bluuebunny/crossref_metadata_2025 huggingface dataset:
Transfer of nitric oxide by blood from upstream to downstream resistance vessels causes microvascular dilation
Authors: Bohlen H. G. , Zhou X. , Unthank J. L. , Miller S. J. , Bills R.
Published: August 2009

The discovery that hemoglobin, albumin, and glutathione carry and release nitric oxide (NO) may have consequences for movement of NO by blood within microvessels. We hypothesize that NO in plasma or bound to proteins likely survives to downstream locations. To confirm this hypothesis, there must be a finite NO concentration ([NO]) in arteriolar blood, and upstream resistance vessels must be able to increase the vessel wall [NO] of downstream arterioles. Arteriolar blood NO was measured with NO-sensitive microelectrodes, and vessel wall [NO] was consistently 25–40% higher than blood [NO]. Localized suppression of NO production in large arterioles over 500–1,000 μm with l-nitroarginine reduced the [NO] ∼40%, indicating as much as 60% of the wall NO was from blood transfer. Flow in mesenteric arteries was elevated by occlusion of adjacent arteries to induce a flow-mediated increase in arterial NO production. Both arterial wall and downstream arteriolar [NO] increased and the arterioles dilated as the blood [NO] was increased. To study receptor-mediated NO generation, bradykinin was locally applied to upstream large arterioles and NO measured there and in downstream arterioles. At both sites, [NO] increased and both sets of vessels dilated. When isoproterenol was applied to the upstream vessels, they dilated, but neither the [NO] or diameter downstream arterioles increased. These observations indicate that NO can move in blood from upstream to downstream resistance vessels. This mechanism allows larger vessels that generate large [NO] to influence vascular tone in downstream vessels in response to both flow and receptor stimuli.
Role of MCP-1 in tumor necrosis factor-α-induced endothelial dysfunction in type 2 diabetic mice
Authors: Yang Jiyeon , Park Yoonjung , Zhang Hanrui , Gao Xue , Wilson Emily , Zimmer Warren , Abbott Louise , Zhang Cuihua
Published: August 2009

Tumor necrosis factor-α (TNF-α) upregulates the expression of monocyte chemoattractant protein-1 (MCP-1) and adhesion molecules in type 2 diabetes. We hypothesized that TNF-α and MCP-1 may interact to contribute to the evolution of vascular inflammation and endothelial dysfunction in coronary arterioles in type 2 diabetes. To test this hypothesis, we administered anti-MCP-1 to block MCP-1 signaling in genetically modified mice with type 2 diabetes (Leprdb) and in heterozygote (m Leprdb) lean control. Anti-MCP-1 partially restored vasodilation to the endothelium-dependent vasodilator acetylcholine in isolated, cannulated, and pressurized coronary arterioles in Leprdbmice but did not affect vasodilation in m Leprdbmice. Anti-MCP-1 attenuated superoxide production and the protein expression of nitrotyrosine, which is an indicator of peroxynitrite production, in isolated coronary arterioles of Leprdbmice. Immunostaining results showed that the expression of MCP-1 and vascular cellular adhesion molecule-1 is colocalized with endothelial cells and macrophages. Anti-TNF-α or anti-MCP-1 markedly reduced macrophage infiltration and the number of MCP-1-positive endothelium in Leprdbmice. The neutralization of TNF-α or anti-MCP-1 reduced the expression of adhesion molecules, suggesting that proinflammatory cytokines interact to amplify the signaling process that leads to vascular dysfunction. These findings demonstrate that the endothelial dysfunction occurring in type 2 diabetes is the result of the effects of the inflammatory cytokine TNF-α and TNF-α-related signaling, including the expression of MCP-1 and adhesion molecules, which further exacerbates vessel inflammation and oxidative stress.
GPD1L links redox state to cardiac excitability by PKC-dependent phosphorylation of the sodium channel SCN5A
Authors: Valdivia Carmen R. , Ueda Kazuo , Ackerman Michael J. , Makielski Jonathan C.
Published: August 2009

The SCN5A-encoded cardiac sodium channel underlies excitability in the heart, and dysfunction of sodium current ( INa) can cause fatal ventricular arrhythmia in maladies such as long QT syndrome, Brugada syndrome (BrS), and sudden infant death syndrome (SIDS). The gene GPD1L encodes the glycerol phosphate dehydrogenase 1-like protein with homology to glycerol phosphate dehydrogenase (GPD1), but the function for this enzyme is unknown. Mutations in GPD1L have been associated with BrS and SIDS and decrease INa through an unknown mechanism. Using a heterologous expression system, we show that GPD1L associated with SCN5A and that the BrS- and SIDS-related mutations in GPD1L caused a loss of enzymatic function resulting in glycerol-3-phosphate PKC-dependent phosphorylation of SCN5A at serine 1503 (S1503) through a GPD1L-dependent pathway. The direct phosphorylation of S1503 markedly decreased INa. These results show a function for GPD1L in cell physiology and a mechanism linking mutations in GPD1L to sudden cardiac arrest. Because the enzymatic step catalyzed by GPD1L depends upon nicotinamide adenine dinucleotide, this GPD1L pathway links the metabolic state of the cell to INa and excitability and may be important more generally in cardiac ischemia and heart failure.
T-type calcium channels are regulated by hypoxia/reoxygenation in ventricular myocytes
Authors: Pluteanu Florentina , Cribbs Leanne L.
Published: August 2009

