bluuebunny/crossref_metadata_2025 huggingface dataset:
Losartan improves aortic endothelium-dependent relaxation via proline-rich tyrosine kinase 2/Src/Akt pathway in type 2 diabetic Goto-Kakizaki rats
Authors: Nemoto Shingo , Kobayashi Tsuneo , Taguchi Kumiko , Matsumoto Takayuki , Kamata Katsuo
Published: September 2011

In diabetic states, endothelial dysfunction is related to vascular complications. We hypothesized that insulin-induced relaxation and the associated proline-rich tyrosine kinase 2 (Pyk2)/Src/Akt pathway would be abnormal in aortas from the Goto-Kakizaki (GK) type 2 diabetic rat, which exhibits hyperglycemia/insulin resistance, and that losartan treatment of such rats (25 mg·kg−1·day−1for 2 wk) would correct these abnormalities. Endothelium-dependent relaxation was by measuring isometric force in helical strips of aortas from four groups, each of 30 rats: normal Wistar (control), GK (diabetic), losartan-treated normal, and losartan-treated GK. Pyk2, Src, and Akt/endothelial nitric oxide synthase (eNOS) signaling-pathway protein levels and activities were assayed mainly by Western blotting and partly by immunohistochemistry. In GK (vs. age-matched control) aortas, various insulin-stimulated levels [nitric oxide production and the phosphorylations of eNOS at Ser1177, of Akt at Thr308, of phosphoinositide-dependent kinase-1 (PDK1) at Ser241, of Src at Tyr416, and of Pyk2 at Tyr579] were all significantly decreased and unaffected by either Src inhibitor (PP2) or Pyk2 inhibitor (AG17), while the insulin-stimulated levels of insulin receptor substrate (IRS)-1 phosphorylation at Ser307, total-eNOS, and total-Akt were significantly increased. Losartan treatment normalized these altered levels. The insulin-stimulated phosphorylation levels of Src/PDK1/Akt/eNOS, but not of Pyk2, were decreased by PP2 in control and losartan-treated GK, but not in GK, aortas. These results suggest that in the GK diabetic aorta increased phospho-IRS-1 (at Ser307) and decreased Pyk2/Src activity inhibit insulin-induced stimulation of the PDK/Akt/eNOS pathway. The observed increase in phospho-IRS-1 (at Ser307) may result from increased angiotensin II activity.
Mis-sizing of stent promotes intimal hyperplasia: impact of endothelial shear and intramural stress
Authors: Chen Henry Y. , Sinha Anjan K. , Choy Jenny S. , Zheng Hai , Sturek Michael , Bigelow Brian , Bhatt Deepak L. , Kassab Ghassan S.
Published: September 2011

Stent can cause flow disturbances on the endothelium and compliance mismatch and increased stress on the vessel wall. These effects can cause low wall shear stress (WSS), high wall shear stress gradient (WSSG), oscillatory shear index (OSI), and circumferential wall stress (CWS), which may promote neointimal hyperplasia (IH). The hypothesis is that stent-induced abnormal fluid and solid mechanics contribute to IH. To vary the range of WSS, WSSG, OSI, and CWS, we intentionally mismatched the size of stents to that of the vessel lumen. Stents were implanted in coronary arteries of 10 swine. Intravascular ultrasound (IVUS) was used to size the coronary arteries and stents. After 4 wk of stent implantation, IVUS was performed again to determine the extent of IH. In conjunction, computational models of actual stents, the artery, and non-Newtonian blood were created in a computer simulation to yield the distribution of WSS, WSSG, OSI, and CWS in the stented vessel wall. An inverse relation ( R2 = 0.59, P < 0.005) between WSS and IH was found based on a linear regression analysis. Linear relations between WSSG, OSI, and IH were observed ( R2 = 0.48 and 0.50, respectively, P < 0.005). A linear relation ( R2 = 0.58, P < 0.005) between CWS and IH was also found. More statistically significant linear relations between the ratio of CWS to WSS (CWS/WSS), the products CWS × WSSG and CWS × OSI, and IH were observed ( R2 = 0.67, 0.54, and 0.56, respectively, P < 0.005), suggesting that both fluid and solid mechanics influence the extent of IH. Stents create endothelial flow disturbances and intramural wall stress concentrations, which correlate with the extent of IH formation, and these effects were exaggerated with mismatch of stent/vessel size. These findings reveal the importance of reliable vessel and stent sizing to improve the mechanics on the vessel wall and minimize IH.
A role for cardiotrophin-1 in myocardial remodeling induced by aldosterone
Authors: López-Andrés Natalia , Martin-Fernandez Beatriz , Rossignol Patrick , Zannad Faiez , Lahera Vicente , Fortuno Maria Antonia , Cachofeiro Victoria , Díez Javier
Published: September 2011

