bluuebunny/crossref_metadata_2025 huggingface dataset:
The Investigation of Electrochemical Properties and Ionic Motion of Functionalized Copolymer Electrolytes Based on Polysiloxane
Authors: Wang Fu-Ming , Wang Yung-Yun , Wan Chi-Chao
Published: May 2009

The effect of EO side chain functionalization on the transport and electrochemical properties of polysiloxane electrolytes has been examined in this report. First, a study of the electrochemical stability of the electrolytes by linear sweep voltammetry shows that the polymer electrolytes have a negligible effect on the electrolyte stability windows. In addition, the parameters of cation mobility in polysiloxane electrolytes, such as ionic transference numbers and diffusion coefficients, were increased by increasing the lengths of the EO side chain. However, cation mobility in polymer structures is quite different compared to liquid-based systems and is probably suppressed, resulting in their polymer structure. Therefore, Positron Annihilation Lifetime Spectroscopy (PALS) was used to study the relationship between orthopositronium (o-Ps) lifetime, free volume radius, free volume of micro voids and EO side chain affection at different temperatures. Finally, a battery application with LiCoO2 and LiFePO4/ polymer electrolyte/ lithium metal electrode was monitored for its potential use in the future.
Investigation on the Anion Complexation Ability of Organoboron Additives in Lithium-ion Battery Electrolytes - Spectroscopic Approach
Authors: Zukowska G. , Szczechura Marzena , Marcinek Marek , Zubrowska Anna , Adamczyk-Woźniak Agnieszka , Sporzyński Andrzej , Wieczorek Władysław
Published: May 2009

In this paper we present our systematic studies on the application of organoboron compounds as anion complexing additives to polymer electrolytes. The anion trapping ability of these compounds is discussed regarding the stability of various compounds, both triarylboranes as well as arylboronic esters. A possible mechanism of degradation/complexation is verified by the FTIR, and NMR spectroscopy.
Preparation and Performance of Novel Acrylonitrile (AN)-based Copolymer Gel Electrolytes for Lithium Ion Batteries
Authors: Pu Weihua , Zhang Shichao , Zhang Lan , He Xiangming , Wan Chunrong , Jiang Changyin
Published: May 2009

A novel acrylonitrile (AN)-based copolymer, P(acrylonitrile(AN)- methyl methacrylate(MMA)-methoxy polyethylene glycol(350) monoacrylate(MPGA)-lithium acrylate(LiAc)) (PAMMGLiAc) gel electrolytes was prepared in this paper. The physical properties of the AN-based copolymer membranes were characterized by IR, NMR, TGA, DSC and tensile test. The electrochemical characteristics of the AN-based gel electrolytes were investigated by electrochemical impedance spectroscopy (EIS) and linear sweep voltammetry (LSV). The results show that the gel electrolytes have high ionic conductivity over 2×10-3S/cm at room temperature, good mechanical properties and a sufficient electrochemical stability with a decomposition voltage as high as 6V vs. Li. The Li/gel electrolyte/LiFePO4 coin cells with the prepared copolymer gel electrolytes also showed a good charge/discharge performance.
Ionic Liquids and their Analogs―Electrochemical Behavior at Electrode/Electrolyte Interface
Authors: Matsui Tooru , Deguchi Masaki , Yoshizawa Hiroshi
Published: May 2009

Electrolytes of high ionic salt concentration were prepared with substances that are all solid at room temperature, using ionic liquids as references. Electrochemical intercalation of positive ions into a graphite electrode was examined with electrolytes using ionic liquids or their analogs. The reaction at the interface between the graphite and the electrolyte was highly dependent on the structures of positive and negative ions as well as the amount of an organic solvent coexisting-competitive intercalation by lithium and quarternary ammonium ions, or decomposition of the organic solvent without any intercalation of positive ions. The interface reaction was investigated from electrochemical potentials of the ion intercalation and the passivation film formation on the graphite electrode. Impedance analysis also helped the understanding of the interface phenomena, giving a model of association between positive and negative ions near the electrode surface.
Surface Analysis of Solid Electrolyte Interphase on Binder-free Graphite Electrodes in Advanced Electrolytes
Authors: Xiao Ang , Lucht Brett , Yang Li , Kang S , Abraham Daniel
Published: May 2009

The solid electrode interphase (SEI) on graphite electrodes is important to the performance, calendar life, and safety characteristics of lithium-ion cells. This transaction examines the SEI formed on binder-free (BF) graphite electrodes prepared by electrophoretic deposition. X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared spectroscopy (FTIR) data were obtained on electrodes cycled in cells containing four electrolytes comprising ethylene carbonate (EC): ethylmethyl carbonate (EMC) (3:7 by wt.) solvent and 1.2M LiPF6, 1M LiF2BC2O4, 1M LiBF4, or 0.7M LiB(C2O4)2 salt. Our observations suggest that, in addition to solvent reduction, the reduction of electrolyte salts play an important role in SEI formation.
Charge Transfer and Charge-Discharge Kinetics in Lithium-ion Batteries
Authors: Jow T. R. , Allen Jan L. , Deveney Bridget , Nechev Kamen
Published: May 2009