Low-voltage-activated calcium channels are reexpressed in ventricular myocytes in pathological conditions associated with hypoxic episodes, but a direct relation between oxidative stress and T-type channel function and regulation in cardiomyocytes has not been established. We aimed to investigate low-voltage-activated channel regulation under oxidative stress in neonatal rat ventricular myocytes. RT-PCR measurements of voltage-gated Ca2+ (Cav)3.1 and Cav3.2 mRNA levels in oxidative stress were compared with whole cell patch-clamp recordings of T-type calcium current. The results indicate that hypoxia reduces T-type current density at −30 mV (the hallmark of this channel) based on the shift of the voltage dependence of activation to more depolarized values and downregulation of Cav3.1 at the mRNA level. Upon reoxygenation, both Cav3.1 mRNA levels and the voltage dependence of total T-type current are restored, although differently for activation and inactivation. Using Ni2+, we distinguished different effects of hypoxia/reoxygenation on the two current components. Long-term incubation in the presence of 100 μM CoCl2 reproduced the effects of hypoxia on T-type current activation and inactivation, indicating that the chemically induced oxidative state is sufficient to alter T-type calcium current activity, and that hypoxia-inducible factor-1α is involved in Cav3.1 downregulation. Our results demonstrate that Cav3.1 and Cav3.2 T-type calcium channels are differentially regulated by hypoxia/reoxygenation injury, and, therefore, they may serve different functions in the myocyte in response to hypoxic injury.
Serotonin produces monoamine oxidase-dependent oxidative stress in human heart valves
Authors: Peña-Silva Ricardo A. , Miller Jordan D. , Chu Yi , Heistad Donald D.
Published: August 2009

Heart valve disease and pulmonary hypertension, in patients with carcinoid tumors and people who used the fenfluramine-phentermine combination for weight control, have been associated with high levels of serotonin in blood. The mechanism by which serotonin induces valvular changes is not well understood. We recently reported that increased oxidative stress is associated with valvular changes in aortic valve stenosis in humans and mice. In this study, we tested the hypothesis that serotonin induces oxidative stress in human heart valves, and examined mechanisms by which serotonin may increase reactive oxygen species. Superoxide (O2·−) was measured in heart valves from explanted human hearts that were not used for transplantation. O2·−levels (lucigenin-enhanced chemoluminescence) were increased in homogenates of cardiac valves and blood vessels after incubation with serotonin. A nonspecific inhibitor of flavin-oxidases (diphenyliodonium), or inhibitors of monoamine oxidase [MAO (tranylcypromine and clorgyline)], prevented the serotonin-induced increase in O2·−. Dopamine, another MAO substrate that is increased in patients with carcinoid syndrome, also increased O2·−levels in heart valves, and this effect was attenuated by clorgyline. Apocynin [an inhibitor of NAD(P)H oxidase] did not prevent increases in O2·−during serotonin treatment. Addition of serotonin to recombinant human MAO-A generated O2·−, and this effect was prevented by an MAO inhibitor. In conclusion, we have identified a novel mechanism whereby MAO-A can contribute to increased oxidative stress in human heart valves and pulmonary artery exposed to serotonin and dopamine.
Left ventricular remodeling with exercise in hypertension
Authors: Kolwicz Stephen C. , MacDonnell Scott M. , Renna Brian F. , Reger Patricia O. , Seqqat Rachid , Rafiq Khadija , Kendrick Zebulon V. , Houser Steven R. , Sabri Abdelkarim , Libonati Joseph R.
Published: August 2009

We investigated how exercise training superimposed on chronic hypertension impacted left ventricular remodeling. Cardiomyocyte hypertrophy, apoptosis, and proliferation in hearts from female spontaneously hypertensive rats (SHRs) were examined. Four-month-old SHR animals were placed into a sedentary group (SHR-SED; n = 18) or a treadmill running group (SHR-TRD, 20 m/min, 1 h/day, 5 days/wk, 12 wk; n = 18). Age-matched, sedentary Wistar Kyoto (WKY) rats were controls ( n = 18). Heart weight was greater in SHR-TRD vs. both WKY ( P < 0.01) and SHR-SED ( P < 0.05). Morphometric-derived left ventricular anterior, posterior, and septal wall thickness were increased in SHR-SED relative to WKY and augmented in SHR-TRD. Cardiomyocyte surface area, length, and width were increased in SHR-SED relative to WKY and further increased in SHR-TRD. Calcineurin abundance was increased in SHR-SED vs. WKY ( P < 0.001) and attenuated in SHR-TRD relative to SHR-SED ( P < 0.05). Protein abundance and mRNA of Akt was not different among groups. The rate of apoptosis was increased in SHR-SED relative to WKY and mitigated in SHR-TRD. The abundance of Ki-67+ cells across groups was not statistically different across groups. The abundance of cardiac progenitor cells (c-Kit+ cells) was increased in SHR-TRD relative to WKY. These data suggest that exercise training superimposed on hypertension augmented cardiomyocyte hypertrophy, despite attenuating calcineurin abundance. Exercise training also mitigated apoptosis in hypertension and showed a tendency to enhance the abundance of cardiac progenitor cells, resulting in a more favorable cardiomyocyte number in the exercise-trained hypertensive heart.
Chronic hypercapnia downregulates arginase expression and activity and increases pulmonary arterial smooth muscle relaxation in the newborn rat
Authors: Belik Jaques , Stevens Danielle , Pan Jingyi , Shehnaz Darakhshanda , Ibrahim Christine , Kantores Crystal , Ivanovska Julijana , Grasemann Hartmut , Jankov Robert P.
Published: August 2009

