomous driving status. Both driving frequency and ride receipt matter for older adults' formal and informal involvement. Facilitating ride-giving and developing flexible transportation options may enhance social participation among older adults who cease or begin ceasing to drive. © The Author 2016. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  13. [Epilepsy and driving].

    Science.gov (United States)

    Matsuura, Masato

    2013-01-01

    The amends to the driving regulations in Japan made in 2002 lifted the absolute ban on driving by persons with epilepsy (PWE) and granted licenses to PWE after a 2-year seizure-free period. In 2010, 3,373 PWE obtained a driving license, 119 had their license withheld for compliance to traffic regulations and to reduce traffic accidents, the Japan Epilepsy Society passed a proposal of more liberal rules for fitness-to-drive on 11th October 2012; according to this proposal, people with a history of epilepsy can be declared fit-to-drive after a one-year seizure-free period. On 25th October 2012, the Japan License Authority introduced new penal regulations for PWE who do not comply with traffic regulations and proposed a voluntary notification system for a physician in charge of a non-compliant PWE. Public acceptance of these new regulations is needed for reconciliation between the attenuation of traffic accidents and the promotion of living rights of PWE in Japan.

  14. Epilepsy and driving

    Directory of Open Access Journals (Sweden)

    Matej Mavrič

    2015-05-01

    Full Text Available Epilepsy poses a risk for all participants in road traffic; therefore people with epilepsy do not meet the criteria for an unlimited driving license. Their driving is affected not only by epileptic seizures causing impaired consciousness and involuntary movements, but also by antiepileptic drugs with their many unwanted affects. The experts have not yet agreed on whether people with epilepsy have an increased risk of experiencing a road traffic accident. However, recent data suggests that the overall risk is lower compared to other medical conditions. Scientific evidence forms the basis of legislation, which by limiting people with epilepsy, enables all participants in road traffic to drive in the safest possible environment. The legislation that governs epilepsy and driving in Slovenia has been recently thoroughly reformed and thus allows a less discriminatory management of people with epilepsy. Although people with epilepsy experience many issues in their daily life, including their personal relationships and employment, they often list the need for driving as a top concern in surveys. General physicians play an important role in managing the issues of people with epilepsy.

  15. Gears and gear drives

    CERN Document Server

    Jelaska, Damir T

    2012-01-01

    Understanding how gears are formed and how they interact or 'mesh' with each other is essential when designing equipment that uses gears or gear trains. The way in which gear teeth are formed and how they mesh is determined by their geometry and kinematics, which is the topic of this book.  Gears and Gear Drives provides the reader with comprehensive coverage of gears and gear drives. Spur, helical, bevel, worm and planetary gears are all covered, with consideration given to their classification, geometry, kinematics, accuracy control, load capacity and manufacturing. Cylindric

  16. Practice Safe Driving.

    Science.gov (United States)

    2017-07-01

    More than 30,000 people die in motor vehicle collisions each year in the United States. Distracted, drowsy, and drunk driving cause most motor vehicle collision injuries and deaths. An editorial published in the October 2016 issue of JOSPT identified the global need for effective strategies to reduce, if not eliminate, preventable injuries, including whiplash-associated disorders and deaths from distracted driving. This is a call to action for everyone who gets behind the wheel of a car. J Orthop Sports Phys Ther 2017;47(7):449. doi:10.2519/jospt.2017.0506.

  17. Toroidal drive with half stator

    Directory of Open Access Journals (Sweden)

    Lizhong Xu

    2015-06-01

    Full Text Available The toroidal drive can transmit large torque. However, it is a hard work to produce small toroidal stator which limits the miniaturization of the toroidal drive. Here, a novel toroidal drive with half stator is proposed for which the small stator can be produced easily. For the novel toroidal drive, three-dimensional design and the motion simulation are done; the forces and the contact stress in drive system are investigated; and the output torque is compared with one of the normal toroidal drives. Results show that the output torque of the toroidal drive with half stator is almost the same as the output torque of the normal toroidal drive, and the half stator toroidal drive is a good design for realizing the miniaturization of the toroidal drive.

  18. Complex patterns of synchrony in networks undergoing exogenous drive

    Science.gov (United States)

    Waddell, Jack; Zochowski, Michal

    2007-03-01

    It has been established that various exogenous oscillatory drives modulate neural activity (and potentially information processing) in the brain. We explore the effect of an exogenous drive on the spatio-temporal pattern formation of a network of coupled non-identical R"ossler oscillators. We investigate the formation and properties of the phase locked states, dependent on the network properties as well as those of the external drive. We have found that such drive has a complex effect on the pattern formation in the network, depending on the coupling strength between the oscillators, drive strength as well as its frequency relative to the oscillators.

  19. Comparing Expert and Novice Driving Behavior in a Driving Simulator

    Directory of Open Access Journals (Sweden)

    Hiran B. Ekanayake

    2014-02-01

    Full Text Available This paper presents a study focused on comparing driving behavior of expert and novice drivers in a mid-range driving simulator with the intention of evaluating the validity of driving simulators for driver training. For the investigation, measurements of performance, psychophysiological measurements, and self-reported user experience under different conditions of driving tracks and driving sessions were analyzed. We calculated correlations between quantitative and qualitative measures to enhance the reliability of the findings. The experiment was conducted involving 14 experienced drivers and 17 novice drivers. The results indicate that driving behaviors of expert and novice drivers differ from each other in several ways but it heavily depends on the characteristics of the task. Moreover, our belief is that the analytical framework proposed in this paper can be used as a tool for selecting appropriate driving tasks as well as for evaluating driving performance in driving simulators.

  20. Electric-Drive Vehicles

    Energy Technology Data Exchange (ETDEWEB)

    Septon, Kendall K [National Renewable Energy Laboratory (NREL), Golden, CO (United States)

    2017-09-11

    Electric-drive vehicles use electricity as their primary fuel or to improve the efficiency of conventional vehicle designs. These vehicles can be divided into three categories: Hybrid electric vehicles (HEVs), Plug-in hybrid electric vehicles (PHEVs), All-electric vehicles (EVs). Together, PHEVs and EVs can also be referred to as plug-in electric vehicles (PEVs).

  1. Chaos in drive systems

    Directory of Open Access Journals (Sweden)

    Kratochvíl C.

    2007-10-01

    Full Text Available The purpose of this article is to provide an elementary introduction to the subject of chaos in the electromechanical drive systems. In this article, we explore chaotic solutions of maps and continuous time systems. These solutions are also bounded like equilibrium, periodic and quasiperiodic solutions.

  2. To study propulsion drives

    OpenAIRE

    Rassylkin, Anton; Vodovozov, Valery

    2013-01-01

    This paper describes a test bench developed to study and monitor the propulsion drives of electric vehicles at Tallinn University of Technology. The composition and performance of the setup are explained. The charging process of the supercapacitor bank is described as an example of the test bench application. The developed simulation model of the supercapacitor bank is presented and discussed.

  3. Drive-Through Training

    Science.gov (United States)

    Carter, Margie

    2010-01-01

    In this article, the author discusses how the early childhood field's approach to staff training reflects the drive-through, fast-food culture. Year after year directors send their teachers to workshops to get some quick refresher techniques. The author suggests that rather than focusing professional development on topics, focus on observing…

  4. Driving While Intoxicated.

    Science.gov (United States)

    Brick, John

    Alcohol intoxication increases the risk of highway accidents, the relative risk of crash probability increasing as a function of blood alcohol content (BAC). Because alcohol use is more prevalent than use of other drugs, more is known about the relationship between alcohol use and driving. Most states presume a BAC of .10% to be evidence of drunk…

  5. Gaze-controlled Driving

    DEFF Research Database (Denmark)

    Tall, Martin; Alapetite, Alexandre; San Agustin, Javier

    2009-01-01

    We investigate if the gaze (point of regard) can control a remote vehicle driving on a racing track. Five different input devices (on-screen buttons, mouse-pointing low-cost webcam eye tracker and two commercial eye tracking systems) provide heading and speed control on the scene view transmitted...

  6. Electric-Drive Vehicles

    Energy Technology Data Exchange (ETDEWEB)

    None

    2017-09-01

    Electric-drive vehicles use electricity as their primary fuel or to improve the efficiency of conventional vehicle designs. These vehicles can be divided into three categories: Hybrid electric vehicles (HEVs), Plug-in hybrid electric vehicles (PHEVs), All-electric vehicles (EVs). Together, PHEVs and EVs can also be referred to as plug-in electric vehicles (PEVs).

  7. Bax-inhibitor-1 knockdown phenotypes are suppressed by Buffy and exacerbate degeneration in a Drosophila model of Parkinson disease.

    Science.gov (United States)

    M'Angale, P Githure; Staveley, Brian E

    2017-01-01

    Bax inhibitor-1 (BI-1) is an evolutionarily conserved cytoprotective transmembrane protein that acts as a suppressor of Bax-induced apoptosis by regulation of endoplasmic reticulum stress-induced cell death. We knocked down BI-1 in the sensitive dopa decarboxylase (Ddc) expressing neurons of Drosophila melanogaster to investigate its neuroprotective functions. We additionally sought to rescue the BI-1-induced phenotypes by co-expression with the pro-survival Buffy and determined the effect of BI-1 knockdown on the neurodegenerative α-synuclein-induced Parkinson disease (PD) model. We used organismal assays to assess longevity of the flies to determine the effect of the altered expression of BI-1 in the Ddc-Gal4-expressing neurons by employing two RNAi transgenic fly lines. We measured the locomotor ability of these RNAi lines by computing the climbing indices of the climbing ability and compared them to a control line that expresses the lacZ transgene. Finally, we performed biometric analysis of the developing eye, where we counted the number of ommatidia and calculated the area of ommatidial disruption. The knockdown of BI-1 in these neurons was achieved under the direction of the Ddc-Gal4 transgene and resulted in shortened lifespan and precocious loss of locomotor ability. The co-expression of Buffy, the Drosophila anti-apoptotic Bcl-2 homologue, with BI-1-RNAi resulted in suppression of the reduced lifespan and impaired climbing ability. Expression of human α-synuclein in Drosophila dopaminergic neurons results in neuronal degeneration, accompanied by the age-dependent loss in climbing ability. We exploited this neurotoxic system to investigate possible BI-1 neuroprotective function. The co-expression of α-synuclein with BI-1-RNAi results in a slight decrease in lifespan coupled with an impairment in climbing ability. In supportive experiments, we employed the neuron-rich Drosophila compound eye to investigate subtle phenotypes that result from altered gene

  8. Bax-inhibitor-1 knockdown phenotypes are suppressed by Buffy and exacerbate degeneration in a Drosophila model of Parkinson disease

    Directory of Open Access Journals (Sweden)

    P. Githure M’Angale

    2017-02-01

    Full Text Available Background Bax inhibitor-1 (BI-1 is an evolutionarily conserved cytoprotective transmembrane protein that acts as a suppressor of Bax-induced apoptosis by regulation of endoplasmic reticulum stress-induced cell death. We knocked down BI-1 in the sensitive dopa decarboxylase (Ddc expressing neurons of Drosophila melanogaster to investigate its neuroprotective functions. We additionally sought to rescue the BI-1-induced phenotypes by co-expression with the pro-survival Buffy and determined the effect of BI-1 knockdown on the neurodegenerative α-synuclein-induced Parkinson disease (PD model. Methods We used organismal assays to assess longevity of the flies to determine the effect of the altered expression of BI-1 in the Ddc-Gal4-expressing neurons by employing two RNAi transgenic fly lines. We measured the locomotor ability of these RNAi lines by computing the climbing indices of the climbing ability and compared them to a control line that expresses the lacZ transgene. Finally, we performed biometric analysis of the developing eye, where we counted the number of ommatidia and calculated the area of ommatidial disruption. Results The knockdown of BI-1 in these neurons was achieved under the direction of the Ddc-Gal4 transgene and resulted in shortened lifespan and precocious loss of locomotor ability. The co-expression of Buffy, the Drosophila anti-apoptotic Bcl-2 homologue, with BI-1-RNAi resulted in suppression of the reduced lifespan and impaired climbing ability. Expression of human α-synuclein in Drosophila dopaminergic neurons results in neuronal degeneration, accompanied by the age-dependent loss in climbing ability. We exploited this neurotoxic system to investigate possible BI-1 neuroprotective function. The co-expression of α-synuclein with BI-1-RNAi results in a slight decrease in lifespan coupled with an impairment in climbing ability. In supportive experiments, we employed the neuron-rich Drosophila compound eye to investigate

  9. Automated Driving System Architecture to Ensure Safe Delegation of Driving Authority

    Science.gov (United States)

    YUN, Sunkil; NISHIMURA, Hidekazu

    2016-09-01

    In this paper, the architecture of an automated driving system (ADS) is proposed to ensure safe delegation of driving authority between the ADS and a driver. Limitations of the ADS functions may activate delegation of driving authority to a driver. However, it leads to severe consequences in emergency situations where a driver may be drowsy or distracted. To address these issues, first, the concept model for the ADS in the situation for delegation of driving authority is described taking the driver's behaviour and state into account. Second, the behaviour / state of a driver and functional flow / state of ADS and the interactions between them are modelled to understand the context where the ADS requests to delegate the driving authority to a driver. Finally, the proposed architecture of the ADS is verified under the simulations based on the emergency braking scenarios. In the verification process using simulation, we have derived the necessary condition for safe delegation of driving authority is that the ADS should assist s driver even after delegating driving authority to a driver who has not enough capability to regain control of the driving task.

  10. Can We Study Autonomous Driving Comfort in Moving-Base Driving Simulators? A Validation Study.

    Science.gov (United States)

    Bellem, Hanna; Klüver, Malte; Schrauf, Michael; Schöner, Hans-Peter; Hecht, Heiko; Krems, Josef F

    2017-05-01

    To lay the basis of studying autonomous driving comfort using driving simulators, we assessed the behavioral validity of two moving-base simulator configurations by contrasting them with a test-track setting. With increasing level of automation, driving comfort becomes increasingly important. Simulators provide a safe environment to study perceived comfort in autonomous driving. To date, however, no studies were conducted in relation to comfort in autonomous driving to determine the extent to which results from simulator studies can be transferred to on-road driving conditions. Participants ( N = 72) experienced six differently parameterized lane-change and deceleration maneuvers and subsequently rated the comfort of each scenario. One group of participants experienced the maneuvers on a test-track setting, whereas two other groups experienced them in one of two moving-base simulator configurations. We could demonstrate relative and absolute validity for one of the two simulator configurations. Subsequent analyses revealed that the validity of the simulator highly depends on the parameterization of the motion system. Moving-base simulation can be a useful research tool to study driving comfort in autonomous vehicles. However, our results point at a preference for subunity scaling factors for both lateral and longitudinal motion cues, which might be explained by an underestimation of speed in virtual environments. In line with previous studies, we recommend lateral- and longitudinal-motion scaling factors of approximately 50% to 60% in order to obtain valid results for both active and passive driving tasks.