Hyperaldosteronim is associated with left ventricular (LV) hypertrophy (LVH) and fibrosis. Cardiotrophin (CT)-1 is a cytokine that induces myocardial remodeling. We investigated whether CT-1 mediates aldosterone (Aldo)-induced myocardial remodeling in two experimental models. Wistar rats were treated with Aldo-salt (1 mg·kg−1·day−1) with or without spironolactone (200 mg·kg−1·day−1) for 3 wk. Wild-type (WT) and CT-1-null mice were infused with Aldo (1 mg·kg−1·day−1) for 3 wk. Hemodynamic parameters were analyzed. LVH, fibrosis, inflammation, and CT-1 expression were evaluated in both experimental models by histopathological analysis, RT-PCR, Western blot analysis, and ELISA. Hypertensive Aldo-treated rats exhibited increased LV end-diastolic pressure and −dP/d t compared with controls. The cardiac index, LV cross-sectional area and wall thickness, cardiomyocyte size, collagen deposition, and inflammation were increased in Aldo-salt-treated rats. Myocardial expression of molecular markers assessing LVH and fibrosis as well as CT-l levels were also augmented by Aldo-salt. Spironolactone treatment reversed all the above effects. CT-1 correlated positively with hemodynamic, histological, and molecular parameters showing myocardial remodeling. In WT and CT-1-null mice, Aldo infusion did not modify blood pressure. Whereas Aldo treatment induced LVH, fibrosis, and inflammation in WT mice, the mineralocorticoid did not provoke cardiac remodeling in CT-1-null mice. In conclusion, in experimental hyperaldosteronism, the increase in CT-1 expression was associated with parameters showing LVH and fibrosis. CT-1-null mice were resistant to Aldo-induced LVH and fibrosis. These data suggest a key role for CT-1 in cardiac remodeling induced by Aldo independent of changes in blood pressure levels.
Arterial vasodilatory and ventricular diastolic reserves determine the stroke volume response to exercise in elderly female hypertensive patients
Authors: Sahlén Anders , Abdula Goran , Norman Mikael , Manouras Aristomenis , Brodin Lars-Åke , Lund Lars H. , Shahgaldi Kambiz , Winter Reidar
Published: September 2011

Elderly female hypertensives with arterial stiffening constitute a majority of patients with heart failure with preserved ejection fraction (HFpEF), a condition characterized by inability to increase cardiac stroke volume (SV) with physical exercise. As SV is determined by the interaction between the left ventricle (LV) and its load, we wished to study the role of arterial hemodynamics for exertional SV reserve in patients at high risk of HFpEF. Twenty-one elderly (67 ± 9 yr) female hypertensive patients were studied at rest and during supine bicycle stress using echocardiography including pulsed-wave Doppler to record flow in the LV outflow tract and arterial tonometry for central arterial pressure waveforms. Arterial compliance was estimated based on an exponential relationship between pressure and volume. The ratio of aortic pressure-to-flow in early systole was used to derive characteristic impedance, which was subsequently subtracted from total resistance (mean arterial pressure/cardiac output) to yield systemic vascular resistance (SVR). It was found that patients with depressed SV reserve ( NoRes; reserve <15%; n = 10) showed decreased arterial compliance during exercise, while patients with SV reserve ≥15% ( Res; n = 11) showed increased compliance. Exercise produced parallel increases in LV end-diastolic volume and arterial volume in Res patients while NoRes patients exhibited a lesser decrease in SVR and a drop in effective arterial volume. Poor SV reserve in elderly female hypertensives is due to simultaneous failure of LV preload and arterial vasodilatory reserves. Abnormal arterial function contributes to a high risk of HFpEF in these patients.
SNARE-mediated rapid lysosome fusion in membrane raft clustering and dysfunction of bovine coronary arterial endothelium
Authors: Han Wei-Qing , Xia Min , Zhang Chun , Zhang Fan , Xu Ming , Li Ning-Jun , Li Pin-Lan
Published: September 2011

The present study attempted to evaluate whether soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) mediate lysosome fusion in response to death receptor activation and contribute to membrane raft (MR) clustering and consequent endothelial dysfunction in coronary arterial endothelial cells. By immunohistochemical analysis, vesicle-associated membrane proteins 2 (VAMP-2, vesicle-SNAREs) were found to be abundantly expressed in the endothelium of bovine coronary arteries. Direct lysosome fusion monitoring by N-(3-triethylammoniumpropyl)-4-[4-(dibutylamino)styryl]pyridinium dibromide (FM1-43) quenching demonstrated that the inhibition of VAMP-2 with tetanus toxin or specific small interfering ribonucleic acid (siRNA) almost completely blocked lysosome fusion to plasma membrane induced by Fas ligand (FasL), a well-known MR clustering stimulator. The involvement of SNAREs was further confirmed by an increased interaction of VAMP-2 with a target-SNARE protein syntaxin-4 after FasL stimulation in coimmunoprecipitation analysis. Also, the inhibition of VAMP-2 with tetanus toxin or VAMP-2 siRNA abolished FasL-induced MR clustering, its colocalization with a NADPH oxidase unit gp91 phox, and increased superoxide production. Finally, FasL-induced impairment of endothelium-dependent vasodilation was reversed by the treatment of bovine coronary arteries with tetanus toxin or VAMP-2 siRNA. VAMP-2 is critical to lysosome fusion in MR clustering, and this VAMP-2-mediated lysosome-MR signalosomes contribute to redox regulation of coronary endothelial function.
4-D blood flow in the human right ventricle
Authors: Fredriksson Alexandru G. , Zajac Jakub , Eriksson Jonatan , Dyverfeldt Petter , Bolger Ann F. , Ebbers Tino , Carlhäll Carl-Johan
Published: September 2011