In rats, chronic hypercapnia has been reported to ameliorate hypoxia-induced pulmonary hypertension in newborn and adult and to enhance endothelium-dependent vasorelaxation in adult pulmonary arteries. The underlying mechanisms accounting for chronic hypercapnia-induced improvements in pulmonary vascular function are not understood. Hypothesizing that downregulation of arginase activity may be contributory, we examined relaxation responses and arginase activity and expression in pulmonary arteries from newborn rats that were exposed (from birth to 14 days) to either mild-to-moderate (5.5% inhaled CO2) or severe (10% CO2) hypercapnia with either normoxia or hypoxia (13% O2). Pulmonary arteries from pups exposed to normoxia and chronic hypercapnia (5.5 or 10% CO2) contracted less in response to a thromboxane A2 analog, U-46619, and showed enhanced endothelium-dependent (but not independent) relaxation compared with arteries from normocapnic pups ( P < 0.01). Parallel with these changes, arginase activity and arginase I (but not II) expression in lung and pulmonary arterial tissue were significantly decreased ( P < 0.05). Exposure to 10% CO2 significantly increased ( P < 0.01) pulmonary arterial tissue nitric oxide (nitrite) generation. In pups chronically exposed to hypoxia (13% O2), severe hypercapnia (10% CO2) significantly ( P < 0.05) enhanced endothelium-dependent relaxation, increased nitric oxide generation, and decreased arginase activity but not expression. We conclude that chronic hypercapnia-induced downregulation of lung arginase expression and/or activity may reduce pulmonary vascular resistance by enhancing nitric oxide generation and thus endothelium-dependent relaxation. This mechanism may explain some of the beneficial effects of chronic hypercapnia on experimental pulmonary hypertension.
Regulation of intrapleural fibrinolysis by urokinase-α-macroglobulin complexes in tetracycline-induced pleural injury in rabbits
Authors: Komissarov Andrey A. , Mazar Andrew P. , Koenig Kathy , Kurdowska Anna K. , Idell Steven
Published: August 2009

The proenzyme single-chain urokinase plasminogen activator (scuPA) more effectively resolved intrapleural loculations in rabbits with tetracycline (TCN)-induced loculation than a range of clinical doses of two-chain uPA (Abbokinase) and demonstrated a trend toward greater efficacy than single-chain tPA (Activase) (Idell S et al., Exp Lung Res 33: 419, 2007.). scuPA more slowly generates durable intrapleural fibrinolytic activity than Abbokinase or Activase, but the interactions of these agents with inhibitors in pleural fluids (PFs) have been poorly understood. PFs from rabbits with TCN-induced pleural injury treated with intrapleural scuPA, its inactive Ser195Ala mutant, Abbokinase, Activase, or vehicle, were analyzed to define the mechanism by which scuPA induces durable fibrinolysis. uPA activity was elevated in PFs of animals treated with scuPA, correlated with the ability to clear pleural loculations, and resisted (70–80%) inhibition by PAI-1. α-macroglobulin (αM) but not urokinase receptor complexes immunoprecipitated from PFs of scuPA-treated rabbits retained uPA activity that resists PAI-1 and activates plasminogen. Conversely, little plasminogen activating or enzymatic activity resistant to PAI-1 was detectable in PFs of rabbits treated with Abbokinase or Activase. Consistent with these findings, PAI-1 interacts with scuPA much slower than with Activase or Abbokinase in vitro. An equilibrium between active and inactive scuPA (kon= 4.3 h−1) limits the rate of its inactivation by PAI-1, favoring formation of complexes with αM. These observations define a newly recognized mechanism that promotes durable intrapleural fibrinolysis via formation of αM/uPA complexes. These complexes promote uPA-mediated plasminogen activation in scuPA-treated rabbits with TCN-induced pleural injury.
Mechanism regulating proasthmatic effects of prolonged homologous β2-adrenergic receptor desensitization in airway smooth muscle
Authors: Nino Gustavo , Hu Aihua , Grunstein Judith S. , Grunstein Michael M.
Published: August 2009

Use of long-acting β2-adrenergic receptor (β2AR) agonists to treat asthma incurs an increased risk of asthma morbidity with impaired bronchodilation and heightened bronchoconstriction, reflecting the adverse effects of prolonged homologous β2AR desensitization on airway smooth muscle (ASM) function. Since phosphodiesterase 4 (PDE4) regulates ASM relaxation and contractility, we examined whether the changes in ASM function induced by prolonged homologous β2AR desensitization are attributed to altered expression and action of PDE4. Cultured human ASM cells and isolated rabbit ASM tissues exposed for 24 h to the long-acting β2AR agonist salmeterol exhibited impaired acute β2AR-mediated cAMP accumulation and relaxation, respectively, together with ASM constrictor hyperresponsiveness. These proasthmatic-like changes in ASM function were associated with upregulated PDE4 activity due to enhanced expression of the PDE4D5 isoform and were prevented by pretreating the ASM preparations with the PDE4 inhibitor rolipram or with inhibitors of either PKA or ERK1/2 signaling. Extended studies using gene silencing and pharmacological approaches demonstrated that: 1) the mechanism underlying upregulated PDE4D5 expression following prolonged β2AR agonist exposure involves PKA-dependent activation of Giprotein signaling via its βγ-subunits, which elicits downstream activation of ERK1/2 and its induction of PDE4D5 transcription; and 2) the induction of PDE4 activity and consequent changes in ASM responsiveness are prevented by pretreating the β2AR agonist-exposed ASM preparations with inhibitors of Gi-βγ signaling. Collectively, these findings identify that the proasthmatic changes in ASM function resulting from prolonged homologous β2AR desensitization are attributed to upregulated PDE4 expression induced by Gi-βγ-mediated cross-talk between the PKA and ERK1/2 signaling pathways.
Cardiac and skeletal muscle fatty acid transport and transporters and triacylglycerol and fatty acid oxidation in lean and Zucker diabetic fatty rats
Authors: Bonen Arend , Holloway Graham P. , Tandon Narendra N. , Han Xiao-Xia , McFarlan Jay , Glatz Jan F. C. , Luiken Joost J. F. P.
Published: August 2009