  11. Lower hybrid current drive in tokamak plasmas

    Energy Technology Data Exchange (ETDEWEB)

    Ushigusa, Kenkichi [Japan Atomic Energy Research Inst., Naka, Ibaraki (Japan). Naka Fusion Research Establishment

    1999-03-01

    Past ten years progress on Lower Hybrid Current Drive (LHCD) experiments have demonstrated the largest non-inductive current (3.6 MA, JT-60U), the longest current sustainment (2 hours, TRIAM-1M), non-inductive current drive at the highest density (n-bar{sub e} - 10{sup 20}m{sup -3}, ALCATOR-C) and the highest current drive efficiency ({eta}{sub CD} = 3.5x10{sup 19} m{sup -2}A/W, JT-60). These results indicate that LHCD is one of the most promising methods to drive non-inductive current in the present tokamak plasmas. This paper presents recent experimental results on LHCD experiments. Basic theories of LH waves, the wave propagation and the current drive are briefly summarized. The main part of this paper describes several important results and their physical pictures on recent LHCD experiments; 1) the experimental set-up, 2) the current drive efficiency, 3) the control of current profile and MHD activities, 4) the global energy confinement, 5) the global power flow, 6) fast electron behavior, 7) interaction between LH waves and thermal/fast ions, 8) combination with other CD method. (author)

  12. Driving and engine cycles

    CERN Document Server

    Giakoumis, Evangelos G

    2017-01-01

    This book presents in detail the most important driving and engine cycles used for the certification and testing of new vehicles and engines around the world. It covers chassis and engine-dynamometer cycles for passenger cars, light-duty vans, heavy-duty engines, non-road engines and motorcycles, offering detailed historical information and critical review. The book also provides detailed examples from SI and diesel engines and vehicles operating during various cycles, with a focus on how the engine behaves during transients and how this is reflected in emitted pollutants, CO2 and after-treatment systems operation. It describes the measurement methods for the testing of new vehicles and essential information on the procedure for creating a driving cycle. Lastly, it presents detailed technical specifications on the most important chassis-dynamometer cycles around the world, together with a direct comparison of those cycles.

  13. Drive-by-Downloads

    Energy Technology Data Exchange (ETDEWEB)

    Narvaez, Julia; Endicott-Popovsky, Barbara E.; Seifert, Christian; Aval, Chiraag U.; Frincke, Deborah A.

    2010-02-01

    Abstract: Drive-by-downloads are malware that push, and then execute, malicious code on a client system without the user's consent. The purpose of this paper is to introduce a discussion of the usefulness of antivirus software for detecting the installation of such malware, providing groundwork for future studies. Client honeypots collected drive-by malware which was then evaluated using common antivirus products. Initial analysis showed that most of such antivirus products identified less than 70% of these highly polymorphic malware programs. Also, it was observed that the antivirus products tested, even when successfully detecting this malware, often failed to classify it, leading to the conclusion that further work could involve not only developing new behavioral detection technologies, but also empirical studies that improve general understanding of these threats. Toward that end, one example of malicious code was analyzed behaviorally to provide insight into next steps for the future direction of this research.

  14. The influence of music on mood and performance while driving.

    Science.gov (United States)

    van der Zwaag, Marjolein D; Dijksterhuis, Chris; de Waard, Dick; Mulder, Ben L J M; Westerink, Joyce H D M; Brookhuis, Karel A

    2012-01-01

    Mood can influence our everyday behaviour and people often seek to reinforce, or to alter their mood, for example by turning on music. Music listening while driving is a popular activity. However, little is known about the impact of music listening while driving on physiological state and driving performance. In the present experiment, it was investigated whether individually selected music can induce mood and maintain moods during a simulated drive. In addition, effects of positive, negative, and no music on driving behaviour and physiological measures were assessed for normal and high cognitive demanding rides. Subjective mood ratings indicated that music successfully maintained mood while driving. Narrow lane width drives increased task demand as shown in effort ratings and increased swerving. Furthermore, respiration rate was lower during music listening compared to rides without music, while no effects of music were found on heart rate. Overall, the current study demonstrates that music listening in car influences the experienced mood while driving, which in turn can impact driving behaviour. PRACTITIONERS SUMMARY: Even though it is a popular activity, little is known about the impact of music while driving on physiological state and performance. We examined whether music can induce moods during high and low simulated drives. The current study demonstrates that in car music listening influences mood which in turn can impact driving behaviour. The current study shows that listening to music can positively impact mood while driving, which can be used to affect state and safe behaviour. Additionally, driving performance in high demand situations is not negatively affected by music.

  15. Sex Chromosome Drive

    OpenAIRE

    Helleu, Quentin; Gérard, Pierre R.; Montchamp-Moreau, Catherine

    2015-01-01

    Sex chromosome drivers are selfish elements that subvert Mendel's first law of segregation and therefore are overrepresented among the products of meiosis. The sex-biased progeny produced then fuels an extended genetic conflict between the driver and the rest of the genome. Many examples of sex chromosome drive are known, but the occurrence of this phenomenon is probably largely underestimated because of the difficulty to detect it. Remarkably, nearly all sex chromosome drivers are found in t...

  16. Parkinson's disease and driving ability.

    Science.gov (United States)

    Singh, Rajiv; Pentland, Brian; Hunter, John; Provan, Frances

    2007-04-01

    To explore the driving problems associated with Parkinson's disease (PD) and to ascertain whether any clinical features or tests predict driver safety. The driving ability of 154 individuals with PD referred to a driving assessment centre was determined by a combination of clinical tests, reaction times on a test rig and an in-car driving test. The majority of cases (104, 66%) were able to continue driving although 46 individuals required an automatic transmission and 10 others needed car modifications. Ability to drive was predicted by the severity of physical disease, age, presence of other associated medical conditions, particularly dementia, duration of disease, brake reaction, time on a test rig and score on a driving test (all pdriving history were not correlated. Discriminant analysis revealed that the most important features in distinguishing safety to drive were severe physical disease (Hoehn and Yahr stage 3), reaction time, moderate disease associated with another medical condition and high score on car testing. Most individuals with PD are safe to drive, although many benefit from car modifications or from using an automatic transmission. A combination of clinical tests and in-car driving assessment will establish safety to drive, and a number of clinical correlates can be shown to predict the likely outcome and may assist in the decision process. This is the largest series of consecutive patients seen at a driving assessment centre reported to date, and the first to devise a scoring system for on-road driving assessment.

  17. Marijuana and actual driving performance

    Science.gov (United States)

    1993-11-01

    This report concerns the effects of marijuana smoking on actual driving performance. It presents the results of one pilot and three actual driving studies. The pilot study's major purpose was to establish the THC dose current marijuana users smoke to...

  18. Drunk driving among novice drivers, possible prevention with additional psychological module in driving school curriculum.

    Science.gov (United States)

    Eensoo, Diva; Paaver, Marika; Harro, Jaanus

    2011-01-01

    Road traffic collisions caused by drunk driving pose a significant public health problem all over the world. Therefore additional preventive activities against drunk driving should be worked out. The aim of the study was to assess drunk driving in novice drivers after a psychological intervention taking into account also impulsivity, law obedience, and alcohol-related measures. An intervention study was started with 1889 car driver's license attempters during their driving school studies. Subjects were classified as intervention group (n=1083, mean age 23.1 (SD=7.4) years), control group (n=517, mean age 22.8 (SD=7.1) years) and "lost" group (n=289, mean age 23.0 (SD=6.9) years). "Lost" group subjects had been assigned into the intervention group, but they did not participate in the intervention. Subjects of the intervention group participated in a psychological intervention on the dangers of impulsive behavior in traffic. After a three year follow-up period it appeared that in the control group and in the lost group there was a significantly higher proportion of drunk drivers than in the intervention group, 3.3% (n=17), 3.5% (n=10) and 1.5% (n=10) (p=0.026), respectively. Survival analysis confirmed that psychological intervention had a significant impact on drunk driving (p=0.015), and the impact of the intervention was persistent also in the case of higher scores in Mild social deviance. In subjects with higher scores in impulsivity measures and alcohol-related problems the impact of short psychological intervention was not sufficient for preventing drunk driving. It can be concluded that psychological intervention used during the driving school studies is an effective primary prevention activity against drunk driving. However, for drivers with high scores in impulsivity measures and alcohol-related problems, the short psychological intervention is not sufficient in reducing drunk driving behavior.

  19. Drive system failure control for distributed drive electric vehicles

    Science.gov (United States)

    Liu, Tao; Tang, Yuan; Wang, Jianfeng; Li, Yaou; Yang, Na; Liu, Yiqun

    2017-09-01

    Aiming at the failure problem of distributed electric drive vehicle, the conventional control strategy of drive system failure is designed according to the characteristics of each wheel torque independent control and the redundant configuration of the power unit. On this basis, combined with the traditional body stability control technology, the direct yaw moment control method is used. The simulation results show that the conventional control method designed of the drive system failure can effectively improve the driving condition of the vehicle. The driving stability of the vehicle is further improved after the direct yaw torque control is applied.

  20. Impaired Driving. Prevention Resource Guide.

    Science.gov (United States)

    Lane, Amy

    This booklet focuses on impaired driving. The first section presents 21 facts on impaired driving. These include the number of people who lost their lives in alcohol-related crashes; the leading cause of death for young people; the average amount of alcohol consumed by people arrested for driving under the influence; the estimation that a tax…

  1. TLR3 is required for survival following Coxsackievirus B3 infection by driving T lymphocyte activation and polarization: The role of dendritic cells

    National Research Council Canada - National Science Library

    Renata Sesti-Costa; Marcela Cristina Santiago Françozo; Grace Kelly Silva; José Luiz Proenca-Modena; João Santana Silva

    2017-01-01

    .... In the current study, we found that TLR3 expression in dendritic cells plays a role in their activation upon CVB3 infection in vitro, as TLR3-deficient dendritic cells up-regulate CD80 and CD86...

  2. High mTORC1 activity drives glycolysis addiction and sensitivity to G6PD inhibition in acute myeloid leukemia cells.

    Science.gov (United States)

    Poulain, L; Sujobert, P; Zylbersztejn, F; Barreau, S; Stuani, L; Lambert, M; Palama, T L; Chesnais, V; Birsen, R; Vergez, F; Farge, T; Chenevier-Gobeaux, C; Fraisse, M; Bouillaud, F; Debeissat, C; Herault, O; Récher, C; Lacombe, C; Fontenay, M; Mayeux, P; Maciel, T T; Portais, J-C; Sarry, J-E; Tamburini, J; Bouscary, D; Chapuis, N

    2017-11-01

    Alterations in metabolic activities are cancer hallmarks that offer a wide range of new therapeutic opportunities. Here we decipher the interplay between mTORC1 activity and glucose metabolism in acute myeloid leukemia (AML). We show that mTORC1 signaling that is constantly overactivated in AML cells promotes glycolysis and leads to glucose addiction. The level of mTORC1 activity determines the sensitivity of AML cells to glycolysis inhibition as switch-off mTORC1 activity leads to glucose-independent cell survival that is sustained by an increase in mitochondrial oxidative phosphorylation. Metabolic analysis identified the pentose phosphate pathway (PPP) as an important pro-survival pathway for glucose metabolism in AML cells with high mTORC1 activity and provided a clear rational for targeting glucose-6-phosphate dehydrogenase (G6PD) in AML. Indeed, our analysis of the cancer genome atlas AML database pinpointed G6PD as a new biomarker in AML, as its overexpression correlated with an adverse prognosis in this cohort. Targeting the PPP using the G6PD inhibitor 6-aminonicotinamide induces in vitro and in vivo cytotoxicity against AML cells and synergistically sensitizes leukemic cells to chemotherapy. Our results demonstrate that high mTORC1 activity creates a specific vulnerability to G6PD inhibition that may work as a new AML therapy.

  3. Offset Compound Gear Drive

    Science.gov (United States)

    Stevens, Mark A.; Handschuh, Robert F.; Lewicki, David G.

    2010-01-01

    The Offset Compound Gear Drive is an in-line, discrete, two-speed device utilizing a special offset compound gear that has both an internal tooth configuration on the input end and external tooth configuration on the output end, thus allowing it to mesh in series, simultaneously, with both a smaller external tooth input gear and a larger internal tooth output gear. This unique geometry and offset axis permits the compound gear to mesh with the smaller diameter input gear and the larger diameter output gear, both of which are on the same central, or primary, centerline. This configuration results in a compact in-line reduction gear set consisting of fewer gears and bearings than a conventional planetary gear train. Switching between the two output ratios is accomplished through a main control clutch and sprag. Power flow to the above is transmitted through concentric power paths. Low-speed operation is accomplished in two meshes. For the purpose of illustrating the low-speed output operation, the following example pitch diameters are given. A 5.0 pitch diameter (PD) input gear to 7.50 PD (internal tooth) intermediate gear (0.667 reduction mesh), and a 7.50 PD (external tooth) intermediate gear to a 10.00 PD output gear (0.750 reduction mesh). Note that it is not required that the intermediate gears on the offset axis be of the same diameter. For this example, the resultant low-speed ratio is 2:1 (output speed = 0.500; product of stage one 0.667 reduction and stage two 0.750 stage reduction). The design is not restricted to the example pitch diameters, or output ratio. From the output gear, power is transmitted through a hollow drive shaft, which, in turn, drives a sprag during which time the main clutch is disengaged.