Charge transfer and charge-discharge kinetics of practical Li-ion cells were investigated using AC impedance and DC pulse methods. Preliminary AC impedance results indicated that the activation energy for charge transfer for high power Li-ion cells employing carbonate-linear ester solvent mixtures was similar to that for cells employing carbonate solvents as reported before. At 100 milliseconds (ms), the pulsed DC impedance indicated that the charge and discharge kinetics were fast and at about the same rate. At 15 seconds (s), the pulsed DC charge resistance was apparently higher than the discharge resistance especially at temperatures below -20 oC. The slower charging kinetics may be limited by the electron transfer step including intercalation and diffusion of Li into the carbonaceous anode.
Thermal Behavior of Ionic Liquid Electrolytes in Lithium-ion Cells
Authors: Ue Makoto , Tokuda Hiroyuki , Kawai Tomohiro , Yanagidate Miwa , Otake Yumiko
Published: May 2009

The thermal behavior of ionic liquids in lithium-ion cells was examined by a Calvet-type calorimeter using typical ionic liquid electrolytes and the charged electrodes (a LixC6 anode and a LiyNi1/3Mn1/3Co1/3O2 cathode) obtained by disassembling the lithium-ion cells with a conventional carbonate solvent electrolyte. Although ionic liquid electrolytes showed a little bit different thermal behavior compared with the conventional electrolyte, general features were almost the same. Cell safety does not directly connect to non-flammability of electrolytes based on the thermal runaway mechanism. Due to the lack of carbonate structure, ionic liquids produce much less CO2, which might be an advantage of ionic liquids for the cell safety.
Physicochemical Properties of Non-Aqueous Solvents and Electrolytes for Lithium Battery Applications
Authors: Ding Michael S. , Jow T. R.
Published: May 2009

Physicochemical properties of many carbonate and ester solvents and their solutions of lithium and quaternary ammonium salts are systematically and consistently reviewed and summarized, based on the molecular structures and properties of these solvents and salts and their interactions to form mixed solvents and electrolytes and on an array of experimental results accumulated through the years in combination with some pertinent literature values.
An Organic Electrolyte Mixed with a Quaternary Phosphonium Salt for Lithium Secondary Batteries
Authors: Tsunashima Katsuhiko , Yonekawa Fumihiro , Kikuchi Masahiro , Sugiya Masashi
Published: May 2009

The electrolytic properties of a mixed electrolyte containing methyltributylphosphonium bis(trifluoromethylsulfonyl)imide and an organic electrolyte based on lithium hexafluorophosphate, ethylene carbonate and ethyl methyl carbonate are reported. It was found that the conductivity and viscosity of the mixed phosphonium electrolyte were similar to those of the corresponding ammonium electrolyte; however, larger voltammetric response of lithium in the mixed phosphonium electrolyte and higher charge-discharge performance of the cell containing the mixed phosphonium electrolyte than those of the corresponding ammonium electrolyte were observed. In addition, the mixed phosphonium electrolyte gave relatively high cycling performance to the cell, even when compared to the more conductive organic electrolyte than the mixed phosphonium electrolyte.
A New Concept for Lithium Primary Cells using Poly(Carbon Monofluoride) Cathode -The Effect of Quinone Compounds as an Electrolyte Additive
Authors: Noda Daisuke , Takeda Masayuki , Kinoshita Shinichi , Ue Makoto
Published: May 2009

Lithium primary cells using a poly(carbon mono-fluoride), (CF)n, cathode, have peculiarities; the cell voltage drops drastically at high current discharge, and the recovery of dropped voltage requires many hours. Therefore, the next discharge step starts before the cell voltage returns the normal state, which results in successive drop in the cell voltage. The concept of discharge supporting additives was proposed to solve this problem and demonstrated by the pulse discharge tests of Li/(CF)n coin type cells employing the quinone compounds.
Inhibiting gluconeogenesis prevents fatty acid-induced increases in endogenous glucose production
Authors: Kehlenbrink Sylvia , Tonelli Julia , Koppaka Sudha , Chandramouli Visvanathan , Hawkins Meredith , Kishore Preeti
Published: May 2009