We examined fatty acid transporters, transport, and metabolism in hearts and red and white muscles of lean and insulin-resistant ( week 6) and type 2 diabetic ( week 24) Zucker diabetic fatty (ZDF) rats. Cardiac fatty acid transport was similar in lean and ZDF hearts at week 6 but was reduced at week 24 (−40%) in lean but not ZDF hearts. Red muscle of ZDF rats exhibited an early susceptibility to upregulation (+66%) of fatty acid transport at week 6 that was increased by 50% in lean and ZDF rats at week 24 but remained 44% greater in red muscle of ZDF rats. In white muscle, no differences were observed in fatty acid transport between groups or from week 6 to week 24. In all tissues (heart and red and white muscle), FAT/CD36 protein and plasmalemmal content paralleled the changes in fatty acid transport. Triacylglycerol content in red and white muscles, but not heart, in lean and ZDF rats correlated with fatty acid transport ( r = 0.91) and sarcolemmal FAT/CD36 ( r = 0.98). Red and white muscle fatty acid oxidation by isolated mitochondria was not impaired in ZDF rats but was reduced by 18–24% in red muscle of lean rats at week 24. Thus, in red, but not white, muscle of insulin-resistant and type 2 diabetic animals, a marked upregulation in fatty acid transport and intramuscular triacylglycerol was associated with increased levels of FAT/CD36 expression and plasmalemmal content. In heart, greater rates of fatty acid transport and FAT/CD36 in ZDF rats ( week 24) were attributable to the inhibition of age-related reductions in these parameters. However, intramuscular triacylglycerol did not accumulate in hearts of ZDF rats. Thus insulin resistance and type 2 diabetes are accompanied by tissue-specific differences in FAT/CD36 and fatty acid transport and metabolism. Upregulation of fatty acid transport increased red muscle, but not cardiac, triacylglycerol accumulation. White muscle lipid metabolism dysregulation was not observed.
Loss of vagal anti-inflammatory effect: in vivo visualization and adoptive transfer
Authors: O'Mahony Caitlin , van der Kleij Hanneke , Bienenstock John , Shanahan Fergus , O'Mahony Liam
Published: August 2009

The vagus nerve is a conduit for bidirectional signaling between the brain and the viscera. Vagal signaling has been shown to downregulate gastrointestinal inflammation, and the mechanism is thought to involve acetylcholine binding to the alpha-7 subunit of the nicotinic acetylcholine receptor on macrophages. The aims of this study were to quantify the impact of vagotomy in vivo by visualizing nuclear factor (NF)-κB activity and to determine if the proinflammatory impact of vagotomy could be transferred by lymphocytes. Real-time biophotonic imaging revealed that subdiaphragmatic vagotomy resulted in increased levels of NF-κB in vivo. NF-κB activation was further exaggerated in vivo following exposure to 4% DSS for 5 days. Vagotomized animals also exhibited higher disease activity scores and secreted more proinflammatory cytokines. Adoptive transfer of CD4+T cells from vagotomized animals (but not CD4+T cells from sham-operated controls) to naive dextran sulfate sodium (DSS)-treated recipients resulted in increased inflammatory scores. Further examination of the CD4+T cells revealed that adoptive transfer of the CD25−population alone from vagotomized donors (but not sham-operated donors) was sufficient to aggravate colitis in DSS-treated recipients. Increased DSS-induced inflammation was associated with reduced CD4+CD25+Foxp3+regulatory T cell numbers in recipients. This study clearly demonstrates the ability of the vagus nerve to modulate activity of the proinflammatory transcription factor NF-κB in vivo. The proinflammatory effect of vagotomy is transferable using splenic T cells and highlights a previously unappreciated cellular mechanism for linking central parasympathetic processes with mucosal inflammation and immune homeostasis.
Adaptation of the length-active tension relationship in rabbit detrusor
Authors: Speich John E. , Almasri Atheer M. , Bhatia Hersch , Klausner Adam P. , Ratz Paul H.
Published: August 2009

Studies have shown that the length-tension ( L-T) relationships in airway and vascular smooth muscles are dynamic and can adapt to length changes over a period of time. Our prior studies have shown that the passive L-T relationship in rabbit detrusor smooth muscle (DSM) is also dynamic and that DSM exhibits adjustable passive stiffness (APS) characterized by a passive L-T curve that can shift along the length axis as a function of strain history and activation history. The present study demonstrates that the active L-T curve for DSM is also dynamic and that the peak active tension produced at a particular muscle length is a function of both strain and activation history. More specifically, this study reveals that the active L-T relationship, or curve, does not have a unique peak tension value with a single ascending and descending limb, but instead reveals that multiple ascending and descending limbs can be exhibited in the same DSM strip. This study also demonstrates that for DSM strips not stretched far enough to reveal a descending limb, the peak active tension produced by a maximal KCl-induced contraction at a short, passively slack muscle length of 3 mm was reduced by 58.6 ± 4.1% ( n = 1 5) following stretches to and contractions at threefold the original muscle length, 9 mm. Moreover, five subsequent contractions at the short muscle length displayed increasingly greater tension; active tension produced by the sixth contraction was 91.5 ± 9.1% of that produced by the prestretch contraction at that length. Together, these findings indicate for the first time that DSM exhibits length adaptation, similar to vascular and airway smooth muscles. In addition, our findings demonstrate that preconditioning, APS and adaptation of the active L-T curve can each impact the maximum total tension observed at a particular DSM length.
Endogenous Calcium Buffering Capacity of Substantia Nigral Dopamine Neurons
Authors: Foehring R. C. , Zhang X. F. , Lee J.C.F. , Callaway J. C.
Published: August 2009