  4. Belowground carbon allocation by trees drives seasonal patterns of extracellular enzyme activities by altering microbial community composition in a beech forest soil

    Science.gov (United States)

    Kaiser, Christina; Koranda, Marianne; Kitzler, Barbara; Fuchslueger, Lucia; Schnecker, Jörg; Schweiger, Peter; Rasche, Frank; Zechmeister-Boltenstern, Sophie; Sessitsch, Angela; Richter, Andreas

    2010-01-01

    Plant seasonal cycles alter carbon (C) and nitrogen (N) availability for soil microbes, which may affect microbial community composition and thus feed back on microbial decomposition of soil organic material and plant N availability. The temporal dynamics of these plant–soil interactions are, however, unclear. Here, we experimentally manipulated the C and N availability in a beech forest through N fertilization or tree girdling and conducted a detailed analysis of the seasonal pattern of microbial community composition and decomposition processes over 2 yr. We found a strong relationship between microbial community composition and enzyme activities over the seasonal course. Phenoloxidase and peroxidase activities were highest during late summer, whereas cellulase and protease peaked in late autumn. Girdling, and thus loss of mycorrhiza, resulted in an increase in soil organic matter-degrading enzymes and a decrease in cellulase and protease activity. Temporal changes in enzyme activities suggest a switch of the main substrate for decomposition between summer (soil organic matter) and autumn (plant litter). Our results indicate that ectomycorrhizal fungi are possibly involved in autumn cellulase and protease activity. Our study shows that, through belowground C allocation, trees significantly alter soil microbial communities, which may affect seasonal patterns of decomposition processes. PMID:20553392

  5. Electrical machines and drives

    CERN Document Server

    Hindmarsh, John

    2002-01-01

    Recent years have brought substantial developments in electrical drive technology, with the appearance of highly rated, very-high-speed power-electronic switches, combined with microcomputer control systems.This popular textbook has been thoroughly revised and updated in the light of these changes. It retains its successful formula of teaching through worked examples, which are put in context with concise explanations of theory, revision of equations and discussion of the engineering implications. Numerous problems are also provided, with answers supplied.The third edition in

  6. Electric drive design methodology

    CERN Document Server

    Jufer, Marcel

    2013-01-01

    An electric drive that is designed or adapted to a specific application must take into account all the elements of the chain of constituent elements in its use and deployment. In addition to the motor, the transmission, power electronics, control, sensors, and electrical protection systems must be taken into account. The motor and the transmission can be optimized and designed to obtain the best energy efficiency assessment, in particular for dynamic nodes. An inventory and a characterization of these various components is proposed as part of this book's examination and explanation

  7. Measurement of Driving Terms

    CERN Document Server

    Schmidt, F; Faus-Golfe, A

    2001-01-01

    In 2000 a series of MDs has been performed at the SPS to measure resonance driving terms. Theory predicts that these terms can be determined by harmonic analysis of BPM data recorded after applying single kicks at various amplitudes. Strong sextupoles were introduced to create a sizeable amount of nonlinearities. Experiments at injection energy (26 GeV) with single bunch as well as one experiment at 120 GeV with 84 bunches were carried out. The expected nonlinear content is compared to the experimenteal observation.

  8. Electrical machines & drives

    CERN Document Server

    Hammond, P

    1985-01-01

    Containing approximately 200 problems (100 worked), the text covers a wide range of topics concerning electrical machines, placing particular emphasis upon electrical-machine drive applications. The theory is concisely reviewed and focuses on features common to all machine types. The problems are arranged in order of increasing levels of complexity and discussions of the solutions are included where appropriate to illustrate the engineering implications. This second edition includes an important new chapter on mathematical and computer simulation of machine systems and revised discussions o

  9. Driving electrostatic transducers

    DEFF Research Database (Denmark)

    Nielsen, Dennis; Knott, Arnold; Andersen, Michael A. E.

    2013-01-01

    depended, nonlinear and high bias voltage for linearization) must be developed. This paper analyzes power stages and bias configurations suitable for driving an electrostatic transducer. Measurement results of a 300 V prototype amplifier are shown. Measuring THD across a high impedance source is discussed......Electrostatic transducers represent a very interesting alternative to the traditional inefficient electrodynamic transducers. In order to establish the full potential of these transducers, power amplifiers which fulfill the strict requirements imposed by such loads (high impedance, frequency......, and a high voltage attenuation interface for an audio analyzer is presented. THD below 0:1% is reported....

  10. Toroidal drive with half stator

    OpenAIRE

    Lizhong Xu; Linping Fu

    2015-01-01

    The toroidal drive can transmit large torque. However, it is a hard work to produce small toroidal stator which limits the miniaturization of the toroidal drive. Here, a novel toroidal drive with half stator is proposed for which the small stator can be produced easily. For the novel toroidal drive, three-dimensional design and the motion simulation are done; the forces and the contact stress in drive system are investigated; and the output torque is compared with one of the normal toroidal d...

  11. Driving on ice: impaired driving skills in current methamphetamine users.

    Science.gov (United States)

    Bosanquet, David; Macdougall, Hamish G; Rogers, Stephen J; Starmer, Graham A; McKetin, Rebecca; Blaszczynski, Alexander; McGregor, Iain S

    2013-01-01

    Previous research indicates a complex link between methamphetamine (METH) and driving performance. Acute dosing with amphetamines has improved driving-related performance in some laboratory studies, while epidemiological studies suggest an association between METH use, impaired driving, and accident culpability. Current METH users were compared to a control group of nonusers on driving simulator performance. Groups were matched for age, gender, and driving experience. Subjects were assessed for current drug use, drug dependence, and drug levels in saliva/blood as well as personality variables, sleepiness, and driving performance. METH users, most of whom met the criteria for METH dependence, were significantly more likely to speed and to weave from side to side when driving. They also left less distance between their vehicle and oncoming vehicles when making a right-hand turn. This risky driving was not associated with current blood levels of METH or its principal metabolite, amphetamine, which varied widely within the METH group. Other drugs were detected (principally low levels of THC or MDMA) in some METH users, but at levels that were unlikely to impair driving performance. There were higher levels of impulsivity and antisocial personality disorder in the METH-using cohort. These findings confirm indications from epidemiological studies of an association between METH use and impaired driving ability and provide a platform for future research to further explore the factors contributing to increased accident risk in this population.

  12. Population Growth, Energy Use, and Pollution: Understanding the Driving Forces of Global Change. Hands-On! Developing Active Learning Modules on the Human Dimensions of Global Change.

    Science.gov (United States)

    Kuby, Michael

    Since the beginning of the scientific revolution in the 1700s, the absolute scale of the human economy has increased many times over, and, with it, the impact on the natural environment. This learning module's activities introduce the student to linkages among population growth, energy use, level of economic and technological development and their…

  13. Technology as a driving force

    Energy Technology Data Exchange (ETDEWEB)

    Torvund, T. [Norsk Hydro A/S (Norway)

    1994-12-31

    The competitiveness of the Norwegian Continental shelf has been put firmly on the agenda in Norway since the report from a working group set up by the Ministry of Industry and Energy was released in February this year. If there is to be secured a long future for oil and gas activities, a reduction in the time and costs used in the projects of the order of 40-50%, without jeopardizing the high safety and environmental standards achieved in Norway. The paper addresses how technology can be a driving force in achieving these aims. But technology alone cannot do the job. Progress and changes in several other areas are also necessary, and the new scenario also calls for improved relations between all actors in the North Sea, authorities, oil companies, contractors and labour unions. 15 figs.

  14. Glaucoma and Driving: On-Road Driving Characteristics.

    Directory of Open Access Journals (Sweden)

    Joanne M Wood

    Full Text Available To comprehensively investigate the types of driving errors and locations that are most problematic for older drivers with glaucoma compared to those without glaucoma using a standardized on-road assessment.Participants included 75 drivers with glaucoma (mean = 73.2±6.0 years with mild to moderate field loss (better-eye MD = -1.21 dB; worse-eye MD = -7.75 dB and 70 age-matched controls without glaucoma (mean = 72.6 ± 5.0 years. On-road driving performance was assessed in a dual-brake vehicle by an occupational therapist using a standardized scoring system which assessed the types of driving errors and the locations where they were made and the number of critical errors that required an instructor intervention. Driving safety was rated on a 10-point scale. Self-reported driving ability and difficulties were recorded using the Driving Habits Questionnaire.Drivers with glaucoma were rated as significantly less safe, made more driving errors, and had almost double the rate of critical errors than those without glaucoma. Driving errors involved lane positioning and planning/approach, and were significantly more likely to occur at traffic lights and yield/give-way intersections. There were few between group differences in self-reported driving ability.Older drivers with glaucoma with even mild to moderate field loss exhibit impairments in driving ability, particularly during complex driving situations that involve tactical problems with lane-position, planning ahead and observation. These results, together with the fact that these drivers self-report their driving to be relatively good, reinforce the need for evidence-based on-road assessments for evaluating driving fitness.

  15. [Epilepsy and Driving].

    Science.gov (United States)

    Takagi, Shunsuke; Matsuura, Masato

    2017-10-01

    In Japan, the Road Traffic Act was amended in 2013, and the revision was enacted in 2014. This revision includes new rules such as the requirement that a driver declare medical conditions on licensing, with a penalty for false statements. There is also a new voluntary notification system that enables doctors to report unlawful drivers. At the same time, the new Criminal Law Act was enacted. This act provides a penalty for causing death or injury to other persons by driving under the influence of specific drugs or diseases, including epilepsy. There is a prison term of up to 15 years for this violation. These new laws are the result of several tragic motor vehicle accidents caused by patients with epilepsy who were unfit to drive, and severe punishments are involved. Japan still requires a longer seizure-free period for licensing of patients with epilepsy (2 or 5 years), as opposed to the shorter periods required by other developed countries (US, 3 to 12 months; EU, 12 months). It is debatable whether harsh punishments are more effective in reducing accidents. Further reevaluation and discussion are needed on this issue because a restrictive policy for handicapped persons should be based on scientific evidence and should not be biased by prejudice and discrimination.

  16. Drive for the divine

    Directory of Open Access Journals (Sweden)

    Darryl Wooldridge

    2015-03-01

    Full Text Available Although the present article stands alone, it is a continuation of ‘Living in the not-yet’ (published in vol. 71, issue 1 of HTS. Both articles are derivatives of a larger study that discusses God as the centre of an often inarticulate and inchoate but innate human desire and pursuit to enjoy and reflect the divine image (imago Dei in which every human being was created. The current article sets forth foundational considerations and speaks to the ineffaceable drive within humans to find God. It is a reciprocated drive – a response to God who first sought and continues to seek humans – a correlate and concomitant seeking in response to God. Although surely not the final word, this article discusses God as spirit and spiritual, by whom human beings have been created as imago Dei or God’s self-address, showing God’s heart as toward his creation, and humans most especially. Also discussed here is that humans are destined to join the perichoretic relationship that God has enjoyed from eternity. Moreover, in his ascension and glory, Jesus sends the Spirit of adoption into creation so that human creation might enter this same perichoretic relationship with God.

  17. Learning to drive: learners' self-reported cognitive failure level predicts driving instructor's observation rating of driving performance.

    Science.gov (United States)

    Elfering, Achim; Ruppen, Veronique; Grebner, Simone

    2013-01-01

    Evidence increases that cognitive failure may be used to screen for drivers at risk. Until now, most studies have relied on driving learners. This exploratory pilot study examines self-report of cognitive failure in driving beginners and error during real driving as observed by driving instructors. Forty-two driving learners of 14 driving instructors filled out a work-related cognitive failure questionnaire. Driving instructors observed driving errors during the next driving lesson. In multiple linear regression analysis, driving errors were regressed on cognitive failure with the number of driving lessons as an estimator of driving experience controlled. Higher cognitive failure predicted more driving errors (p < .01) when age, gender and driving experience were controlled in analysis. Cognitive failure was significantly associated with observed driving errors. Systematic research on cognitive failure in driving beginners is recommended.

  18. Age and inconsistency in driving performance.

    Science.gov (United States)

    Bunce, David; Young, Mark S; Blane, Alison; Khugputh, Priya

    2012-11-01

    Research in cognitive neuropsychology suggests that investigation of the within-person variability, or inconsistency, of cognitive performance may provide valuable insights into ageing mental processes. It is rare though, for this interest in intraindividual variability to extend to everyday activities. As this may provide important information about driving behaviour, we therefore assessed age differences in driving inconsistency in younger (n=24, M age=21.29 years) and older (n=21, M age=71.24 years) persons who drove in residential, urban and motorway conditions in a fully immersive driving simulator. In measures of headway (maintaining a safe distance to a preceding vehicle) and lateral lane position, older drivers exhibited significantly greater performance inconsistency, and this was particularly marked in the faster motorway condition. Older drivers also recorded greater perceived mental demands associated with driving, and greater within-person variability across a range of cognitive measures. The findings suggest that age-related deficits in attentional and executive control may affect the consistency of driving performance in older persons. Discussion considers interventions to introduce in-vehicle systems to help maintain attention in older drivers, and to intervene when safety-critical boundaries are exceeded. Copyright © 2012 Elsevier Ltd. All rights reserved.

  19. [Impact of ageing on driving: decline and compensatory strategies].

    Science.gov (United States)

    Suriá Martínez, Raquel; Ortigosa Quiles, Juan Manuel; Riquelme Marín, Antonio

    2015-01-01

    Driving by the elderly is a growing reality, and an activity that helps to maintain a sense of personal freedom. But the driving quality can be affected by aging. Therefore, the objective of this study is to compare the perception of a group of drivers on the age-related changes and the adjustments made in the driving depending on age. A sample of 312 drivers from 20 to 80 years-old were recruited from medical centers for renewal of driving license, as well as in license points recovery centers. The participants were given a questionnaire on driving characteristics and questionnaire on driving adjustments. There were statistically significant differences in both the perceived decline and in compensatory adjustments, noting that drivers age 65 years and older scored higher means than others. The group from 70 to 80-years-old used compensatory strategies: "Do not drive if it rains" "avoid overtaking", "Do not drive at night," "only drive in certain areas" or "park in a line". Since age influences driving, the greater use compensatory strategies lessens the impact that aging has on this skill. Copyright © 2014 SEGG. Published by Elsevier Espana. All rights reserved.