Right ventricular (RV) function is a powerful prognostic indicator in many forms of heart disease, but its assessment remains challenging and inexact. RV dysfunction may alter the normal patterns of RV blood flow, but those patterns have been incompletely characterized. We hypothesized that, based on anatomic differences, the proportions and energetics of RV flow components would differ from those identified in the left ventricle (LV) and that the portion of the RV inflow passing directly to outflow ( Direct Flow) would be prepared for effective systolic ejection as a result of preserved kinetic energy (KE) compared with other RV flow components. Three-dimensional, time-resolved phase-contrast velocity, and balanced steady-state free-precession morphological data were acquired in 10 healthy subjects using MRI. A previously validated method was used to separate the RV and LV end-diastolic volumes into four flow components and measure their volume and KE over the cardiac cycle. The RV Direct Flow: 1) followed a smoothly curving route that did not extend into the apical region of the ventricle; 2) had a larger volume and possessed a larger presystolic KE (0.4 ± 0.3 mJ) than the other flow components ( P < 0.001 and P < 0.01, respectively); and 3) represented a larger part of the end-diastolic blood volume compared with the LV Direct Flow ( P < 0.01). These findings suggest that diastolic flow patterns distinct to the normal RV create favorable conditions for ensuing systolic ejection of the Direct Flow component. These flow-specific aspects of RV diastolic-systolic coupling provide novel perspectives on RV physiology and may add to the understanding of RV pathophysiology.
Heart rate-associated mechanical stress impairs carotid but not cerebral artery compliance in dyslipidemic atherosclerotic mice
Authors: Bolduc Virginie , Drouin Annick , Gillis Marc-Antoine , Duquette Natacha , Thorin-Trescases Nathalie , Frayne-Robillard Isabelle , Des Rosiers Christine , Tardif Jean-Claude , Thorin Eric
Published: September 2011

The cardiac cycle imposes a mechanical stress that dilates elastic carotid arteries, while shear stress largely contributes to the endothelium-dependent dilation of downstream cerebral arteries. In the presence of dyslipidemia, carotid arteries stiffen while the endothelial function declines. We reasoned that stiffening of carotid arteries would be prevented by reducing resting heart rate (HR), while improving the endothelial function would regulate cerebral artery compliance and function. Thus we treated or not 3-mo-old male atherosclerotic mice (ATX; LDLr-/−:hApoB+/+) for 3 mo with the sinoatrial pacemaker current inhibitor ivabradine (IVA), the β-blocker metoprolol (METO), or subjected mice to voluntary physical training (PT). Arterial (carotid and cerebral artery) compliance and endothelium-dependent flow-mediated cerebral dilation were measured in isolated pressurized arteries. IVA and METO similarly reduced ( P < 0.05) 24-h HR by ≈15%, while PT had no impact. As expected, carotid artery stiffness increased ( P < 0.05) in ATX mice compared with wild-type mice, while cerebral artery stiffness decreased ( P < 0.05); this paradoxical increase in cerebrovascular compliance was associated with endothelial dysfunction and an augmented metalloproteinase-9 (MMP-9) activity ( P < 0.05), without changing the lipid composition of the wall. Reducing HR (IVA and METO) limited carotid artery stiffening, but plaque progression was prevented by IVA only. In contrast, IVA maintained and PT improved cerebral endothelial nitric oxide synthase-dependent flow-mediated dilation and wall compliance, and both interventions reduced MMP-9 activity ( P < 0.05); METO worsened endothelial dysfunction and compliance and did not reduce MMP-9 activity. In conclusion, HR-dependent mechanical stress contributes to carotid artery wall stiffening in severely dyslipidemic mice while cerebrovascular compliance is mostly regulated by the endothelium.
Pressure-volume relation analysis of mouse ventricular function
Authors: Cingolani Oscar H. , Kass David A.
Published: September 2011

Nearly 40 years ago, the Sagawa laboratory spawned a renaissance in the use of instantaneous ventricular pressure-volume (P-V) relations to assess cardiac function. Since then, this analysis has taken hold as the most comprehensive way to quantify ventricular chamber function and energetics and cardiovascular interactions. First studied in large mammalian hearts and later in humans employing a catheter-based method, P-V analysis was translated to small rodents in the late 1990s by the Kass laboratory. Over the past decade, this approach has become a gold standard for comprehensive examination of in vivo cardiac function in mice, facilitating a new era of molecular cardiac physiology. The catheter-based method remains the most widely used approach in mice. In this brief review, we discuss this instrumentation, the theory behind its use, and how volume signals are calibrated and discuss elements of P-V analysis. The goal is to provide a convenient summary of earlier investigations and insights for users whose primary interests lie in genetic/molecular studies rather than in biomedical engineering.
Shedding of the endothelial glycocalyx in arterioles, capillaries, and venules and its effect on capillary hemodynamics during inflammation
Authors: Lipowsky Herbert H. , Gao Lujia , Lescanic Ann
Published: September 2011