Dopamine (DA)-containing cells from the substantia nigra pars compacta (SNc) play a major role in the initiation of movement. Loss of these cells results in Parkinson's disease (PD). Changes in intracellular calcium ion concentration ([Ca2+]i) elicit several events in DA cells, including spike afterhyperpolarizations (AHPs) and subthreshold oscillations underlying autonomous firing. Continuous Ca2+load due to Ca2+-dependent rhythmicity has been proposed to cause the death of DA cells in PD and normal aging. Because of the physiological and pathophysiological importance of [Ca2+]iin DA cells, we characterized their intrinsic Ca2+-buffering capacity (KS) in brain slices. We introduced a fluorescent Ca2+-sensitive exogenous buffer (200 μM fura-2) and cells were tracked from break-in until steady state by stimulating with a single action potential (AP) every 30 s and measuring the Ca2+transient from the proximal dendrite. DA neurons filled exponentially with a τ of about 5–6 min. [Ca2+]iwas assumed to equilibrate between the endogenous Ca2+buffer and the exogenous Ca2+indicator buffer. Intrinsic buffering was estimated by extrapolating from the linear relationships between the amplitude or time constant of the Ca2+transients versus [fura-2]. Extrapolated Ca2+-transients in the absence of fura-2 had mean peak amplitudes of 293.7 ± 65.3 nM and τ = 124 ± 13 ms (postnatal day 13 [P13] to P17 animals). Intrinsic buffering increased with age in DA neurons. For cells from animals P13–P17, KSwas estimated to be about 110 ( n = 20). In older animals (P25–P32), the estimate was about 179 ( n = 10). These relatively low values may reflect the need for rapid Ca2+signaling, e.g., to allow activation of sK channels, which shape autonomous oscillations and burst firing. Low intrinsic buffering may also make DA cells vulnerable to Ca2+-dependent pathology.
Modulation of Intrinsic Spiking in Spinal Cord Neurons
Authors: Czarnecki Antonny , Magloire Vincent , Streit Jürg
Published: August 2009

The vertebrate spinal cord is equipped with a number of neuronal networks that underlie repetitive patterns of behavior as locomotion. Activity in such networks is mediated not only by intrinsic cellular properties but also by synaptic coupling. In this study, we focused on the modulation of the intrinsic activity by 5-hydroxytryptamine (5-HT, serotonin) and the cholinergic agonist muscarine in spinal cord cultures (embryonic age 14 rats). We investigated theses cultures (slices and dissociated cells) at the network level using multielectrode arrays (MEAs) and at the cellular level using whole cell patch clamp. All cultures showed bursting network activity and intrinsic activity when γ-aminobutyric acid, glycine, and glutamate transmission was blocked. Using MEAs, we observed an increase of the intrinsic activity in the ventral part of the slices with 5-HT and muscarine. In single-cell recordings we found that 43 and 35% of the cells that were silent in the absence of fast synaptic activity were transformed into intrinsically spiking cells by 5-HT and muscarine, respectively. We tested the hypothesis that these neuromodulators act via modulation of the persistent sodium currents ( INaP) in these neurons. We found that 5-HT increased threefold the amplitude of INaP, specifically in the nonintrinsically spiking cells, and thus switched these cells into intrinsically spiking cells via activation of 5-HT2receptor and the phospholipase C pathway. In contrast, the effect of muscarine on nonintrinsically spiking neurons seems to be independent of INaP. We conclude from these findings that serotoninergic and cholinergic modulation can turn silent into spontaneously spiking neurons and thus initiate new sources of activity for rhythm generation in spinal networks.
XRF of cultural heritage materials: Round-robin IV—paint on canvas
Authors: Namowicz C. , Trentelman K. , McGlinchey C.
Published: August 2009

To establish standard working practices and further understanding of the application of X-ray fluorescence (XRF) spectroscopy to works of art and cultural heritage materials, a series of round-robin tests have been conducted biannually since 2002. In 2008 the round-robin explored the application of XRF to the study of paintings on canvas. Thirteen samples, consisting of both modern and traditional pigments on canvas, were distributed to 25 participating institutions for analysis. The samples were designed to explore common challenges encountered in the XRF analysis of painted works including peak overlaps, sum peaks, layering/shielding effects, detection of low-Z pigments, and modern pigments. The results from representative samples highlighting each topic are discussed.
Finite element modeling of residual stress profile patterns in hard turning
Authors: Guo Y. B. , Anurag S.
Published: August 2009

Hard turning, i.e., turning hardened steels, may produce the unique “hook” shaped residual stress (RS) profile characterized by surface compressive RS and subsurface maximum compressive RS. However, the formation mechanism of the unique RS profile is not yet known. In this study, a novel hybrid finite element modeling approach based on thermal-mechanical coupling and internal state variable plasticity model has been developed to predict the unique RS profile patterns by hard turning AISI 52100 steel (62 HRc). The most important controlling factor for the unique characteristics of residual stress profiles has been identified. The transition of maximum residual stress at the surface to the subsurface has been recovered by controlling the plowed depth. The predicted characteristics of residual stress profiles favorably agree with the measured ones. In addition, friction coefficient only affects the magnitude of surface residual stress but not the basic shape of residual stress profiles.
Evaluation of substructure parameters by peak profile analysis of high-resolution neutron diffraction spectra
Authors: Lukáš P. , Strunz P. , Davydov V. , Kužel R.
Published: August 2009