  20. Increased PKC activity and altered GSK3?/NMDAR function drive behavior cycling in HINT1-deficient mice: bipolarity or opposing forces

    OpenAIRE

    Javier Garzón-Niño; María Rodríguez-Muñoz; Elsa Cortés-Montero; Pilar Sánchez-Blázquez

    2017-01-01

    Mice with histidine triad nucleotide-binding protein 1 (HINT1) deletion exhibit manic-like symptoms that evolve into depressive-like behavior in response to stressful paradigms. Molecular and electrophysiological studies have indicated that HINT1?/? mice exhibit increased PKC, PKA, and GSK3? activities, as well as glutamate N-methyl-D-aspartate receptor (NMDAR)/?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptor (AMPAR) and NR2B/NR2A subunit ratios. Pharmacological interventions stabiliz...

  1. Driving during alcohol hangover among dutch professional truck drivers

    NARCIS (Netherlands)

    Verster, Joris C; Van Der Maarel, Martin A; McKinney, Adele; Olivier, Berend; De Haan, Lydia

    2014-01-01

    OBJECTIVES: Alcohol hangover may impair potentially dangerous daily activities such as driving a car or operating heavy machinery. The purpose of the present study was to determine (1) whether driving during alcohol hangover is a problem of concern among professional Dutch truck drivers and (2) to

  2. Changes in EEG alpha power during simulated driving: a demonstration.

    Science.gov (United States)

    Schier, M A

    2000-08-01

    The aim was to assess the suitability of EEG-based techniques to recording activity during a driving simulation task. To achieve this, an inexpensive driving simulator (comprising a steering wheel, pedals and gear shift) were made to function with a personal computer running 'Need for Speed' simulation software. Simulators of this type are both inexpensive and relatively realistic. The EEG was recorded from four sites on the scalp (P3, P4, F3, F4) for two laps during the driving task, and during a replay task. The driving task involved participants driving a vehicle on a simulated undulating, sealed surface circuit, without any other vehicles present. Two men were participants in this experiment. Power spectra were computed and integrated to produce values of relative alpha activity for each channel and recording epoch, a time-series of alpha activity during each recorded segment. Overall values for alpha activity indicated an increase for replay compared to driving, and also driving on lap 5 compared to driving on lap 2. The EEG changes are consistent with the notion of overall reduction of attention during the later laps and the replay task and indicate the potential of such measures for complex motor behaviour.

  3. Acceptance of and Engagement in Risky Driving Behaviors by Teenagers

    Science.gov (United States)

    Sarkar, Sheila; Andreas, Marie

    2004-01-01

    Data gathered from 1,430 teenage student drivers and 880 teenage traffic violators were used to examine the levels of exposure to risky driving behaviors and perceptions concerning the level of danger of such behaviors. For student drivers, 55% reported exposure to risky driving by being in a car with a driver engaging in such activities as drunk…

  4. Do We Blindly Trust Self-Driving Cars

    DEFF Research Database (Denmark)

    Andersen, Kamilla Egedal; Köslich, Simon; Pedersen, Bjarke Maigaard Kjær

    2017-01-01

    - to-day activities, such as driving a car, we carried out a series of experiments with an autonomous car simulator. Partici- pants (N=73) engaged in a scenario with no, correct or false audible information regarding the state of traffic around the self-driving vehicle, and were told they could assume...

  5. Music mood induction and maintenance while driving : A simulator study

    NARCIS (Netherlands)

    Dijksterhuis, Chris; van der Zwaag, Marjolein; de Waard, Dick; Westerink, Joyce; Brookhuis, Karel; Mulder, Ben L. J. M.

    2010-01-01

    It is common knowledge that mood can influence our everyday behaviour and people often seek to reinforce, or to alter their mood, for example by turning on music. Music listening while driving is a common activity. However, the actual impact of music listening while driving on physical state and

  6. Stroke while driving: Frequency and association with automobile accidents.

    Science.gov (United States)

    Inamasu, Joji; Nakatsukasa, Masashi; Tomiyasu, Kazuhiro; Mayanagi, Keita; Nishimoto, Masaaki; Oshima, Takeo; Yoshii, Masami; Miyatake, Satoru; Imai, Akira

    2017-01-01

    Background Cardiovascular events while driving have occasionally been reported. In contrast, there have been few studies on stroke while driving. Aim The objectives of this study were to (1) report the frequency of stroke while driving and (2) evaluate its association with automobile accidents. Methods Clinical data prospectively acquired between January 2011 and December 2016 on 2145 stroke patients (1301 with ischemic stroke, 585 with intracerebral hemorrhage, and 259 with subarachnoid hemorrhage) were reviewed to identify patients who sustained a stroke while driving. The ratio of driving to performing other activities was evaluated for each stroke type. Furthermore, the drivers' response to stroke was reviewed to understand how automobile accidents occurred. Results Among the 2145 patients, 85 (63 ischemic stroke, 20 intracerebral hemorrhage, and 2 subarachnoid hemorrhage) sustained a stroke while driving. The ratio of driving to performing other activities was significantly higher in ischemic stroke (4.8%) than in intracerebral hemorrhage (3.4%) or subarachnoid hemorrhage (0.8%). A majority of drivers either continued driving or pulled over to the roadside after suffering a stroke. However, 14 (16%) patients were involved in automobile accidents. In most patients, an altered mental status due to severe stroke was the presumed cause of the accident. Conclusion Stroke occurred while driving in 4.0% of all strokes and accidents occurred in 16% of these instances.

  7. A decision ladder analysis of eco-driving: the first step towards fuel-efficient driving behaviour.

    Science.gov (United States)

    McIlroy, Rich C; Stanton, Neville A

    2015-01-01

    This paper provides a decision ladder analysis of eco-driving, and a discussion of the resultant models in terms of the skills, rules and knowledge taxonomy of human behaviour and how this can inform the design of an in-vehicle, eco-driving support system. In order to understand the types of behaviours that characterise fuel-efficient driving, a review was conducted of the academic literature and of more publicly available resources, such as governmental, car manufacturers' and specific eco-driving organisations' websites. The review identified four largely distinct driving activities that play a central role in the use of fuel in the private road vehicle. A focus group involving four researchers in the transport ergonomics field, followed by a series of five interviews with eco-driving experts, served to validate, supplement and further specify the models. Practitioner Summary: This paper presents a decision ladder analysis of eco-driving. A four-member focus group and five interviews with eco-driving experts were conducted; the resultant models are discussed in terms of supporting fuel-efficient driving behaviours in the novice eco-driver through their potential to inform the design of an in-vehicle eco-driving support system.

  8. Auditory driving of the autonomic nervous system: Listening to theta-frequency binaural beats post-exercise increases parasympathetic activation and sympathetic withdrawal.

    Science.gov (United States)

    McConnell, Patrick A; Froeliger, Brett; Garland, Eric L; Ives, Jeffrey C; Sforzo, Gary A

    2014-01-01

    Binaural beats are an auditory illusion perceived when two or more pure tones of similar frequencies are presented dichotically through stereo headphones. Although this phenomenon is thought to facilitate state changes (e.g., relaxation), few empirical studies have reported on whether binaural beats produce changes in autonomic arousal. Therefore, the present study investigated the effects of binaural beating on autonomic dynamics [heart rate variability (HRV)] during post-exercise relaxation. Subjects (n = 21; 18-29 years old) participated in a double-blind, placebo-controlled study during which binaural beats and placebo were administered over two randomized and counterbalanced sessions (within-subjects repeated-measures design). At the onset of each visit, subjects exercised for 20-min; post-exercise, subjects listened to either binaural beats ('wide-band' theta-frequency binaural beats) or placebo (carrier tones) for 20-min while relaxing alone in a quiet, low-light environment. Dependent variables consisted of high-frequency (HF, reflecting parasympathetic activity), low-frequency (LF, reflecting sympathetic and parasympathetic activity), and LF/HF normalized powers, as well as self-reported relaxation. As compared to the placebo visit, the binaural-beat visit resulted in greater self-reported relaxation, increased parasympathetic activation and increased sympathetic withdrawal. By the end of the 20-min relaxation period there were no observable differences in HRV between binaural-beat and placebo visits, although binaural-beat associated HRV significantly predicted subsequent reported relaxation. Findings suggest that listening to binaural beats may exert an acute influence on both LF and HF components of HRV and may increase subjective feelings of relaxation.

  9. Auditory driving of the autonomic nervous system: Listening to theta-frequency binaural beats post-exercise increases parasympathetic activation and sympathetic withdrawal

    Directory of Open Access Journals (Sweden)

    Patrick eMcConnell

    2014-11-01

    Full Text Available Binaural beats are an auditory illusion perceived when two or more pure tones of similar frequencies are presented dichotically through stereo headphones. Although this phenomenon is thought to facilitate state changes (e.g., relaxation, few empirical studies have reported on whether binaural beats produce changes in autonomic arousal. Therefore, the present study investigated the effects of binaural beating on autonomic dynamics (heart-rate variability (HRV during post-exercise relaxation. Subjects (n = 21; 18-29 years old participated in a double-blind, placebo-controlled study during which binaural beats and placebo were administered over two randomized and counterbalanced sessions (within-subjects repeated-measures design. At the onset of each visit, subjects exercised for 20-min; post-exercise, subjects listened to either binaural beats (‘wide-band’ theta-frequency binaural beats or placebo (carrier tone for 20-min while relaxing alone in a quiet, low-light environment. Dependent variables consisted of high frequency (HF, reflecting parasympathetic activity, low frequency (LF, reflecting sympathetic and parasympathetic activity and LF/HF normalized powers, as well as self-reported relaxation. As compared to the placebo visit, the binaural beat visit resulted in greater self-reported relaxation, as well as increased parasympathetic activation and sympathetic withdrawal. By the end of the 20-min relaxation period there were no observable differences in HRV between binaural beat and placebo visits, although binaural-beat associated HRV significantly predicted subsequent reported relaxation. Findings suggest that listening to binaural beats may exert an acute influence on both LF and HF components of HRV and may increase subjective feelings of relaxation.

  10. Mycobacterium tuberculosis Latent Antigen Rv2029c from the Multistage DNA Vaccine A39 Drives TH1 Responses via TLR-mediated Macrophage Activation

    Directory of Open Access Journals (Sweden)

    Haibo Su

    2017-11-01

    Full Text Available Targeting of Mycobacterium tuberculosis (MTB latent antigens comprises a crucial strategy for the development of alternative tuberculosis (TB vaccine(s that protects against TB reactivation. Here, we generated a multistage DNA vaccine, A39, containing the early antigens Ag85A and Rv3425 as well as the latency-associated protein Rv2029c, which conferred protective immunity in a pre-exposure mouse model. Moreover, administration of the A39 vaccination after MTB exposure inhibited reactivation and resulted in significantly lower bacterial loads in the lungs and spleen of mice, compared to those in the control population. Subsequently, we investigated the effect of Rv2029c on innate immunity and characterized the molecular details of the interaction of this protein with the host via iTRAQ proteomic and biochemical assay analyses. Rv2029c activated macrophages, triggered the production of pro-inflammatory cytokines, and promoted toll-like receptor/mitogen-activated protein kinase (TLR/MAPK-dependent macrophage apoptosis. Furthermore, Rv2029c treatment enhanced the ability of Mycobacterium bovis Bacillus Calmette-Guérin (BCG-infected macrophages to present antigens to CD4+ T cells in vitro, which correlated with an increase in MHC-II expression. Lastly, Rv2029c-treated macrophages activated T cells, effectively polarized CD4+ and CD8+ T cells to secrete IFN-γ and IL-2, and specifically expanded a population of CD44highCD62LlowCD4+/CD8+ effector/memory cells, indicating that Rv2029c, as a specific recall antigen, contributes to Th1 polarization in T cell immunity. These results suggest that Rv2029c and A39 comprise promising targets for the development of next-generation clinical TB therapeutic vaccines.

  11. Modulation of Low-Voltage-Activated Inward Current Permeable to Sodium and Calcium by DARPP-32 Drives Spontaneous Firing of Insect Octopaminergic Neurosecretory Cells.

    Science.gov (United States)

    Lapied, Bruno; Defaix, Antoine; Stankiewicz, Maria; Moreau, Eléonore; Raymond, Valérie

    2017-01-01

    Identification of the different intracellular pathways that control phosphorylation/dephosphorylation process of ionic channels represents an exciting alternative approach for studying the ionic mechanisms underlying neuronal pacemaker activity. In the central nervous system of the cockroach Periplaneta americana, octopaminergic neurons, called dorsal unpaired median (DUM; DUM neurons), generate spontaneous repetitive action potentials. Short-term cultured adult DUM neurons isolated from the terminal abdominal ganglion (TAG) of the nerve cord were used to study the regulation of a tetrodotoxin-sensitive low-voltage-activated (LVA) channel permeable to sodium and calcium (Na/Ca), under whole cell voltage- and current-clamp conditions. A bell-shaped curve illustrating the regulation of the amplitude of the maintained current vs. [ATP]i was observed. This suggested the existence of phosphorylation mechanisms. The protein kinase A (PKA) inhibitor, H89 and elevating [cyclic adenosine 3', 5' monophosphate, cAMP]i, increased and decreased the current amplitude, respectively. This indicated a regulation of the current via a cAMP/PKA cascade. Furthermore, intracellular application of PP2B inhibitors, cyclosporine A, FK506 and PP1/2A inhibitor, okadaic acid decreased the current amplitude. From these results and because octopamine (OA) regulates DUM neuron electrical activity via an elevation of [cAMP]i, we wanted to know if, like in vertebrate dopaminergic neurons, OA receptor (OAR) stimulation could indirectly affect the current via PKA-mediated phosphorylation of Dopamine- and cAMP-regulated Phosphoprotein-32 (DARPP-32) known to inhibit PP1/2A. Experiments were performed using intracellular application of phospho-DARPP-32 and non-phospho-DARPP-32. Phospho-DARPP-32 strongly reduced the current amplitude whereas non-phospho-DARPP-32 did not affect the current. All together, these results confirm that DARPP-32-mediated inhibition of PP1/2A regulates the maintained sodium

  12. Who is driving my car? Development and analysis of a control transition strategy for collaborative automated congestion driving

    NARCIS (Netherlands)

    Urhahne, Joseph

    2016-01-01

    The role of the driver is changing now that vehicles with driving automation technologies appear on the road. It evolves from being an active controller of the vehicle to being a supervisor of the automated ride. The driver has to collaborate with the driving automation and remains responsible for

  13. QUICK RELEASABLE DRIVE

    Science.gov (United States)

    Dickson, J.J.