The endothelial glycocalyx has been identified as a barrier to transvascular exchange of fluid, macromolecules, and leukocyte-endothelium [endothelial cell (EC)] adhesion during the inflammatory process. Shedding of glycans and structural changes of the glycocalyx have been shown to occur in response to several agonists. To elucidate the effects of glycan shedding on microvascular hemodynamics and capillary resistance to flow, glycan shedding in microvessels in mesentery (rat) was induced by superfusion with 10−7M fMLP. Shedding was quantified by reductions of fluorescently labeled lectin (BS-1) bound to the EC and reductions in thickness of the barrier to infiltration of 70-kDa dextran on the EC surface. Red cell velocities (two-slit technique), pressure drops (dual servo-null method), and capillary hematocrit (direct cell counting) were measured in parallel experiments. The results indicate that fMLP caused shedding of glycans in all microvessels with reductions in thickness of the barrier to 70-kDa dextran of 110, 80, and 123 nm, in arterioles, capillaries, and venules, respectively. Intravascular volumetric flows fell proportionately in all three divisions in response to rapid obstruction of venules by white blood cell (WBC)-EC adhesion, and capillary resistance to flow rose 18% due to diminished deformability of activated WBCs. Capillary resistance fell significantly 26% over a 30-min period, as glycans were shed from the EC surface to increase effective capillary diameter, whereas capillary hematocrit and anatomic diameter remained invariant. This decrease in capillary resistance mitigates the increase in resistance due to diminished WBC deformability, and hence these concurrent rheological events may be of equal importance in affecting capillary flow during the inflammatory process.
Hypoxia induces downregulation of PPAR-γ in isolated pulmonary arterial smooth muscle cells and in rat lung via transforming growth factor-β signaling
Authors: Gong Kaizheng , Xing Dongqi , Li Peng , Aksut Baran , Ambalavanan Namasivayam , Yang Qinglin , Nozell Susan E. , Oparil Suzanne , Chen Yiu-Fai
Published: September 2011

Chronic hypoxia activates transforming growth factor-β (TGF-β) signaling and leads to pulmonary vascular remodeling. Pharmacological activation of peroxisome proliferator-activated receptor-γ (PPAR-γ) has been shown to prevent hypoxia-induced pulmonary hypertension and vascular remodeling in rodent models, suggesting a vasoprotective effect of PPAR-γ under chronic hypoxic stress. This study tested the hypothesis that there is a functional interaction between TGF-β/Smad signaling pathway and PPAR-γ in isolated pulmonary artery small muscle cells (PASMCs) under hypoxic stress. We observed that chronic hypoxia led to a dramatic decrease of PPAR-γ protein expression in whole lung homogenates (rat and mouse) and hypertrophied pulmonary arteries and isolated PASMCs. Using a transgenic model of mouse with inducible overexpression of a dominant-negative mutant of TGF-β receptor type II, we demonstrated that disruption of TGF-β pathway significantly attenuated chronic hypoxia-induced downregulation of PPAR-γ in lung. Similarly, in isolated rat PASMCs, antagonism of TGF-β signaling with either a neutralizing antibody to TGF-β or the selective TGF-β receptor type I inhibitor SB431542 effectively attenuated hypoxia-induced PPAR-γ downregulation. Furthermore, we have demonstrated that TGF-β1 treatment suppressed PPAR-γ expression in PASMCs under normoxia condition. Chromatin immunoprecipitation analysis showed that TGF-β1 treatment significantly increased binding of Smad2/3, Smad4, and the transcriptional corepressor histone deacetylase 1 to the PPAR-γ promoter in PASMCs. Conversely, treatment with the PPAR-γ agonist rosiglitazone attenuated TGF-β1-induced extracellular matrix molecule expression and growth factor in PASMCs. These data provide strong evidence that activation of TGF-β/Smad signaling, via transcriptional suppression of PPAR-γ expression, mediates chronic hypoxia-induced downregulation of PPAR-γ expression in lung.
The PPARγ ligand rosiglitazone attenuates hypoxia-induced endothelin signaling in vitro and in vivo
Authors: Kang Bum-Yong , Kleinhenz Jennifer M. , Murphy Tamara C. , Hart C. Michael
Published: September 2011

Peroxisome proliferator-activated receptor (PPAR) γ activation attenuates hypoxia-induced pulmonary hypertension (PH) in mice. The current study examined the hypothesis that PPARγ attenuates hypoxia-induced endothelin-1 (ET-1) signaling to mediate these therapeutic effects. To test this hypothesis, human pulmonary artery endothelial cells (HPAECs) were exposed to normoxia or hypoxia (1% O2) for 72 h and treated with or without the PPARγ ligand rosiglitazone (RSG, 10 μM) during the final 24 h of exposure. HPAEC proliferation was measured with MTT assays or cell counting, and mRNA and protein levels of ET-1 signaling components were determined. To explore the role of hypoxia-activated transcription factors, selected HPAECs were treated with inhibitors of hypoxia-inducible factor (HIF)-1α (chetomin) or nuclear factor (NF)-κB (caffeic acid phenethyl ester, CAPE). In parallel studies, male C57BL/6 mice were exposed to normoxia (21% O2) or hypoxia (10% O2) for 3 wk with or without gavage with RSG (10 mg·kg−1·day−1) for the final 10 days of exposure. Hypoxia increased ET-1, endothelin-converting enzyme-1, and endothelin receptor A and B levels in mouse lung and in HPAECs and increased HPAEC proliferation. Treatment with RSG attenuated hypoxia-induced activation of HIF-1α, NF-κB activation, and ET-1 signaling pathway components. Similarly, treatment with chetomin or CAPE prevented hypoxia-induced increases in HPAEC ET-1 mRNA and protein levels. These findings indicate that PPARγ activation attenuates a program of hypoxia-induced ET-1 signaling by inhibiting activation of hypoxia-responsive transcription factors. Targeting PPARγ represents a novel therapeutic strategy to inhibit enhanced ET-1 signaling in PH pathogenesis.
Activation of hypoxia-inducible factor-1 protects airway epithelium against oxidant-induced barrier dysfunction
Authors: Olson Nels , Hristova Milena , Heintz Nicholas H. , Lounsbury Karen M. , van der Vliet Albert
Published: September 2011