The peak profile shape analysis has been preferentially used in the evaluation of X-ray and synchrotron powder diffraction pattern. However, neutron diffraction facilities of new generation frequently offer the instrumental resolution high enough to efficiently study the effects of broadening of neutron diffraction profiles. The present paper describes the procedure for a detailed evaluation of Bragg peak shape based on the method of transformed model fitting (TMF) which has been recently developed particularly for the treatment of neutron diffraction profiles. Microstructure modeling is performed in the reciprocal space and the convolution of the model with the instrumental resolution curve is fitted to the profiles recorded in the diffraction experiment.
Leptin Enhances Synthesis of Proinflammatory Mediators in Human Osteoarthritic Cartilage—Mediator Role of NO in Leptin-InducedPGE2, IL-6, and IL-8 Production
Authors: Vuolteenaho Katriina , Koskinen Anna , Kukkonen Meiju , Nieminen Riina , Päivärinta Unto , Moilanen Teemu , Moilanen Eeva
Published: August 2009

Obesity is an important risk factor for osteoarthritis (OA) in weight-bearing joints, but also in hand joints, pointing to an obesity-related metabolic factor that influences on the pathogenesis of OA. Leptin is an adipokine regulating energy balance, and it has recently been related also to arthritis and inflammation as a proinflammatory factor. In the present paper, the effects of leptin on human OA cartilage were studied. Leptin alone or in combination with IL-1 enhanced the expression of iNOS and COX-2, and production of NO,PGE2, IL-6, and IL-8. The results suggest that the effects of leptin are mediated through activation of transcription factor nuclear factorκB (NF-κB) and mitogen-activated protein kinase (MAPK) pathway c-JunNH2-terminal kinase (JNK). Interestingly, inhibition of leptin-induced NO production with a selective iNOS inhibitor 1400 W inhibited also the production of IL-6, IL-8, andPGE2, and this was reversed by exogenously added NO-donor SNAP, suggesting that the effects of leptin on IL-6, IL-8, andPGE2production are dependent on NO. These findings support the idea of leptin as a factor enhancing the production of proinflammatory factors in OA cartilage and as an agent contributing to the obesity-associated increased risk for osteoarthritis.
A Polyadic pi-Calculus Approach for the Formal Specification of UML-RT
Authors: Bezerra J. M. , Hirata C. M.
Published: August 2009

UML-RT is a UML real-time profile that allows modeling event-driven and distributed systems; however it is not a formal specification language. This paper proposes a formal approach for UML-RT through a mapping of the UML-RT communicating elements into the -calculus (or pi-calculus) process algebra. The formal approach both captures the intended behavior of the system being modeled and provides a rigorous and nonambiguous system description. Our proposal differentiates from other research work because we map UML-RT to -calculus, and we allow the mapping of dynamic reconfiguration of UML-RT unwired ports. We illustrate the usage and applicability of the mapping through three examples. The first example focuses on explaining the mapping; the second one aims to demonstrate the use of the -calculus definitions to verify system requirements; the third case is an example of mobile processes called Handover protocol.
Identification of Nectin-4 Oncoprotein as a Diagnostic and Therapeutic Target for Lung Cancer
Authors: Takano Atsushi , Ishikawa Nobuhisa , Nishino Ryohei , Masuda Ken , Yasui Wataru , Inai Kouki , Nishimura Hitoshi , Ito Hiroyuki , Nakayama Haruhiko , Miyagi Yohei , Tsuchiya Eiju , Kohno Nobuoki , Nakamura Yusuke , Daigo Yataro
Published: August 2009

Gene expression profile analysis of lung cancers revealed the transactivation of an immunoglobulin-like molecule Nectin-4 in the majority of non–small cell lung cancers (NSCLC). Immunohistochemical staining of 422 NSCLCs showed that a high level of Nectin-4 expression was associated with poor prognosis for NSCLC patients (P < 0.0001), and multivariate analysis confirmed its independent prognostic value (P < 0.0001). We established an ELISA to measure serum Nectin-4 and found that serum Nectin-4 levels were significantly higher in NSCLC patients than in healthy volunteers. The proportion of the serum Nectin-4–positive cases was 88 of 164 (53.7%) NSCLCs, whereas only 3 of 131 (2.3%) healthy volunteers were falsely diagnosed as positive, which was superior to carcinoembryonic antigen (CEA) and cytokeratin 19-fragment (CYFRA21-1) in sensitivity and specificity. A combined ELISA for both Nectin-4 and CEA increased sensitivity and classified 65.0% of lung adenocarcinomas as positive with false-positive rate of 4.6%. The use of both Nectin-4 and CYFRA21-1 classified 68.3% of lung squamous cell carcinomas as positive with false-positive rate of 6.1%. Treatment of lung cancer cells with small interfering RNAs against Nectin-4 suppressed its expression and cell growth. In addition, exogenous expression of Nectin-4 increased the lamellipodia formation and the invasive ability of mammalian cells through activation of small GTPase Rac1. Nectin-4 might play a significant role in lung carcinogenesis, and it should be a new candidate serum and tissue biomarker, as well as a therapeutic target. [Cancer Res 2009;69(16):6694–703]
Metformin Disrupts Crosstalk between G Protein–Coupled Receptor and Insulin Receptor Signaling Systems and Inhibits Pancreatic Cancer Growth
Authors: Kisfalvi Krisztina , Eibl Guido , Sinnett-Smith James , Rozengurt Enrique
Published: August 2009