    1958-07-01

    A quick releasable mechanical drive system suitable for use in a nuclear reactor is described. A small reversible motor positions a control rod by means of a worm and gear speed reducer, a magnetic torque clutch, and a bell crank. As the control rod is raised to the operating position, a heavy coil spring is compressed. In the event of an emergency indicated by either a''scram'' signal or a power failure, the current to the magnetic clutch is cut off, thereby freeing the coil spring and the bell crank positioner from the motor and speed reduction gearing. The coil spring will immediately act upon the bell crank to cause the insertion of the control rod. This arrangement will allow the slow, accurate positioning of the control rod during reactor operation, while providing an independent force to rapidly insert the rod in the event of an emergency.

  14. Yaw-rate Control for Electric Vehicle with Active Front/Rear Steering and Driving/Braking Force Distribution of Rear Wheels

    Science.gov (United States)

    Ando, Naoki; Fujimoto, Hiroshi

    Direct yaw-moment control (DYC) is an effective method for achieving stable vehicle motion. In the DYC of vehicles having in-wheel motors (IWMs) and active front and rear steering systems, some of the control inputs are generally redundant. This means that input variables can not be decided uniquely to control each longitudinal, lateral, and yawing motion. The equalization of workload for each wheel on the basis of longitudinal and lateral force distribution enhances the cornering performance of vehicles. Therefore, we have proposed a method for obtaining longitudinal- and latitudinal-force distributions on the basis of the least squares solution of the equations for longitudinal, lateral, and yawing motion. Further, we have proposed a lateral-force control method with tire lateral force sensors and active front/rear steering and a DYC method for reducing the tracking error in this controller. In this paper, we show that the equalization of the workload for each wheel and quick yaw-rate response are achieved by adopting these proposed methods. Simulations and experiments are carried out to confirm the effectiveness of the proposed methods.

  15. The Microtubule-Depolymerizing Activity of a Mitotic Kinesin Protein KIF2A Drives Primary Cilia Disassembly Coupled with Cell Proliferation

    Directory of Open Access Journals (Sweden)

    Tatsuo Miyamoto

    2015-02-01

    Full Text Available The primary cilium is an antenna-like, microtubule-based organelle on the surface of most vertebrate cells for receiving extracellular information. Although primary cilia form in the quiescent phase, ciliary disassembly occurs when quiescent cells re-enter the proliferative phase. It was shown that a mitotic kinase, Polo-like kinase 1 (PLK1, is required for cell-proliferation-coupled primary cilia disassembly. Here, we report that kinesin superfamily protein 2A (KIF2A, phosphorylated at T554 by PLK1, exhibits microtubule-depolymerizing activity at the mother centriole to disassemble the primary cilium in a growth-signal-dependent manner. KIF2A-deficient hTERT-RPE1 cells showed the impairment of primary cilia disassembly following growth stimulation. It was also found that the PLK1-KIF2A pathway is constitutively active in cells from patients with premature chromatid separation (PCS syndrome and is responsible for defective ciliogenesis in this syndrome. These findings provide insights into the roles of the PLK1-KIF2A pathway in physiological cilia disassembly and cilia-associated disorders.

  16. Diet drives quick changes in the metabolic activity and composition of human gut microbiota in a validated in vitro gut model.

    Science.gov (United States)

    Aguirre, Marisol; Eck, Anat; Koenen, Marjorie E; Savelkoul, Paul H M; Budding, Andries E; Venema, Koen

    2016-01-01

    The aim of this study was to screen how rapidly the human gut microbiota responds to diet in an in vitro model of the proximal colon (TIM-2 system). Two experimental diets were provided to the gut bacteria: a high carbohydrate and a high protein diet. The metabolic response and the composition of the microbiota were compared to a control diet simulating an average western meal. Short-chain and branched-chain fatty acids (SCFA and BCFA, respectively) production, in addition to changes in the community composition (profiling), were measured. The activity of the microbiota reflected differences between diets, exhibiting a trade-off between saccharolytic and proteolytic fermentation when compared to the control. Diversity analysis revealed a phylum-specific response depending on the diet tested. Most changes in the microbiome composition occurred during the first 24 h of the experiment. The outcome of this study elucidates the fact that human gut bacteria quickly respond to changes in diet. In addition, it confirms that variations in the concentration of carbohydrates and proteins modify the activity and composition of the microbiota, and these changes can potentially have an impact on the health of the host. Copyright © 2015 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

  17. Underwater acoustic noise generation and propagation resulting from pile driving for Oregon bridge construction.

    Science.gov (United States)

    2014-06-01

    There is growing concern about noise levels from pile driving activities associated with the : construction of highway bridges and other in-water structures. It has been demonstrated that noise : generated from pile driving with an impact hammer can ...

  18. CLIC Drive Beam Phase Stabilisation

    CERN Document Server

    Gerbershagen, Alexander; Schulte, Daniel

    The thesis presents phase stability studies for the Compact Linear Collider (CLIC) and focuses in particular on CLIC Drive Beam longitudinal phase stabilisation. This topic constitutes one of the main feasibility challenges for CLIC construction and is an essential component of the current CLIC stabilisation campaign. The studies are divided into two large interrelated sections: the simulation studies for the CLIC Drive Beam stability, and measurements, data analysis and simulations of the CLIC Test Facility (CTF3) Drive Beam phase errors. A dedicated software tool has been developed for a step-by-step analysis of the error propagation through the CLIC Drive Beam. It uses realistic RF potential and beam loading amplitude functions for the Drive and Main Beam accelerating structures, complete models of the recombination scheme and compressor chicane as well as of further CLIC Drive Beam modules. The tool has been tested extensively and its functionality has been verified. The phase error propagation at CLIC h...

  19. The interaction of R&D and market orientation in improving business performance: An empirically based framework for understanding what drives innovation activity

    DEFF Research Database (Denmark)

    Grunert, Klaus G.; Harmsen, Hanne

    1997-01-01

    in a traditionally low-tech industry, where product development is nevertheless considered to be strategically important, i.e., the food processing industry. The results of a series of case studies indicate that constructs than R&D and market orientation may be more appropriate for understanding innovation......The interplay between R&D skills and competencies and market skills and competencies is in the more recent product development literature seen as a major determinant of successful innovation. The study reported in this paper was done in order to c more light on these two constructs...... and explaining innovation success in the case material. A new set of constructs focusing on what causes specific innovation activities to occur is prop and a revised framework is developed....

  20. Why did we make that cheese? An empirically based framework for understanding what drives innovation activities in a low-tech industry

    DEFF Research Database (Denmark)

    Harmsen, Hanne; Grunert, Klaus G.

    low-tech industry, where product development is nevertheless considered to be strategically important, ie, the food processing industry. The results of a series of case studies indicate that oth constructs than R&D and market orientation may be more appropriate for understanding innovation......The interplay between R&D skills and competencies and market skills and competencies is in the more recent product development literature seen as a major determinant of success for innovation. The study reported in this paper was done in order to more light on these two contructs in a traditionally...... and explaining innovation success in the case material. A new set of constructs focusing on what causes specific innovation activities to occur is prop and a revised framework is developed....

  1. Increased PKC activity and altered GSK3β/NMDAR function drive behavior cycling in HINT1-deficient mice: bipolarity or opposing forces.

    Science.gov (United States)

    Garzón-Niño, Javier; Rodríguez-Muñoz, María; Cortés-Montero, Elsa; Sánchez-Blázquez, Pilar

    2017-02-27

    Mice with histidine triad nucleotide-binding protein 1 (HINT1) deletion exhibit manic-like symptoms that evolve into depressive-like behavior in response to stressful paradigms. Molecular and electrophysiological studies have indicated that HINT1-/- mice exhibit increased PKC, PKA, and GSK3β activities, as well as glutamate N-methyl-D-aspartate receptor (NMDAR)/α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptor (AMPAR) and NR2B/NR2A subunit ratios. Pharmacological interventions stabilized their behavior but through different mechanisms. GSK3β inhibitors and valproate directly attenuated the expression of the manic-like symptoms, whereas PKC inhibition, lamotrigine, or risperidone promoted NMDAR-mediated depressive-like behaviors that counterbalanced the preexisting manic-like symptoms. Naïve HINT1-/- mice exposed to stressful paradigms rapidly manifested depressive-like behaviors in subsequent stressful situations, a capacity that persisted for a couple of weeks thereafter. During the depressive-like phase, citalopram, amitriptyline and MK801 precipitated manic-like behaviors in stressed HINT1-/- mice. Notably, the antagonism of NMDARs prevented HINT1-/- mice from alternating behaviors in response to stress. A comparison with "manic" Black Swiss mice indicated that in HINT1-/- mice, PKC supports manic-like symptoms and reduces the expression of depressive-like behaviors via activation of GSK3β and regulation of NR2B-enriched NMDARs. HINT1-/- mice represent a suitable model for studying human BPD and may facilitate the identification of novel targets and drugs to treat this mental disorder.

  2. Driving Rhythm Method for Driving Comfort Analysis on Rural Highways

    Directory of Open Access Journals (Sweden)

    Bo Yu

    2017-08-01

    Full Text Available Driving comfort is of great significance for rural highways, since the variation characteristics of driving speed are comparatively complex on rural highways. Earlier studies about driving comfort were usually based on the actual geometric road alignments and automobiles, without considering the driver’s visual perception. However, some scholars have shown that there is a discrepancy between actual and perceived geometric alignments, especially on rural highways. Moreover, few studies focus on rural highways. Therefore, in this paper the driver’s visual lane model was established based on the Catmull-Rom spline, in order to describe the driver’s visual perception of rural highways. The real vehicle experiment was conducted on 100 km rural highways in Tibet. The driving rhythm was presented to signify the information during the driving process. Shape parameters of the driver’s visual lane model were chosen as input variables to predict the driving rhythm by BP neural network. Wavelet transform was used to explore which part of the driving rhythm is related to the driving comfort. Then the probabilities of good, fair and bad driving comfort can be calculated by wavelets of the driving rhythm. This work not only provides a new perspective into driving comfort analysis and quantifies the driver’s visual perception, but also pays attention to the unique characteristics of rural highways.

  3. Distracted Driving, A Major Preventable Cause of Motor Vehicle Collisions: "Just Hang Up and Drive".

    Science.gov (United States)

    Kahn, Christopher A; Cisneros, Victor; Lotfipour, Shahram; Imani, Ghasem; Chakravarthy, Bharath

    2015-12-01

    For years, public health experts have been concerned about the effect of cell phone use on motor vehicle collisions, part of a phenomenon known as "distracted driving." The Morbidity and Mortality Weekly Report (MMWR) article "Mobile Device Use While Driving - United States and Seven European Countries 2011" highlights the international nature of these concerns. Recent (2011) estimates from the National Highway Traffic Safety Administration are that 10% of fatal crashes and 17% of injury crashes were reported as distraction-affected. Of 3,331 people killed in 2011 on roadways in the U.S. as a result of driver distraction, 385 died in a crash where at least one driver was using a cell phone. For drivers 15-19 years old involved in a fatal crash, 21% of the distracted drivers were distracted by the use of cell phones. Efforts to reduce cell phone use while driving could reduce the prevalence of automobile crashes related to distracted driving. The MMWR report shows that there is much ground to cover with distracted driving. Emergency physicians frequently see the devastating effects of distracted driving on a daily basis and should take a more active role on sharing the information with patients, administrators, legislators, friends and family.

  4. Driving anger in Ukraine: Appraisals, not trait driving anger, predict anger intensity while driving.

    Science.gov (United States)

    Stephens, A N; Hill, T; Sullman, M J M

    2016-03-01

    Trait driving anger is often, but not always, found to predict both the intensity of anger while driving and subsequent crash-related behaviours. However, a number of studies have not found support for a direct relationship between one's tendency to become angry and anger reported while driving, suggesting that other factors may mediate this relationship. The present self-report study investigated whether, in anger provoking driving situations, the appraisals made by drivers influence the relationship between trait and state anger. A sample of 339 drivers from Ukraine completed the 33-item version of the Driver Anger Scale (DAS; Deffenbacher et al., 1994) and eight questions about their most recent experience of driving anger. A structural equation model found that the intensity of anger experienced was predicted by the negative evaluations of the situation, which was in turn predicted by trait driving anger. However, trait driving anger itself did not predict anger intensity; supporting the hypothesis that evaluations of the driving situation mediate the relationship between trait and state anger. Further, the unique structure of the DAS required to fit the data from the Ukrainian sample, may indicate that the anger inducing situations in Ukraine are different to those of a more developed country. Future research is needed to investigate driving anger in Ukraine in a broader sample and also to confirm the role of the appraisal process in the development of driving anger in both developed and undeveloped countries. Copyright © 2015 Elsevier Ltd. All rights reserved.

  5. Relationship of Impaired Driving Enforcement Intensity to Drinking and Driving on the Roads

    Science.gov (United States)

    Fell, James C.; Waehrer, Geetha; Voas, Robert B.; Auld-Owens, Amy; Carr, Katherine; Pell, Karen

    2014-01-01

    Background It is principally the area of enforcement that offers the greatest opportunity for reducing alcohol-impaired driving in the near future. How much of a reduction in drinking and driving would be achieved by how much improvement in enforcement intensity? Methods We developed logistic regression models to explore how enforcement intensity (six different measures) related to the prevalence of weekend, nighttime drivers in the 2007 National Roadside Survey (NRS) who had been drinking (blood alcohol concentration [BAC]>.00 g/dL), who had BACs>.05 g/dL, and who were driving with an illegal BAC>.08 g/dL. Results Drivers on the roads in our sample of 30 communities who were exposed to fewer than 228 traffic stops per 10,000 population aged 18 and older had 2.4 times the odds of being BAC positive, 3.6 times the odds of driving with a BAC>0.05, and 3.8 times the odds of driving with a BAC>0.08 compared to those drivers on the roads in communities with more than 1,275 traffic stops per 10,000 population. Drivers on the roads in communities with fewer than 3.7 driving-under-the-influence (DUI) arrests per 10,000 population had 2.7 times the odds of BAC-positive drivers on the roads compared to communities with the highest intensity of DUI arrest activity (>38 DUI arrests per 10,000 population). Conclusion The number of traffic stops and DUI arrests per capita were significantly associated with the odds of drinking and driving on the roads in these communities. This might reflect traffic enforcement visibility. The findings in this study may help law enforcement agencies around the country adjust their traffic enforcement intensity to reduce impaired driving in their community. PMID:25515820

  6. Type III Transforming Growth Factor-β Receptor Drives Cardiac Hypertrophy Through β-Arrestin2-Dependent Activation of Calmodulin-Dependent Protein Kinase II.