The respiratory epithelium forms an important barrier against inhaled pollutants and microorganisms, and its barrier function is often compromised during inflammatory airway diseases. Epithelial activation of hypoxia-inducible factor-1 (HIF-1) represents one feature of airway inflammation, but the functional importance of HIF-1 within the respiratory epithelium is largely unknown. Using primary mouse tracheal epithelial (MTE) cells or immortalized human bronchial epithelial cells (16HBE14o−), we evaluated the impact of HIF-1 activation on loss of epithelial barrier function during oxidative stress. Exposure of either 16HBE14o− or MTE cells to H2O2 resulted in significant loss of transepithelial electrical resistance and increased permeability to fluorescein isothiocyanate-dextran (4 kDa), and this was attenuated significantly after prior activation of HIF-1 by preexposure to hypoxia (2% O2; 6 h) or the hypoxia mimics CoCl2 or dimethyloxalylglycine (DMOG). Oxidative barrier loss was associated with reduced levels of the tight junction protein occludin and with hyperoxidation of the antioxidant enzyme peroxiredoxin (Prx-SO2H), events that were also attenuated by prior activation of HIF-1. Involvement of HIF-1 in these protective effects was confirmed using the pharmacological inhibitor YC-1 and by short-hairpin RNA knockdown of HIF-1α. The protective effects of HIF-1 were associated with induction of sestrin-2, a hypoxia-inducible enzyme known to reduce oxidative stress and minimize Prx hyperoxidation. Together, our results suggest that loss of epithelial barrier integrity by oxidative stress is minimized by activation of HIF-1, in part by induction of sestrin-2.
Easy and Rapid Purification of Highly Active Nisin
Authors: Abts André , Mavaro Antonino , Stindt Jan , Bakkes Patrick J. , Metzger Sabine , Driessen Arnold J. M. , Smits Sander H. J. , Schmitt Lutz
Published: September 2011

Nisin is an antimicrobial peptide produced and secreted by several L. lactis strains and is specifically active against Gram-positive bacteria. In previous studies, nisin was purified via cation exchange chromatography at low pH employing a single-step elution using 1 M NaCl. Here, we describe an optimized purification protocol using a five-step NaCl elution to remove contaminants. The obtained nisin is devoid of impurities and shows high bactericidal activity against the nisin-sensitive L. lactis strain NZ9000. Purified nisin exhibits an IC50 of ~3 nM, which is a tenfold improvement as compared to nisin obtained via the one-step elution procedure.
A Two-Step Identification Approach for Twin-Box Models of RF Power Amplifier
Authors: Liu You-Jiang , Zhou Bang-Hua , Zhou Jie , Liu Yi-Nong
Published: September 2011

We propose a two-step identification approach for twin-box model (Wiener or Hammerstein) of RF power amplifier. The linear filter block and the static nonlinearity block are extracted, respectively, based on least-squares method, by iterative calculation. Simulations show that the method can get quite accurate parameters to model different nonlinear models with memory such as Wiener, Hammerstein, Wiener-Hammerstein (W-H), and memory polynomial models, hence, demonstrating its robustness. Furthermore, experimental results show excellent agreement between measured output and modeled output, where one carrier WCDMA signal is used as the excitation for a wideband RF amplifier.
Comparison of Classification Methods for P300 Brain-Computer Interface on Disabled Subjects
Authors: Manyakov Nikolay V. , Chumerin Nikolay , Combaz Adrien , Van Hulle Marc M.
Published: September 2011

We report on tests with a mind typing paradigm based on a P300 brain-computer interface (BCI) on a group of amyotrophic lateral sclerosis (ALS), middle cerebral artery (MCA) stroke, and subarachnoid hemorrhage (SAH) patients, suffering from motor and speech disabilities. We investigate the achieved typing accuracy given the individual patient's disorder, and how it correlates with the type of classifier used. We considered 7 types of classifiers, linear as well as nonlinear ones, and found that, overall, one type of linear classifier yielded a higher classification accuracy. In addition to the selection of the classifier, we also suggest and discuss a number of recommendations to be considered when building a P300-based typing system for disabled subjects.
Integrin-Mediated Cell-Matrix Interaction in Physiological and Pathological Blood Vessel Formation
Authors: Niland Stephan , Eble Johannes A.
Published: September 2011

Physiological as well as pathological blood vessel formation are fundamentally dependent on cell-matrix interaction. Integrins, a family of major cell adhesion receptors, play a pivotal role in development, maintenance, and remodeling of the vasculature. Cell migration, invasion, and remodeling of the extracellular matrix (ECM) are integrin-regulated processes, and the expression of certain integrins also correlates with tumor progression. Recent advances in the understanding of how integrins are involved in the regulation of blood vessel formation and remodeling during tumor progression are highlighted. The increasing knowledge of integrin function at the molecular level, together with the growing repertoire of integrin inhibitors which allow their selective pharmacological manipulation, makes integrins suited as potential diagnostic markers and therapeutic targets.
iASPP and Chemoresistance in Ovarian Cancers: Effects on Paclitaxel-Mediated Mitotic Catastrophe
Authors: Jiang LiLi , Siu Michelle K.Y. , Wong Oscar G.W. , Tam Kai-Fai , Lu Xin , Lam Eric W-F. , Ngan Hextan Y.S. , Le Xiao-Feng , Wong Esther S.Y. , Monteiro Lara J. , Chan Hoi-Yan , Cheung Annie N.Y.
Published: September 2011

Purpose: iASPP is a specific regulator of p53-mediated apoptosis. Herein, we provided the first report on the expression profile of iASPP in ovarian epithelial tumor and its effect on paclitaxel chemosensitivity.