Recently, we identified a novel crosstalk between insulin and G protein–coupled receptor (GPCR) signaling pathways in human pancreatic cancer cells. Insulin enhanced GPCR signaling through a rapamycin-sensitive mTOR-dependent pathway. Metformin, the most widely used drug in the treatment of type 2 diabetes, activates AMP kinase (AMPK), which negatively regulates mTOR. Here, we determined whether metformin disrupts the crosstalk between insulin receptor and GPCR signaling in pancreatic cancer cells. Treatment of human pancreatic cancer cells (PANC-1, MIAPaCa-2, and BxPC-3) with insulin (10 ng/mL) for 5 minutes markedly enhanced the increase in intracellular [Ca2+] induced by GPCR agonists (e.g., neurotensin, bradykinin, and angiotensin II). Metformin pretreatment completely abrogated insulin-induced potentiation of Ca2+ signaling but did not interfere with the effect of GPCR agonists alone. Insulin also enhanced GPCR agonist–induced growth, measured by DNA synthesis, and the number of cells cultured in adherent or nonadherent conditions. Low doses of metformin (0.1–0.5 mmol/L) blocked the stimulation of DNA synthesis, and the anchorage-dependent and anchorage-independent growth induced by insulin and GPCR agonists. Treatment with metformin induced striking and sustained increase in the phosphorylation of AMPK at Thr172 and a selective AMPK inhibitor (compound C, at 5 μmol/L) reversed the effects of metformin on [Ca2+]i and DNA synthesis, indicating that metformin acts through AMPK activation. In view of these results, we tested whether metformin inhibits pancreatic cancer growth. Administration of metformin significantly decreased the growth of MIAPaCa-2 and PANC-1 cells xenografted on the flank of nude mice. These results raise the possibility that metformin could be a potential candidate in novel treatment strategies for human pancreatic cancer. [Cancer Res 2009;69(16):6539–45]
Akairos or Eukairos? The Nickname of the Seleucid King Demetrius III in the Transmission of the Texts of Josephus' War and Antiquities
Authors: Martin Thomas , Levenson David
Published: August 2009

Although modern scholars generally refer to Demetrius III as Eukairos, all the Greek manuscripts of Josephus' War and Antiquities reponed by Niese, as well as all editors since Niese, read Akairos in the three places the nickname is found. Attestations of Eukairos (Greek and Latin Table of Contents, Latin manuscripts of Antiquities, and early editions) are best explained as secondary developments in the transmission of the text. The influence of the Greek editio princeps, which unjustifiably prints Eukairos in all three places in Josephus' text, accounts for the appearance of the nickname in all editions of Josephus' works until the mid-nineteenth century and hence for its use in modern scholarship. Since Josephus is our only source for the nickname, Demetrius III should never be identified as Eukairos. If a nickname is to be used, it should either be Akairos or one (or more) of the official names found on the ruler's coinage.
Stringency in Qumran: A Reassessment
Authors: Noam Vered
Published: August 2009

The attribution of stringency to the Qumranites is prevalent in scholarly research. Indeed it is indisputable that the Sect generally adopts stringent positions, compared to rabbinic halakah. However, closer examination indicates that Qumranic law reflects simple, necessary inferences from Scripture itself, whereas the Tannaitic leniency represents a surprisingly revolutionary divergence from the plain meaning of Scripture. The paper surveys several cases in which the bold and exceptional nature of Tannaitic legislation cannot serve as a criterion for evaluating the stringency of Sectarian law. It goes on to review other instances, where the very same traditions formed the basis of Qumranic as well as rabbinic regulation, except that the latter restricted their scope. The third group of examples shows that it was precisely the unrefined, simple character of Qumranic law, in comparison with the conceptual sophistication of Tannaitic halakah, that occasionally led to the opposite result, in which the Tannaitic halakah was strict, and the Sectarian law lenient. In sum, the strictness of Qumranic law is not “objective” but relative. The understanding that sectarian law reflects a series of inductions not altogether removed from the simple sense of Scripture facilitates a more accurate appreciation of the depth of Tannaitic halakah's groundbreaking leniency.
Kosher Olive Oil in Antiquity Reconsidered
Authors: Rosenblum Jordan
Published: August 2009

Josephus attests several times to a Jewish aversion to the use of Gentile olive oil. In m. 'Abod. Zar. 2:6, this practice is first advocated and then immediately reversed by Rabbi and his court. What is the rationale for this sudden leniency with regard to Gentile olive oil? In a well-known article entitled “Kosher Olive Oil in Antiquity,” Martin Goodman argues that Rabbi's statement is the result of his inability to find a legal basis for the prohibition of Gentile olive oil. Goodman, however, accounts neither for the unique economic and dietary factors associated with olive oil, nor tannaitic legislation regarding other foodstuffs that may shed light on this case. In this article, I reconsider Jewish stances towards Gentile olive oil in antiquity from the time of Josephus to the Tannaitic period.
Influence of Beam Incidence Angle in Laser Welding of Austenitic Stainless Steel using Finite Element Analysis
Authors: Siva Shanmugam N. , Buvanashekaran G. , Sankaranarayanasamy K. , Manonmani K.
Published: August 2009