    Science.gov (United States)

    Lou, Jie; Zhao, Dan; Zhang, Ling-Ling; Song, Shu-Ying; Li, Yan-Chao; Sun, Fei; Ding, Xiao-Qing; Yu, Chang-Jiang; Li, Yuan-Yuan; Liu, Mei-Tong; Dong, Chang-Jiang; Ji, Yong; Li, Hongliang; Chu, Wenfeng; Zhang, Zhi-Ren

    2016-09-01

    The role of type III transforming growth factor-β receptor (TβRIII) in the pathogenesis of heart diseases remains largely unclear. Here, we investigated the functional role and molecular mechanisms of TβRIII in the development of myocardial hypertrophy. Western blot and quantitative real time-polymerase chain reaction analyses revealed that the expression of TβRIII was significantly elevated in human cardiac hypertrophic samples. Consistently, TβRIII expression was substantially increased in transverse aortic constriction (TAC)- and isoproterenol-induced mouse cardiac hypertrophy in vivo and in isoproterenol-induced cardiomyocyte hypertrophy in vitro. Overexpression of TβRIII resulted in cardiomyocyte hypertrophy, whereas isoproterenol-induced cardiomyocyte hypertrophy was greatly attenuated by knockdown of TβRIII in vitro. Cardiac-specific transgenic expression of TβRIII independently led to cardiac hypertrophy in mice, which was further aggravated by isoproterenol and TAC treatment. Cardiac contractile function of the mice was not altered in TβRIII transgenic mice; however, TAC led to significantly decreased cardiac contractile function in TβRIII transgenic mice compared with control mice. Conversely, isoproterenol- and TAC-induced cardiac hypertrophy and TAC-induced cardiac contractile function impairment were partially reversed by suppression of TβRIII in vivo. Our data suggest that TβRIII mediates stress-induced cardiac hypertrophy through activation of Ca(2+)/calmodulin-dependent protein kinase II, which requires a physical interaction of β-arrestin2 with both TβRIII and calmodulin-dependent protein kinase II. Our findings indicate that stress-induced increase in TβRIII expression results in cardiac hypertrophy through β-arrestin2-dependent activation of calmodulin-dependent protein kinase II and that transforming growth factor-β and β-adrenergic receptor signaling are not involved in spontaneous cardiac hypertrophy in cardiac

  7. ER-Coordinated Activities of Rab22a and Rab5a Drive Phagosomal Compaction and Intracellular Processing of Borrelia burgdorferi by Macrophages

    Directory of Open Access Journals (Sweden)

    Xenia Naj

    2015-09-01

    Full Text Available Borrelia burgdorferi is the causative agent of Lyme disease, a multisystemic disorder affecting the skin, joints, and nervous system. Macrophages and dendritic cells counteract Borrelia dissemination through internalization and degradation of spirochetes. We now show that Borrelia internalization by primary human macrophages involves uptake and compaction into Rab22a-positive phagosomes that are in close contact with Rab5a-positive vesicles. Compaction of borreliae involves membrane extrusion from phagosomes, is driven by Rab22a and Rab5a activity, and is coordinated by ER tubules forming contact sites of Rab22a phagosomes with Rab5a vesicles. Importantly, Rab22a and Rab5a depletion leads to reduced localization to lysosomes and to increased intracellular survival of spirochetes. These data show that Rab22a- and Rab5a-driven phagosomal uptake is a crucial step in the vesicular cascade that leads to elimination of spirochetes by macrophages. Rab22a and Rab5a thus present as potential molecular targets for the modulation of intracellular processing of borreliae in human immune cells.

  8. The new active driving safety system ESP (Electronic Stability Program) developed by Mercedes Benz; Das neue aktive Fahrsicherheitssystem ESP (Elektronisches-Stabilitaets-Programm) von Mercedes-Benz

    Energy Technology Data Exchange (ETDEWEB)

    Paul, J. [Mercedes-Benz AG, Stuttgart (Germany); Klinkner, W. [Mercedes-Benz AG, Stuttgart (Germany); Mueller, A. [Mercedes-Benz AG, Stuttgart (Germany)

    1995-12-31

    The new electronic stability program (ESP) offered by Mercedes-Benz as a world novelty in March 1995 is the consequent further development of the anti-lock braking system and the anti-slip control. An improved assessment of the handling properties by a steering wheel sensor, a yaw velocity sensor, a brake pressure sensor and a hydraulic system that brakes each wheel individually and is controlled by a complex logic allow the supervision and the active control of the cross-dynamic handling properties up to limiting ranges. The handling of the vehicle in critical situations (e.g. strong oversteering or understeering) has been considerably improved. (orig.) [Deutsch] Das neue elektronische-Stabilitaets-Programm (ESP), von Mercedes-Benz ab Maerz 1995 als Weltneuheit angeboten, stellt eine konsequente Weiterentwicklung des Antiblockier-Bremssystems (ABS) und der Antriebsschlupfregelung (ASR) dar. Eine erweiterte Fahrzustandserfassung durch Lenkradwinkel-, Giergeschwindigkeit- und Bremsdrucksensor, eine Hydraulik, die jedes Rad individuell abbremsen kann, angesteuert durch eine komplexe Regelungslogik, erlauben erstmals eine Ueberwachung und aktive Regelung des querdynamischen Fahrzustands bis in den Grenzbereich. Die Beherrschbarkeit des Fahrzeugs wird in kritischen Situationen (z.B. starkes Ueber- oder Untersteuern) entscheidend verbessert. (orig.)

  9. XPO1 (CRM1) inhibition represses STAT3 activation to drive a survivin-dependent oncogenic switch in triple negative breast cancer

    Science.gov (United States)

    Cheng, Yan; Holloway, Michael P; Nguyen, Kevin; McCauley, Dilara; Landesman, Yosef; Kauffman, Michael G; Shacham, Sharon; Altura, Rachel A

    2014-01-01

    Inhibition of XPO1 (CRM1)-mediated nuclear export of multiple tumor suppressor proteins has been proposed as a novel cancer therapeutic strategy to turn off oncogenic signals and enhance tumor suppression. Survivin is a multifunctional protein with oncogenic properties when expressed in the cytoplasm that requires the XPO1-RanGTP complex for its nuclear export. We investigated the anti-tumor mechanisms of the drug-like selective inhibitors of nuclear export (SINE) XPO1 antagonists, KPT-185, KPT-251 KPT-276, and KPT-330 in estrogen-receptor positive and triple negative breast cancer (TNBC) cell lines and xenograft models of human breast tumors. KPT compounds significantly inhibited breast cancer cell growth and induced tumor cell death, both in vitro and in vivo. These drugs initially promoted survivin accumulation within tumor cell nuclei. However, their major in vitro effect was to decrease survivin cytoplasmic protein levels, correlating with the onset of apoptosis. XPO1 inhibition repressed Survivin transcription by inhibiting CBP-mediated STAT3 acetylation, and blocking STAT3 binding to the Survivin promoter. Additionally, caspase-3 was activated to cleave survivin, rendering it unavailable to bind XIAP and block the caspase cascade. Collectively, these data demonstrate that XPO1 inhibition by SINE compounds represses STAT3 transactivation to block the selective oncogenic properties of survivin and supports their clinical use in triple negative breast tumors. PMID:24431073

  10. Driving Forces for Covalent Assembly of Porphyrins by Selective C-H Bond Activation and Intermolecular Coupling on a Copper Surface.

    Science.gov (United States)

    Floris, Andrea; Haq, Sam; In't Veld, Mendel; Amabilino, David B; Raval, Rasmita; Kantorovich, Lev

    2016-05-11

    Recent synthesis of covalent organic assemblies at surfaces has opened the promise of producing robust nanostructures for functional interfaces. To uncover how this new chemistry works at surfaces and understand the underlying mechanisms that control bond-breaking and bond-making processes at specific positions of the participating molecules, we study here the coupling reaction of tetra(mesityl)porphyrin molecules, which creates covalently connected networks on the Cu(110) surface by utilizing the 4-methyl groups as unique connection points. Using scanning tunneling microscopy (STM), state-of-the-art density functional theory (DFT), and Nudged Elastic Band (NEB) calculations, we show that the unique directionality of the covalent bonding is found to stem from a chain of highly selective C-H activation and dehydrogenation processes, followed by specific intermolecular C-C coupling reactions that are facilitated by the surface, by steric constraints, and by anisotropic molecular diffusion. These insights provide the first steps toward developing synthetic rules for complex two-dimensional covalent organic chemistry that can be enacted directly at a surface to deliver specific macromolecular structures designed for specific functions.

  11. Activation-induced cell death drives profound lung CD4(+) T-cell depletion in HIV-associated chronic obstructive pulmonary disease.

    Science.gov (United States)

    Popescu, Iulia; Drummond, M Bradley; Gama, Lucio; Coon, Tiffany; Merlo, Christian A; Wise, Robert A; Clements, Janice E; Kirk, Gregory D; McDyer, John F

    2014-10-01

    As overall survival improves, individuals with HIV infection become susceptible to other chronic diseases, including accelerated chronic obstructive pulmonary disease (COPD). To determine whether individuals with HIV-associated COPD exhibit dysregulated lung mucosal T-cell immunity compared with control subjects. Using flow cytometry, we evaluated peripheral blood and lung mucosal T-cell immunity in 14 HIV(+)COPD(+), 13 HIV(+)COPD(-), and 7 HIV(-)COPD(+) individuals. HIV(+)COPD(+) individuals demonstrated profound CD4(+) T-cell depletion with reduced CD4/CD8 T-cell ratios in bronchoalveolar lavage-derived lung mononuclear cells, not observed in peripheral blood mononuclear cells, and diminished CD4(+) T cell absolute numbers, compared with control subjects. Furthermore, HIV(+)COPD(+) individuals demonstrated decreased pulmonary HIV-specific and staphylococcal enterotoxin B-reactive CD4(+) memory responses, including loss of multifunctionality, compared with HIV(+)COPD(-) control subjects. In contrast, lung mucosal HIV-specific CD8(+) T-cell responses were preserved. Lung CD4(+) T cells from HIV(+)COPD(+) individuals expressed increased surface Fas death receptor (CD95) and programmed death-1, but similar bronchoalveolar lavage viral loads as control subjects. However, programmed death-1 expression inversely correlated with HIV-specific lung CD4(+)IFN-γ(+) T-cell responses, suggesting functional exhaustion. Moreover, lung CD4(+) T cells from HIV(+)COPD(+) patients demonstrated increased basal and HIV antigen-induced expression of the early apoptosis marker annexin V compared with control subjects, which was significantly attenuated with anti-Fas blockade. Lastly, lung mucosal, but not blood, CD4(+)/CD8(+) ratios from HIV(+) patients significantly correlated with the FEV1, but not in HIV(-)COPD(+) patients. Together, our results provide evidence for profound lung mucosal CD4(+) T-cell depletion via a Fas-dependent activation-induced cell death mechanism, along with

  12. The man behind the curtain: X-rays drive the UV through NIR variability in the 2013 active galactic nucleus outburst in NGC 2617

    Energy Technology Data Exchange (ETDEWEB)

    Shappee, B. J.; Kochanek, C. S.; Stanek, K. Z.; De Rosa, G.; Mathur, S.; Zu, Y.; Peterson, B. M.; Pogge, R. W.; Jencson, J.; Holoien, T.W-S.; Basu, U.; Beacom, J. F.; Adams, S. [Department of Astronomy, The Ohio State University, Columbus, OH 43210 (United States); Prieto, J. L. [Department of Astrophysical Sciences, Princeton University, Princeton, NJ 08544 (United States); Grupe, D. [Department of Astronomy and Astrophysics, Pennsylvania State University, 525 Davey Lab, University Park, PA 16802 (United States); Komossa, S. [Max-Planck Institut für Radioastronomie, Auf dem Hügel 69, D-53121 Bonn (Germany); Im, M. [CEOU/Department of Physics and Astronomy, Seoul National University, Seoul 151-742 (Korea, Republic of); Szczygieł, D. M. [Warsaw University Astronomical Observatory, Al. Ujazdowskie 4, 00-478 Warsaw (Poland); Brimacombe, J. [Coral Towers Observatory, Cairns, Queensland A-4870 (Australia); Campillay, A., E-mail: shappee@astronomy.ohio-state.edu [Carnegie Observatories, Las Campanas Observatory, Colina El Pino, Casilla 601 (Chile); and others

    2014-06-10

    After the All-Sky Automated Survey for SuperNovae discovered a significant brightening of the inner region of NGC 2617, we began a ∼70 day photometric and spectroscopic monitoring campaign from the X-ray through near-infrared (NIR) wavelengths. We report that NGC 2617 went through a dramatic outburst, during which its X-ray flux increased by over an order of magnitude followed by an increase of its optical/ultraviolet (UV) continuum flux by almost an order of magnitude. NGC 2617, classified as a Seyfert 1.8 galaxy in 2003, is now a Seyfert 1 due to the appearance of broad optical emission lines and a continuum blue bump. Such 'changing look active galactic nuclei (AGNs)' are rare and provide us with important insights about AGN physics. Based on the Hβ line width and the radius-luminosity relation, we estimate the mass of central black hole (BH) to be (4 ± 1) × 10{sup 7} M {sub ☉}. When we cross-correlate the light curves, we find that the disk emission lags the X-rays, with the lag becoming longer as we move from the UV (2-3 days) to the NIR (6-9 days). Also, the NIR is more heavily temporally smoothed than the UV. This can largely be explained by a simple model of a thermally emitting thin disk around a BH of the estimated mass that is illuminated by the observed, variable X-ray fluxes.