Experimental Design: Expression and amplification status of iASPP was examined in 203 clinical samples and 17 cell lines using immunohistochemistry, quantitative real-time PCR, and immunoblotting, and correlated with clinicopathologic parameters. Changes in proliferation, mitotic catastrophe, apoptosis, and underlying mechanism in ovarian cancer cells of different p53 status following paclitaxel exposure were also analyzed.

Results: The protein and mRNA expression of iASPP was found to be significantly increased in ovarian cancer samples and cell lines. High iASPP expression was significantly associated with clear cell carcinoma subtype (P = 0.003), carboplatin and paclitaxel chemoresistance (P = 0.04), shorter overall (P = 0.003), and disease-free (P = 0.001) survival. Multivariate analysis confirmed iASPP expression as an independent prognostic factor. Increased iASPP mRNA expression was significantly correlated with gene amplification (P = 0.023). iASPP overexpression in ovarian cancer cells conferred resistance to paclitaxel by reducing mitotic catastrophe in a p53-independent manner via activation of separase, whereas knockdown of iASPP enhanced paclitaxel-mediated mitotic catastrophe through inactivating separase. Both securin and cyclin B1/CDK1 complex were involved in regulating separase by iASPP. Conversely, overexpressed iASPP inhibited apoptosis in a p53-dependent mode.

Conclusions: Our data show an association of iASPP overexpression with gene amplification in ovarian cancer and suggest a role of iASPP in poor patient outcome and chemoresistance, through blocking mitotic catastrophe. iASPP should be explored further as a potential prognostic marker and target for chemotherapy. Clin Cancer Res; 17(21); 6924–33. ©2011 AACR.
The Clinically Active PARP Inhibitor AG014699 Ameliorates Cardiotoxicity but Does Not Enhance the Efficacy of Doxorubicin, despite Improving Tumor Perfusion and Radiation Response in Mice
Authors: Ali Majid , Kamjoo Marzieh , Thomas Huw D. , Kyle Suzanne , Pavlovska Ivanda , Babur Muhammed , Telfer Brian A. , Curtin Nicola J. , Williams Kaye J.
Published: September 2011

AG014699 was the first inhibitor of the DNA repair enzyme PARP-1 to enter clinical trial in cancer patients. In addition to enhancing the cytotoxic effect of DNA-damaging chemotherapies, we have previously shown that AG014699 is vasoactive, thereby having the potential to improve drug biodistribution. The effectiveness of the clinical agent doxorubicin is confounded both by poor tumor penetration and cardiotoxicity elicited via PARP hyperactivation. In this study, we analyzed the impact of AG014699 on doxorubicin tolerance and response in breast (MDA-MB-231) and colorectal (SW620, LoVo) tumor models in vitro and in vivo. As anticipated, AG014699 did not potentiate the response to doxorubicin in vitro. In vivo, AG014699 did not influence the pharmacokinetics of doxorubicin; however, it did ameliorate cardiotoxicity. Both toxicity and extent of amelioration were more pronounced in male than in female mice. AG014699 improved vessel perfusion in both MDA-MB-231 and SW620 tumors; however, this neither led to improved tumor-accumulation of doxorubicin nor enhanced therapeutic response. In contrast, when combined with radiotherapy, AG014699 significantly enhanced response both in vitro and in vivo. Real-time assessment of tumor vessel function and companion histologic studies indicate that doxorubicin causes a profound antivascular effect that counters the positive effect of AG014699 on perfusion. These data indicate that although AG014699 can enhance response to some chemotherapeutic drugs via improved delivery, this does not apply to doxorubicin. PARP inhibitors may still be of use to counter doxorubicin toxicity, and if the gender effect translates from rodents to humans, this would have greater effect in males. Mol Cancer Ther; 10(12); 2320–9. ©2011 AACR.
PET Imaging May Provide a Novel Biomarker and Understanding of Right Ventricular Dysfunction in Patients With Idiopathic Pulmonary Arterial Hypertension
Authors: Bokhari Sabahat , Raina Amresh , Berman Rosenweig Erika , Schulze P. Christian , Bokhari Justin , Einstein Andrew J. , Barst Robyn J. , Johnson Lynne L.
Published: September 2011

Background—

The clinical course in pulmonary arterial hypertension (PAH) is variable, and there is limited information on the determinants and progression of right ventricular (RV) dysfunction. The objective is to develop PET metabolic imaging of the RV as a noninvasive tool in patients with PAH.

Methods and Results—

We performed PET scanning in 16 patients with idiopathic PAH (age, 41±14 years, 82% women) using
13
N-NH
3
for perfusion imaging and
18
F-fluorodeoxyglucose for metabolic imaging. The myocardium was divided into 6 regions of interest (3 left ventricular [LV], 3 RV), and time-activity curves were generated. A 2- compartment model was used to calculate myocardial blood flow (MBF), and Patlak analysis was used to calculate the rate of myocardial glucose uptake (MGU). All patients underwent cardiac catheterization, cardiac MRI, and cardiopulmonary exercise testing with gas exchange. MBF, MGU, and the ratio of RV/LV MGU were correlated to clinical parameters. Pulmonary artery (PA) pressure was 79±19/30±8 mm Hg (mean, 48±10 mm Hg). MBF was 0.84±0.33 mL/g per minute for the LV and 0.45±0.14 mL/g per minute for the RV. Mean MGU was 136±72 nmol/g per minute for the LV and 96±69 nmol/g per minute for the RV. The ratio of RV/LV MGU correlated significantly with PA systolic (
r
=0.75,
P
=0.0085) and mean (
r
=0.87,
P
=0.001) pressure and marginally with maximum oxygen consumption (
r
=−0.59,
P
=0.05). RV free wall MGU also correlated well with mean PA pressure (
r
=0.66,
P
=0.03).