This paper presents the influence of beam incidence angle on austenitic stainless steel sheet subjected to a high density laser beam having Gaussian power density distribution. Bead‐on trials are conducted on 3.15 mm thick commercial AISI 304 austenitic stainless steel sheet using a Nd:YAG laser source with a maximum output of 2kW in the continuous wave mode. The effects of beam incident angle on the weld bead geometry are studied using finite element analysis. Experiments are conducted with 600, 1000 and 1400W laser power and 800, 1400 and 2000mm/min welding speed. A three dimensional finite element model is developed for the simulation of non‐linear transient thermal analysis of the weld bead geometry for different beam incident angles using the finite element code ANSYS. The result reveals that by increasing the beam incident angle with constant beam power and welding speed, there is a considerable reduction in the depth of penetration‐to‐width ratio (d/w). Further, it is noticed that the process enters into conduction mode of welding from the keyhole mode of welding as the beam angle is increased beyond 10o. The comparison of the simulation results and the experimental data for weld bead geometry with different beam incident angles show good agreement.
Theoretical Studies of Convectively Forced Mesoscale Flows in Three Dimensions. Part II: Shear Flow with a Critical Level
Authors: Han Ji-Young , Baik Jong-Jin
Published: August 2009

Convectively forced mesoscale flows in a shear flow with a critical level are theoretically investigated by obtaining analytic solutions for a hydrostatic, nonrotating, inviscid, Boussinesq airflow system. The response to surface pulse heating shows that near the center of the moving mode, the magnitude of the vertical velocity becomes constant after some time, whereas the magnitudes of the vertical displacement and perturbation horizontal velocity increase linearly with time. It is confirmed from the solutions obtained in present and previous studies that this result is valid regardless of the basic-state wind profile and dimension. The response to 3D finite-depth steady heating representing latent heating due to cumulus convection shows that, unlike in two dimensions, a low-level updraft that is necessary to sustain deep convection always occurs at the heating center regardless of the intensity of vertical wind shear and the heating depth. For deep heating across a critical level, little change occurs in the perturbation field below the critical level, although the heating top height increases. This is because downward-propagating gravity waves induced by the heating above, but not near, the critical level can hardly affect the flow response field below the critical level. When the basic-state wind backs with height, the vertex of V-shaped perturbations above the heating top points to a direction rotated a little clockwise from the basic-state wind direction. This is because the V-shaped perturbations above the heating top is induced by upward-propagating gravity waves that have passed through the layer below where the basic-state wind direction is clockwise relative to that above.
Relative Contribution of Greenhouse Gases and Ozone-Depleting Substances to Temperature Trends in the Stratosphere: A Chemistry–Climate Model Study
Authors: Stolarski Richard S. , Douglass Anne R. , Newman Paul A. , Pawson Steven , Schoeberl Mark R.
Published: August 2009

The temperature of the stratosphere has decreased over the past several decades. Two causes contribute to that decrease: well-mixed greenhouse gases (GHGs) and ozone-depleting substances (ODSs). This paper addresses the attribution of temperature decreases to these two causes and the implications of that attribution for the future evolution of stratospheric temperature. Time series analysis is applied to simulations of the Goddard Earth Observing System Chemistry–Climate Model (GEOS CCM) to separate the contributions of GHGs from those of ODSs based on their different time-dependent signatures. The analysis indicates that about 60%–70% of the temperature decrease of the past two decades in the upper stratosphere near 1 hPa and in the lower midlatitude stratosphere near 50 hPa resulted from changes attributable to ODSs, primarily through their impact on ozone. As ozone recovers over the next several decades, the temperature should continue to decrease in the middle and upper stratosphere because of GHG increases. The time series of observed temperature in the upper stratosphere is approaching the length needed to separate the effects of ozone-depleting substances from those of greenhouse gases using temperature time series data.
Observed Large-Scale Structures and Diabatic Heating and Drying Profiles during TWP-ICE
Authors: Xie Shaocheng , Hume Timothy , Jakob Christian , Klein Stephen A. , McCoy Renata B. , Zhang Minghua
Published: August 2009

This study documents the characteristics of the large-scale structures and diabatic heating and drying profiles observed during the Tropical Warm Pool–International Cloud Experiment (TWP-ICE), which was conducted in January–February 2006 in Darwin during the northern Australian monsoon season. The examined profiles exhibit significant variations between four distinct synoptic regimes that were observed during the experiment. The active monsoon period is characterized by strong upward motion and large advective cooling and moistening throughout the entire troposphere, while the suppressed and clear periods are dominated by moderate midlevel subsidence and significant low- to midlevel drying through horizontal advection. The midlevel subsidence and horizontal dry advection are largely responsible for the dry midtroposphere observed during the suppressed period and limit the growth of clouds to low levels. During the break period, upward motion and advective cooling and moistening located primarily at midlevels dominate together with weak advective warming and drying (mainly from horizontal advection) at low levels. The variations of the diabatic heating and drying profiles with the different regimes are closely associated with differences in the large-scale structures, cloud types, and rainfall rates between the regimes. Strong diabatic heating and drying are seen throughout the troposphere during the active monsoon period while they are moderate and only occur above 700 hPa during the break period. The diabatic heating and drying tend to have their maxima at low levels during the suppressed periods. The diurnal variations of these structures between monsoon systems, continental/coastal, and tropical inland-initiated convective systems are also examined.
The CASA Integrated Project 1 Networked Radar System
Authors: Junyent Francesc , Chandrasekar V. , McLaughlin D. , Insanic E. , Bharadwaj N.
Published: August 2009

This paper describes the Collaborative Adaptive Sensing of the Atmosphere (CASA) Integrated Project 1 (IP1) weather radar network, the first distributed collaborative adaptive sensing test bed of the Engineering Research Center for Collaborative Adaptive Sensing of the Atmosphere. The radar network and radar node hardware and software architectures are described, as well as the different interfaces between the integrated subsystems. The system’s operation and radar node control and weather data flow are explained. The key features of the radar nodes are presented, as well as examples of different data products.