  13. Fitness-to-drive Disagreements in Individuals With Dementia.

    Science.gov (United States)

    Ranchet, Maud; Tant, Mark; Akinwuntan, Abiodun E; Morgan, John C; Devos, Hannes

    2017-10-01

    We sought to investigate the agreement between medical and practical fitness-to-drive recommendations in active drivers with dementia. In this retrospective study, 68 patients underwent medical, visual, and road tests at an official center of the Belgian Road Safety Institute. Physicians provided medical fitness-to-drive recommendations using 1 of 3 categories (favorable, reserved, or unfavorable). On-road assessors used the same 3 categories to make practical fitness-to-drive recommendations. Agreement between the medical and practical fitness-to-drive recommendations was calculated using the percentage of agreement (p0) and weighted kappa (kw). Low agreement was found between physicians and on-road assessors regarding their fitness-to-drive recommendations (p0 = 43%, kw = 0.11, p = .20). Compared with the on-road assessors, the physicians overestimated the fitness to drive of 24 (35%) patients and underestimated the fitness to drive of 15 (22%) patients. Patients who incurred more traffic violations were more likely to be overestimated than underestimated by the physician (p = .03). This study showed disagreements between the fitness-to-drive recommendations made by the physicians and the on-road assessors in more than half of drivers with dementia. Efforts need to be made to improve the communication between physicians and on-road assessors for joint decision making of fitness to drive in dementia.

  14. Purification of barley dimeric α-amylase inhibitor-1 (BDAI-1) and avenin-like protein-a (ALP) from beer and their impact on beer foam stability.

    Science.gov (United States)

    Iimure, Takashi; Kihara, Makoto; Sato, Kazuhiro; Ogushi, Kensuke

    2015-04-01

    Foam stability is a key factor of beer quality for consumers and brewers. Recent beer proteome analyses have suggested that barley dimeric α-amylase inhibitor-1 (BDAI-1) and avenin-like protein-a (ALP) derived from barley are important for beer foam stability. In this study, BDAI-1 and ALP were purified from a Japanese commercial beer sample using salt precipitation and column chromatography. The purification level was verified using two-dimensional gel electrophoresis, mass spectrometry, and database searches. Purified BDAI-1 and ALP were added to a beer sample to compare the foam stability to that of a control beer sample. As a result, beer foam stability was significantly improved by BDAI-1 but not by ALP, thereby suggesting that BDAI-1 affects beer foam stability whereas ALP does not. Copyright © 2014 Elsevier Ltd. All rights reserved.

  15. Orthopedic Activity in Field Hospitals Following Earthquakes in Nepal and Haiti : Variability in Injuries Encountered and Collaboration with Local Available Resources Drive Optimal Response.

    Science.gov (United States)

    Bar-On, Elhanan; Blumberg, Nehemia; Joshi, Amit; Gam, Arnon; Peyser, Amos; Lee, Evgeny; Kashichawa, Shree Krishna; Morose, Alexander; Schein, Ophir; Lehavi, Amit; Kreiss, Yitshak; Bader, Tarif

    2016-09-01

    Field hospitals have been deployed by the Israel Defense Forces (IDF) Medical Corps in numerous disaster events. Two recent deployments were following earthquakes in Haiti in 2010 and in Nepal in 2015. Despite arrival in similar timetables, the mode of operation was different-independently in Haiti and in collaboration with a local hospital in Nepal. The pathology encountered in the two hospitals and the resultant treatment requirements were significantly different between the two events. The purpose of this study was to analyze these differences and their implications for preparation and planning of future deployments. Data were obtained from IDF records and analyzed using SPSS™ software. 1686 patients were treated in Nepal versus 1111 in Haiti. The caseload in Nepal included significantly less earthquake-related injuries (26 vs. 66 %) with 28 % of them sustaining fractures versus 47 % in Haiti. Femoral fractures accounted for 7.9 % of fractures in Nepal versus 26.4 % in Haiti with foot fractures accounting for 23.8 and 6.4 %, respectively. The rate of open fracture was similar at 29.4 % in Nepal and 27.5 % in Haiti. 18.1 % of injured patients in Nepal underwent surgery, and 32.9 % of which was skeletal compared to 32 % surgical cases (58.8 % skeletal) in Haiti. 74.2 % of patients in Nepal and 34.3 % in Haiti were treated for pathology unrelated to the earthquake. The reasons for the variability in activities between the two hospitals include the magnitude of the disaster, the functionality of the local medical system which was relatively preserved in Nepal and destroyed in Haiti and the mode of operation which was independent in Haiti and collaborative with a functioning local hospital in Nepal. Emergency medical teams (EMTs) may encounter variable caseloads despite similar disaster scenarios. Advance knowledge of the magnitude of the disaster, the functionality of the local medical system, and the collaborative possibilities will help in planning

  16. Hydroacoustic pile driving noise study - comprehensive report : final report.

    Science.gov (United States)

    2016-12-28

    Alaska DOT&PF and JASCO Applied Sciences partnered to characterize underwater noise from pile driving activities to inform the assessment of the potential impact of such noise on marine mammals. JASCO measured underwater sounds at the Kake, Auke Bay,...

  17. Driving Resistance from Railroad Trains

    DEFF Research Database (Denmark)

    Lindgreen, Erik Bjørn Grønning; Sorenson, Spencer C

    2005-01-01

    This report methods and parameters for calculating the driving resistance of railroad trains. Calculations and comparisons are presented for aerodynamic, rolling and total resistance for a variety of freight trains under different loading conditions, operating speed and configuration. Simplified...... methods are presented for the estimation of the driving resistance for passenger trains. This report is a supplement to the ARTEMIS rail emissions model....

  18. Driving When You Have Cataracts

    Science.gov (United States)

    ... to plan car trips to avoid times when vision may be most affected; for example, driving west at dusk into a setting sun or ... lens will likely be replaced with a clear, artificial lens. With a new, clear lens, you will most likely be able to keep driving safely for many years to come. Cataract surgery ...

  19. Low Sex Drive in Women

    Science.gov (United States)

    Diseases and Conditions Low sex drive in women By Mayo Clinic Staff A woman's sexual desire naturally fluctuates over the years. Highs and lows commonly ... and anti-seizure medications also can cause low sex drive in women. If you have a persistent ...

  20. Motor Integrated Variable Speed Drives

    DEFF Research Database (Denmark)

    Singh, Yash Veer

    A new trend in the variable speed drives (VSDs) is to develop fully integrated systems, which lead to low-cost products with shorter design cycles. Motor Integrated design of VSDs will reduce cable length to connect drive with machine windings and installation time for end user. The electric drives...... are expected to have minimum effect on grid and motor connected to it, i.e. currents drawn from grid should be within specified limits and currents injecting in to machine should not overheat the machine windings to avoid insulation failure due to harmonics. It is also necessary that electric drives should...... when it comes to the development of any kind of power converter topology for power electronic applications. Concerning the use of a power converter in motor integrated VSDs, the first two mentioned aspects receive an even greater im-portance. Power converter design for integrated drives poses a host...

  1. Highly efficient, gearless drive; Hocheffizienter, getriebeloser Antrieb

    Energy Technology Data Exchange (ETDEWEB)

    Niederer, R.

    2004-07-01

    Highly efficient, gearless variable-speed drive systems for low-speed applications have been developed. These systems consist of an inverter with active switches (IGBTs, MOSFETs, resp.) and a synchronous machine excited with permanent magnets. Therefore, these systems can be used for drive as well as for generator applications. They operate very efficiently since a gearbox is obsolete, furthermore weight, dimensions, noise and maintenance can be reduced. The inverter controllers do not require any speed sensors, thus reliability is increased and costs are decreased. Application for low-speed variable-speed drive systems can be found in industrial applications, cable railways or wind turbines. Both systems have been optimized in several iterative loops, in what regards overall efficiency and material expenditure. For both systems, prototypes have been developed and tested. Both prototypes performed reliably and fulfilled the expectations. The high power system (1200 kW, 20 rpm) operated at rated load with an overall efficiency of 93.1%, the lower power system (3 kW, 60 rpm) with an overall efficiency of 85%. Thus the losses of these new systems are at rated load about 4% lower compared to conventional drive systems equipped with a mechanical gearbox. (author)

  2. Exploring Forensic Implications of the Fusion Drive

    OpenAIRE

    Shruti Gupta; Marcus Rogers

    2014-01-01

    This paper explores the forensic implications of Apple's Fusion Drive. The Fusion Drive is an example of auto-tiered storage. It uses a combination of a flash drive and a magnetic drive. Data is moved between the drives automatically to maximize system performance. This is different from traditional caches because data is moved and not simply copied. The research included understanding the drive structure, populating the drive, and then accessing data in a controlled setting to observe data m...

  3. Feminization of agriculture: Trends and driving forces

    OpenAIRE

    Lastarria-Cornhiel, Susana

    2006-01-01

    "This paper will describe how women have increased their labor in two types of agricultural production - smallholder production and agro-export agriculture - and the economic and socio-cultural forces that are driving this trend. Finally, this paper examines whether women's participation in income-producing activities, whether as wage workers or as family workers in cash cropping, contributes to empowerment and improves their status within the household." (Excerpt from Executive Summary)

  4. Driving the Landscape

    Science.gov (United States)

    Haff, P. K.

    2012-12-01

    Technological modification of the earth's surface (e.g., agriculture, urbanization) is an old story in human history, but what about the future? The future of landscape in an accelerating technological world, beyond a relatively short time horizon, lies hidden behind an impenetrable veil of complexity. Sufficiently complex dynamics generates not only the trajectory of a variable of interest (e.g., vegetation cover) but also the environment in which that variable evolves (e.g., background climate). There is no way to anticipate what variables will define that environment—the dynamics creates its own variables. We are always open to surprise by a change of conditions we thought or assumed were fixed or by the appearance of new phenomena of whose possible existence we had been unaware or thought unlikely. This is especially true under the influence of technology, where novelty is the rule. Lack of direct long-term predictability of landscape change does not, however, mean we cannot say anything about its future. The presence of persistence (finite time scales) in a system means that prediction by a calibrated numerical model should be good for a limited period of time barring bad luck or faulty implementation. Short-term prediction, despite its limitations, provides an option for dealing with the longer-term future. If a computer-controlled car tries to drive itself from New York to Los Angeles, no conceivable (or possible) stand-alone software can be constructed to predict a priori the space-time trajectory of the vehicle. Yet the drive is normally completed easily by most drivers. The trip is successfully completed because each in a series of very short (linear) steps can be "corrected" on the fly by the driver, who takes her cues from the environment to keep the car on the road and headed toward its destination. This metaphor differs in a fundamental way from the usual notion of predicting geomorphic change, because it involves a goal—to reach a desired

  5. Electric vehicle drive systems

    Science.gov (United States)

    Appleyard, M.

    1992-01-01

    New legislation in the State of California requires that 2% of vehicles sold there from 1998 will be 'zero-emitting'. This provides a unique market opportunity for developers of electric vehicles but substantial improvements in the technology are probably required if it is to be successfully exploited. There are around a dozen types of battery that are potentially relevant to road vehicles but, at the present, lead/acid and sodium—sulphur come closest to combining acceptable performance, life and cost. To develop an efficient, lightweight electric motor system requires up-to-date techniques of magnetics design, and the latest power-electronic and microprocessor control methods. Brushless machines, coupled with solid-state inverters, offer the most economical solution for mass production, even though their development costs are higher than for direct-current commutator machines. Fitted to a small car, even the highest energy-density batteries will only provide around 200 km average range before recharging. Therefore, some form of supplementary on-board power generation will probably be needed to secure widespread acceptance by the driving public. Engine-driven generators of quite low power can achieve useful increases in urban range but will fail to qualify as 'zero-emitting'. On the other hand, if the same function could be economically performed by a small fuel-cell using hydrogen derived from a methanol reformer, then most of the flexibility provided by conventional vehicles would be retained. The market prospects for electric cars would then be greatly enhanced and their dependence on very advanced battery technology would be reduced.

  6. Meeting the occupational needs of a neurologically impaired client for driving: a case review.

    Science.gov (United States)

    Rolland, Beth; Dickerson, Anne E; Brooks, Johnell

    2013-10-01

    Driving as a means of community mobility is an activity highly valued by individuals. When a medical condition impacts a person's ability to drive, occupational therapy practitioners should address this instrumental task of daily living with the client in order for the client to know if and when return to driving might be possible. This case review illustrates how the task of driving motivated a neurologically impaired client in therapy as well as how driving evaluation and driving rehabilitation intervention should not be done in isolation, but with the communication that will optimally assist the client to return to functional performance.

  7. Mild Cognitive Impairment and driving: Does in-vehicle distraction affect driving performance?

    Science.gov (United States)

    Beratis, Ion N; Pavlou, Dimosthenis; Papadimitriou, Eleonora; Andronas, Nikolaos; Kontaxopoulou, Dionysia; Fragkiadaki, Stella; Yannis, George; Papageorgiou, Sokratis G

    2017-06-01

    In-vehicle distraction is considered to be an important cause of road accidents. Drivers with Mild Cognitive Impairment (MCI), because of their attenuated cognitive resources, may be vulnerable to the effects of distraction; however, previous relevant research is lacking. The main objective of the current study was to explore the effect of in-vehicle distraction on the driving performance of MCI patients, by assessing their reaction time at unexpected incidents and accident probability. Thirteen patients with MCI (age: 64.5±7.2) and 12 cognitively intact individuals (age: 60.0±7.7), all active drivers were introduced in the study. The driving simulator experiment included three distraction conditions: (a) undistracted driving, (b) conversing with passenger and (c) conversing through a hand-held mobile phone. The mixed ANOVA models revealed a greater effect of distraction on MCI patients. Specifically, the use of mobile phone induced a more pronounced impact on reaction time and accident probability in the group of patients, as compared to healthy controls. On the other hand, in the driving condition "conversing with passenger" the interaction effects regarding reaction time and accident probability were not significant. Notably, the aforementioned findings concerning the MCI patients in the case of the mobile phone were observed despite the effort of the drivers to apply a compensatory strategy by reducing significantly their speed in this driving condition. Overall, the current findings indicate, for the first time, that a common driving practice, such as the use of mobile phone, may have a detrimental impact on the driving performance of individuals with MCI. Copyright © 2017. Published by Elsevier Ltd.

  8. Hereditary ovarian cancer and two-compartment tumor metabolism: epithelial loss of BRCA1 induces hydrogen peroxide production, driving oxidative stress and NFκB activation in the tumor stroma.