Conclusions—

PET scanning with
13
N-NH
3
and
18
F-fluorodeoxyglucose is a feasible modality for quantifying RV blood flow and metabolism in patients with idiopathic PAH.
Linking Lighting Appraisals to Work Behaviors
Authors: Veitch Jennifer A. , Stokkermans Mariska G. M. , Newsham Guy R.
Published: September 2011

Among those concerned with practical matters of office design, demonstrations that the work environment affects employees’ well-being and work behaviors are thought to be important to support client decision making. Veitch, Newsham, Boyce, and Jones developed a conceptual model in which lighting appraisal and visual capabilities predicted aesthetic judgments, mood, and performance. This article extends that model to include measures of work engagement, using experimental data originally reported by Newsham, Veitch, Arsenault, and Duval. Structural equation modeling showed strong fit to a model in which lighting appraisals indirectly influenced work engagement through aesthetic judgments and mood. This evidence that providing a satisfactory work environment can contribute to employee effectiveness merits further study by environmental and organizational psychologists.
Physical and Cognitive Effects of Virtual Reality Integrated Training
Authors: Stone Richard T. , Watts Kristopher P. , Zhong Peihan , Wei Chen-Shuang
Published: September 2011

Objective: The objective of this study was to evaluate the cognitive and physical impact of virtual reality (VR) integrated training versus traditional training methods in the domain of weld training.

Background: Weld training is very important in various industries and represents a complex skill set appropriate for advanced training intervention. As such, there has been a long search for the most successful and most cost-effective method for training new welders.

Method: Participants in this study were randomly assigned to one of two separate training courses taught by sanctioned American Welding Society certified welding instructors; the duration of each course was 2 weeks. After completing the training for a specific weld type, participants were given the opportunity to test for the corresponding certification. Participants were evaluated in terms of their cognitive and physical parameters, total training time exposure, and welding certification awards earned. Each of the four weld types taught in this study represented distinct levels of difficulty and required the development of specialized knowledge and skills.

Results: This study demonstrated that participants in the VR integrated training group (VR50) performed as well as, and in some cases, significantly outperformed, the traditional welding (TW) training group. The VR50 group was found to have a 41.6% increase in overall certifications earned compared with the TW group.

Conclusion: VR technology is a valuable tool for the production of skilled welders in a shorter time and often with more highly developed skills than their traditionally trained counterparts.

Application: These findings strongly support the use of VR integrated training in the welding industry.
Shining New Light on the Hawthorne Illumination Experiments
Authors: Izawa Masumi R. , French Michael D. , Hedge Alan
Published: September 2011

Objective: This study provides an historical and statistical analysis of archival data from the Hawthorne illumination experiments.

Background: Previous accounts of the illumination experiments are fraught with inconsistencies because they have been based on secondary sources. The general consensus has been that variations in light levels had no effect on worker productivity at Hawthorne. All reports and data were thought to have been destroyed, but an archive at Cornell University was found to contain copies of the original documentation and much of the data from all three illumination experiments. Conclusions were originally drawn from visual comparisons of productivity graphs, and the data have never been properly statistically analyzed.

Method: Archival reports, notes, photographs, and letters on the experiments were consulted. Productivity data were extracted from the tables and graphs in the reports and statistically analyzed for each experiment.

Results: Previously unpublished details of the illumination experiments emerged. An effect of lighting on productivity was found in the first treatment sequence for the first experiment, but this finding was not confirmed in the second sequence or in the second and third experiments.

Conclusion: Experimental results provided inconsistent evidence of an association between light levels and productivity. All three experiments were found to be seriously flawed.

Application: This study challenges popular accounts of the “Hawthorne effect,” and the shortcomings of these experiments also have implications for the design of field studies.
Biomechanical Effects of Mobile Computer Location in a Vehicle Cab
Authors: Saginus Kyle A. , Marklin Richard W. , Seeley Patricia , Simoneau Guy G. , Freier Stephen
Published: September 2011

Objective: The objective of this research is to determine the best location to place a conventional mobile computer supported by a commercially available mount in a light truck cab.

Background: U.S. and Canadian electric utility companies are in the process of integrating mobile computers into their fleet vehicle cabs. There are no publications on the effect of mobile computer location in a vehicle cab on biomechanical loading, performance, and subjective assessment.

Method: The authors tested four locations of mobile computers in a light truck cab in a laboratory study to determine how location affected muscle activity of the lower back and shoulders; joint angles of the shoulders, elbows, and wrist; user performance; and subjective assessment. A total of 22 participants were tested in this study.

Results: Placing the mobile computer closer to the steering wheel reduced low back and shoulder muscle activity. Joint angles of the shoulders, elbows, and wrists were also closer to neutral angle. Biomechanical modeling revealed substantially less spinal compression and trunk muscle force. In general, there were no practical differences in performance between the locations. Subjective assessment indicated that users preferred the mobile computer to be as close as possible to the steering wheel.

Conclusion: Locating the mobile computer close to the steering wheel reduces risk of injuries, such as low back pain and shoulder tendonitis.