    Science.gov (United States)

    Martinez-Outschoorn, Ubaldo E; Balliet, Renee M; Lin, Zhao; Whitaker-Menezes, Diana; Howell, Anthony; Sotgia, Federica; Lisanti, Michael P

    2012-11-15

    Mutations in the BRCA1 tumor suppressor gene are commonly found in hereditary ovarian cancers. Here, we used a co-culture approach to study the metabolic effects of BRCA1-null ovarian cancer cells on adjacent tumor-associated stromal fibroblasts. Our results directly show that BRCA1-null ovarian cancer cells produce large amounts of hydrogen peroxide, which can be abolished either by administration of simple antioxidants (N-acetyl-cysteine; NAC) or by replacement of the BRCA1 gene. Thus, the BRCA1 gene normally suppresses tumor growth by functioning as an antioxidant. Importantly, hydrogen peroxide produced by BRCA1-null ovarian cancer cells induces oxidative stress and catabolic processes in adjacent stromal fibroblasts, such as autophagy, mitophagy and glycolysis, via stromal NFκB activation. Catabolism in stromal fibroblasts was also accompanied by the upregulation of MCT4 and a loss of Cav-1 expression, which are established markers of a lethal tumor microenvironment. In summary, loss of the BRCA1 tumor suppressor gene induces hydrogen peroxide production, which then leads to metabolic reprogramming of the tumor stroma, driving stromal-epithelial metabolic coupling. Our results suggest that new cancer prevention trials with antioxidants are clearly warranted in patients that harbor hereditary/familial BRCA1 mutations.

  9. Crystal structures of cytochrome P450 2B4 in complex with the inhibitor 1-biphenyl-4-methyl-1H-imidazole: ligand-induced structural response through alpha-helical repositioning.

    Science.gov (United States)

    Gay, Sean C; Sun, Ling; Maekawa, Keiko; Halpert, James R; Stout, C David

    2009-06-09

    Two different ligand occupancy structures of cytochrome P450 2B4 (CYP2B4) in complex with 1-biphenyl-4-methyl-1H-imidazole (1-PBI) have been determined by X-ray crystallography. 1-PBI belongs to a series of tight binding, imidazole-based CYP2B4 inhibitors. 1-PBI binding to CYP2B4 yields a type II spectrum with a K(s) value of 0.23 microM and inhibits enzyme activity with an IC(50) value of 0.035 microM. Previous CYP2B4 structures have shown a large degree of structural movement in response to ligand size. With two phenyl rings, 1-PBI is larger than 1-(4-chlorophenyl)imidazole (1-CPI) and 4-(4-chlorophenyl)imidazole (4-CPI) but smaller than bifonazole, which is branched and contains three phenyl rings. The CYP2B4-1-PBI complex is a structural intermediate to the closed CPI and the open bifonazole structures. The B/C-loop reorganizes itself to include two short partial helices while closing one side of the active site. The F-G-helix cassette pivots over the I-helix in direct response to the size of the ligand in the active site. A cluster of Phe residues at the fulcrum of this pivot point allows for dramatic repositioning of the cassette with only a relatively small amount of secondary structure rearrangement. Comparisons of ligand-bound CYP2B4 structures reveal trends in plastic region mobility that could allow for predictions of their position in future structures based on ligand shape and size.

  10. Automated driving safer and more efficient future driving

    CERN Document Server

    Horn, Martin

    2017-01-01

    The main topics of this book include advanced control, cognitive data processing, high performance computing, functional safety, and comprehensive validation. These topics are seen as technological bricks to drive forward automated driving. The current state of the art of automated vehicle research, development and innovation is given. The book also addresses industry-driven roadmaps for major new technology advances as well as collaborative European initiatives supporting the evolvement of automated driving. Various examples highlight the state of development of automated driving as well as the way forward. The book will be of interest to academics and researchers within engineering, graduate students, automotive engineers at OEMs and suppliers, ICT and software engineers, managers, and other decision-makers.

  11. Empathic concern drives costly altruism.

    Science.gov (United States)

    FeldmanHall, Oriel; Dalgleish, Tim; Evans, Davy; Mobbs, Dean

    2015-01-15

    Why do we self-sacrifice to help others in distress? Two competing theories have emerged, one suggesting that prosocial behavior is primarily motivated by feelings of empathic other-oriented concern, the other that we help mainly because we are egoistically focused on reducing our own discomfort. Here we explore the relationship between costly altruism and these two sub-processes of empathy, specifically drawing on the caregiving model to test the theory that trait empathic concern (e.g. general tendency to have sympathy for another) and trait personal distress (e.g. predisposition to experiencing aversive arousal states) may differentially drive altruistic behavior. We find that trait empathic concern--and not trait personal distress--motivates costly altruism, and this relationship is supported by activity in the ventral tegmental area, caudate and subgenual anterior cingulate, key regions for promoting social attachment and caregiving. Together, this data helps identify the behavioral and neural mechanisms motivating costly altruism, while demonstrating that individual differences in empathic concern-related brain responses can predict real prosocial choice. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

  12. Empathic concern drives costly altruism

    Science.gov (United States)

    FeldmanHall, Oriel; Dalgleish, Tim; Evans, Davy; Mobbs, Dean

    2015-01-01

    Why do we self-sacrifice to help others in distress? Two competing theories have emerged, one suggesting that prosocial behavior is primarily motivated by feelings of empathic other-oriented concern, the other that we help mainly because we are egoistically focused on reducing our own discomfort. Here we explore the relationship between costly altruism and these two sub-processes of empathy, specifically drawing on the caregiving model to test the theory that trait empathic concern (e.g. general tendency to have sympathy for another) and trait personal distress (e.g. predisposition to experiencing aversive arousal states) may differentially drive altruistic behavior. We find that trait empathic concern – and not trait personal distress – motivates costly altruism, and this relationship is supported by activity in the ventral tegmental area, caudate and subgenual anterior cingulate, key regions for promoting social attachment and caregiving. Together, this data helps identify the behavioral and neural mechanisms motivating costly altruism, while demonstrating that individual differences in empathic concern-related brain responses can predict real prosocial choice. PMID:25462694

  13. Perilla oil and exercise decrease expressions of tumor necrosis factor-alpha, plasminogen activator inhibitor-1 and highly sensitive C-reactive protein in patients with hyperlipidemia.

    Science.gov (United States)

    Wei, Minggang; Xiong, Peihua; Zhang, Ling; Fei, Mei; Chen, Aiping; Li, Fengling

    2013-04-01

    To verify the effects of perilla oil on the regulation of blood lipid levels in patients with hyperlipidemia. Blood was taken from patients prior to and 8 weeks following treatment with perilla oil. Different ways to test for indexes which correlate to hyperlipidemia were performed. Some indexes, which correlate with inflammation and injury to endothelial cells, were tested using enzyme linked immunosorbent assays. Serum lipid levels [triglyceride (TG), total cholesterol (TC), and low-density lipoprotein-cholesterol (LDL-C)] changed significantly after 56 days of treatment. Differences were noted as early as 28 days after treatment began (P oil showed statistically significant recovery levels of high-density lipoprotein-cholesterol (HDL-C) after 28 and 56 days of treatment. Plasma lipids levels were significantly lower after 56 days of treatment (P oil reduced blood lipid levels in patients, and the regulation of cell signaling factor levels had no adverse effects on patients' liver or kidney function, or blood routine examinations. Perilla oil treatment is safe in clinical use, can regulate blood lipid levels and protects the function of endothelial cells.

  14. Correlation between Inflammation and Fibrinolysis in Hypertensive Centrally Obese Subjects: A Study on C-Reactive Protein, Plasminogen Activator Inhibitor-1 and Thrombin Activatable Fibrinolysis Inhibitor

    Directory of Open Access Journals (Sweden)

    Yati Sumiyati

    2012-12-01

    Full Text Available BACKGROUND: Hypertension and central obesity are risk factors of cardiovascular disease. Epidemiology studies have shown that these two conditions are closely linked and often occur simultaneously. Inflammation is an underlying pathomechanism in hypertension and obesity. Vascular inflammation is related to coagulation pathway, whereby high level of inflammation increases the risk of atherothrombosis event. The aim of this study was to investigate the correlation between inflammation and fibrinolysis in hypertensive centrally obese subjects compared with hypertensive non obese subjects. METHODS: This was a cross sectional study conducted in October 2009-June 2010 involving 53 eligible subjects according to the following criteria: men or women aged 30-65 years, had neither diabetes (FPG <126 mg/dL and or OGTT <200 mg/dL nor CKD (eGFR ≥60 mL/minutes. All subjects were not in an acute inflammation state, had no unspecific infection (hs-CRP ≤10 mg/L, or taking anti-inflammation or anti-hypertensive medication. RESULTS: In this study we found that the levels of hs-CRP (2.636 mg/L vs. 1.024 mg/L, p=0.007, PAI-1 (43.58 ng/mL vs. 28.43 ng/mL, p=0.089 and TAFI (12.73 ng/mL vs. 12.19 ng/mL, p=0.479 were respectively higher in hypertensive subjects with central obesity than in hypertensive subjects with no central obesity. In hypertensive centrally obese subjects there was significant positive correlation between hs-CRP and PAI-1 (r=0.491, p=0.001 and TAFI (r=0.312, p=0.0390, meanwhile in hypertensive non-obese subjects significant correlation was found only between hs-CRP and TAFI (r=0.929, p=0.003. CONCLUSIONS: Obesity in hypertensive subjects has higher inflammation state that is correlated with fibrinolysis disruption. KEYWORDS: hypertensive, obesity, hs-CRP, PAI-1, TAFI.

  15. 4G/5G and A-844G Polymorphisms of Plasminogen Activator Inhibitor-1 Associated with Glioblastoma in Iran--a Case-Control Study.

    Science.gov (United States)

    Pooyan, Honari; Ahmad, Ebrahimi; Azadeh, Rakhshan

    2015-01-01

    Glioblastoma is a highly aggressive and malignant brain tumor. Risk factors are largely unknown however, although several biomarkers have been identified which may support development, angiogenesis and invasion of tumor cells. One of these biomarkers is PAI-1. 4G/5G and A-844G are two common polymorphisms in the gene promotor of PAI 1 that may be related to high transcription and expression of this gene. Studies have shown that the prevalence of the 4G and 844G allele is significantly higher in patients with some cancers and genetic disorders. We here assessed the association of 4G/5G and A-844G polymorphisms with glioblastoma cancer risk in Iranians in a case-control study. All 71 patients with clinically confirmed and 140 volunteers with no history and symptoms of glioblastoma as control group were screened for 4G/5G and A-844G polymorphisms of PAI-1, using ARMS-PCR. Genotype and allele frequencies of case and control groups were analyzed using the DeFinetti program. Our results showed significant associations between 4G/5G (p=0.01824) and A-844G (p=0.02012) polymorphisms of the PAI-1 gene with glioblastoma cancer risk in our Iranian population. The results of this study supporting an association of the PAI-1 4G/5G (p=0.01824) and A-844G (p=0.02012) polymorphisms with increasing glioblastoma cancer risk in Iranian patients.

  16. Investigation of Plasminogen Activator Inhibitor-1 (PAI-1) 4G/5G promoter polymorphism in Indian venous thrombosis patients: A case-control study.

    Science.gov (United States)

    Prabhudesai, Aniket; Shetty, Shrimati; Ghosh, Kanjaksha; Kulkarni, Bipin

    2017-09-01

    The role of PAI-1 4G/5G polymorphism in venous thrombosis has been contradictory. PAI-1 4G/4G genotype is associated with elevated levels of PAI-1 resulting in a hypofibrinolytic state and a higher thrombotic risk. In this study, the distribution of genotypes and frequency of alleles of the 4G/5G polymorphism of PAI-1 gene in Indian patients with different types of venous thrombosis was investigated for its role in development of thrombosis. A total of 87 portal vein thrombosis (PVT), 71 Budd-Chiari syndrome (BCS), 156 cerebral vein thrombosis (CVT), and 163 deep vein thrombosis (DVT) patients were studied alongside 251 healthy controls for the PAI-1 4G/5G polymorphism by allele-specific PCR. Frequency of 4G/4G genotype was higher in all groups in comparison with controls. 4G/4G was associated with PVT risk (OR=2.51, 95% CI=1.29-4.96, P=.0075), BCS risk (OR=5.98, 95% CI=2.68-13.42, P<.0001), and DVT risk (OR=1.75, 95% CI=0.98-3.02, P=.0225). This is the first case-control study from India establishing PAI-1 4G/4G as a strong risk factor for abdominal thrombosis (PVT and BCS). Statistically significant association was not found between 4G/4G genotype and CVT risk. PAI-1 4G/4G is a strong risk factor for venous thrombosis in Indian patients and should be included in laboratory testing panel of thrombophilia. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  17. Wood Bark Smoke Induces Lung and Pleural Plasminogen Activator Inhibitor 1 and Stabilizes Its mRNA in Porcine Lung Cells

    Science.gov (United States)

    2011-08-01

    volume assist control (n = 12) or APRV (n = 7). Three of the WBS challenged animals ventilated with CMV did not develop severe hypoxemia within 2 h...plots of the residuals (deviation of the fitted function from the actual data). Statistical significance and medians and values at 75% and 25% intervals...were determined using the Mann Whitney rank sum test as described previously (18). P G 0.05 was considered statistically significant. Box plots of

  18. Motor Integrated Variable Speed Drives

    OpenAIRE

    Singh, Yash Veer

    2015-01-01

    A new trend in the variable speed drives (VSDs) is to develop fully integrated systems, which lead to low-cost products with shorter design cycles. Motor Integrated design of VSDs will reduce cable length to connect drive with machine windings and installation time for end user. The electric drives are expected to have minimum effect on grid and motor connected to it, i.e. currents drawn from grid should be within specified limits and currents injecting in to machine should not overheat the m...

  19. Among High School Seniors, Driving After Marijuana Use Surpasses Drunk Driving

    Science.gov (United States)

    ... Driving After Marijuana Use Surpasses Drunk Driving Among High School Seniors, Driving After Marijuana Use Surpasses Drunk Driving ... NIDA Notes Contributing Writer Nearly 1 in 6 high school seniors who responded to a 2011 survey reported ...

  20. Drowsy driving and automobile crashes

    Science.gov (United States)

    1998-04-01

    Drowsy driving is a serious problem that leads to : thousands of automobile crashes each year. This : report, sponsored by the National Center on : Sleep Disorders Research (NCSDR) of the National : Heart, Lung, and Blood Institute of the : National ...