Application: Results from the study can guide electric utility companies in the installation of mobile computers into vehicle cabs. Results may also be generalized to other industries that use trucklike vehicles, such as construction.
Predictors of Computer Use in Community-Dwelling, Ethnically Diverse Older Adults
Authors: Werner Julie M. , Carlson Mike , Jordan-Marsh Maryalice , Clark Florence
Published: September 2011

Objective: In this study, we analyzed self-reported computer use, demographic variables, psychosocial variables, and health and well-being variables collected from 460 ethnically diverse, community-dwelling elders to investigate the relationship computer use has with demographics, well-being, and other key psychosocial variables in older adults.

Background: Although younger elders with more education, those who employ active coping strategies, or those who are low in anxiety levels are thought to use computers at higher rates than do others, previous research has produced mixed or inconclusive results regarding ethnic, gender, and psychological factors or has concentrated on computer-specific psychological factors only (e.g., computer anxiety). Few such studies have employed large sample sizes or have focused on ethnically diverse populations of community-dwelling elders.

Method: With a large number of overlapping predictors, zero-order analysis alone is poorly equipped to identify variables that are independently associated with computer use. Accordingly, both zero-order and stepwise logistic regression analyses were conducted to determine the correlates of two types of computer use: e-mail and general computer use.

Results: Results indicate that younger age, greater level of education, non-Hispanic ethnicity, behaviorally active coping style, general physical health, and role-related emotional health each independently predicted computer usage.

Conclusion: Study findings highlight differences in computer usage, especially in regard to Hispanic ethnicity and specific health and well-being factors.

Application: Potential applications of this research include future intervention studies, individualized computer-based activity programming, or customizable software and user interface design for older adults responsive to a variety of personal characteristics and capabilities.
Social capital and knowledge transfer: A multi-level analysis
Authors: Wei Jun , Zheng Wei , Zhang Mian
Published: September 2011

This study explores how individual level and team level social capital characteristics manifest their joint influence on knowledge transfer, considering team social capital as a moderator between individual social capital and knowledge transfer. Situated in a post-training context, a survey of 390 individuals from 30 teams in a Chinese bank was conducted. Our results revealed that team social capital interacted with individual social capital in influencing knowledge transfer. At the individual level, distance and structural equivalence between the knowledge seeker and the knowledge source influenced how much knowledge was transferred between them. Furthermore, team network density mitigated the negative effect of distance on knowledge transfer, and team learning culture reduced the positive effect of structural equivalence on knowledge transfer. Theoretical implications based on the findings are drawn.
Developing and Evaluating the Social Axioms Survey in Eleven Countries
Authors: Leung Kwok , Lam Ben C. P. , Bond Michael Harris , Conway Lucian Gideon , Gornick Laura Janelle , Amponsah Benjamin , Boehnke Klaus , Dragolov Georgi , Burgess Steven Michael , Golestaneh Maha , Busch Holger , Hofer Jan , Espinosa Alejandra del Carmen Dominguez , Fardis Makon , Ismail Rosnah , Kurman Jenny , Lebedeva Nadezhda , Tatarko Alexander N. , Sam David Lackland , Teixeira Maria Luisa Mendes , Yamaguchi Susumu , Fukuzawa Ai , Zhang Jianxin , Zhou Fan
Published: September 2011

Based on a deductive, culturally decentered approach, new items were generated to improve the reliability of the original Social Axioms Survey, which measures individuals’ general beliefs about the world. In Study 1, results from 11 countries support the original five-factor structure and achieve higher reliability for the axiom dimensions as measured by the new scale. Moreover, moderate but meaningful associations between axiom and Big-Five personality dimensions were found. Temporal change of social axioms at the culture level was examined and found to be moderate. In Study 2, additional new items were generated for social complexity and fate control, then assessed in Hong Kong and the United States. Reliability was further improved for both dimensions. Additionally, two subfactors of fate control were identified: fate determinism and fate alterability. Fate determinism, but not fate alterability, related positively to neuroticism. Other relationships between axiom and personality dimensions were similar to those reported in Study 1. The short forms of the axiom dimensions were generally reliable and correlated highly with the long forms. This research thus provides a stronger foundation for applying the construct of social axioms around the world.
Multiaxis multilayered non-interlaced/non-Z E-glass/polyester preform and analysis of tensile properties of composite structures by statistical model
Authors: Bilisik Kadir , Yilmaz Banu
Published: September 2011

In this study, non-interlaced/non-Z single layer and multilayered uniaxial, biaxial and multiaxis preform structures were developed to produce E-glass/polyester composite structures. The data generated from the tensile tests of the composite structures were analyzed by using a regression model.

We found that the tensile strength of the E-glass/polyester structures depended on yarn orientation and the number of layers. It was also indicated that the tensile properties of the composite structures were proportional to their total fiber volume fractions. If all the E-glass/polyester structures are made with the same preform packing density, the structures made from coarse fiber show high tensile strength, compared to structures made from fine fiber, due to high fiber volume fraction. All structures showed mode-I type delamination failure which occurred in the out-of-plane direction as a form of interlayer splitting parallel to the applied tensile load direction. Local interlayer failures were observed between warp/warp in uniaxial structures, warp/filling in biaxial structures, and bias/bias and bias/filling in multiaxis structures due to the non-Z yarn reinforcement. The developed regression model was considered as a suitable and viable tool to predict the tensile properties of the composite structures.