Glucose effectiveness, the ability of glucose per se to suppress endogenous glucose production (EGP), is lost in type 2 diabetes mellitus (T2DM). Free fatty acids (FFA) may contribute to this loss of glucose effectiveness in T2DM by increasing gluconeogenesis (GNG) and impairing the response to hyperglycemia. Thus, we first examined the effects of increasing plasma FFA levels for 3, 6, or 16 h on glucose effectiveness in nondiabetic subjects. Under fixed hormonal conditions, hyperglycemia suppressed EGP by 61% in nondiabetic subjects. Raising FFA levels with Liposyn infusion for ≥3 h reduced the normal suppressive effect of glucose by one-half. Second, we hypothesized that inhibiting GNG would prevent the negative impact of FFA on glucose effectiveness. Raising plasma FFA levels increased gluconeogenesis by ∼52% during euglycemia and blunted the suppression of EGP by hyperglycemia. Infusion of ethanol rapidly inhibited GNG and doubled the suppression of EGP by hyperglycemia, thereby restoring glucose effectiveness. In conclusion, elevated FFA levels rapidly increased GNG and impaired hepatic glucose effectiveness in nondiabetic subjects. Inhibiting GNG could have therapeutic potential in restoring the regulation of glucose production in type 2 diabetes mellitus.
Haploinsufficiency of the retinoblastoma protein gene reduces diet-induced obesity, insulin resistance, and hepatosteatosis in mice
Authors: Mercader Josep , Ribot Joan , Murano Incoronata , Feddersen Søren , Cinti Saverio , Madsen Lise , Kristiansen Karsten , Bonet M. Luisa , Palou Andreu
Published: May 2009

Brown adipose tissue activity dissipates energy as heat, and there is evidence that lack of the retinoblastoma protein (pRb) may favor the development of the brown adipocyte phenotype in adipose cells. In this work we assessed the impact of germ line haploinsufficiency of the pRb gene (Rb) on the response to high-fat diet feeding in mice. Rb+/−mice had body weight and adiposity indistinguishable from that of wild-type (Rb+/+) littermates when maintained on a standard diet, yet they gained less body weight and body fat after long-term high-fat diet feeding coupled with reduced feed efficiency and increased rectal temperature. Rb haploinsufficiency ameliorated insulin resistance and hepatosteatosis after high-fat diet in male mice, in which these disturbances were more marked than in females. Compared with wild-type littermates, Rb+/−mice fed a high-fat diet displayed higher expression of peroxisome proliferator-activated receptor (PPAR)γ as well as of genes involved in mitochondrial function, cAMP sensitivity, brown adipocyte determination, and tissue vascularization in white adipose tissue depots. Furthermore, Rb+/−mice exhibited signs of enhanced activation of brown adipose tissue and higher expression levels of PPARα in liver and of PPARδ in skeletal muscle, suggestive of an increased capability for fatty acid oxidation in these tissues. These findings support a role for pRb in modulating whole body energy metabolism and the plasticity of the adipose tissues in vivo and constitute first evidence that partial deficiency in the Rb gene protects against the development of obesity and associated metabolic disturbances.
Limits of isolation and culture: intact vascular endothelium and BKCa
Authors: Sandow Shaun L. , Grayson T. Hilton
Published: May 2009

The potential physiological role of plasmalemmal large-conductance calcium-activated potassium channels (BKCa) in vascular endothelial cells is controversial. Studies of freshly isolated and cultured vascular endothelial cells provide disparate results, both supporting and refuting a role for BKCain endothelial function. Most studies using freshly isolated, intact, healthy arteries provide little support for a physiological role for BKCain the endothelium, although recent work suggests that this may not be the case in diseased vessels. In isolated and cultured vascular endothelial cells, the autocrine action of growth factors, hormones, and vasoactive substances results in phenotypic drift. Such an induced heterogeneity is likely a primary factor accounting for the apparent differences, and often enhanced BKCaexpression and function, in isolated and cultured vascular endothelial cells. In a similar manner, heterogeneity in endothelial BKCaexpression and function in intact arteries may be representative of normal and disease states, BKCabeing absent in normal intact artery endothelium and upregulated in disease where dysfunction induces signals that alter channel expression and function. Indeed, in some intact vessels, there is evidence for the presence of BKCa, such as mRNA and/or specific BK subunits, an observation that is consistent with the potential for rapid upregulation, as may occur in disease. This perspective proposes that the disparity in the results obtained for BKCaexpression and function from freshly isolated and cultured vascular endothelial cells is largely due to variability in experimental conditions and, furthermore, that the expression of BKCain intact artery endothelium is primarily associated with disease. Although answers to physiologically relevant questions may only be available in atypical physiological conditions, such as those of isolation and culture, the limitations of these methods require open and objective recognition.
Effect of a high dose of glucosamine on systemic and tissue inflammation in an experimental model of atherosclerosis aggravated by chronic arthritis
Authors: Largo Raquel , Martínez-Calatrava María José , Sánchez-Pernaute Olga , Marcos M. Esther , Moreno-Rubio Juan , Aparicio César , Egido Jesús , Herrero-Beaumont Gabriel
Published: May 2009

Glucosamine sulfate (GS) is a glycosaminoglycan with anti-inflammatory and immunoregulatory properties. Here we set out to explore the effect of GS administration on markers of systemic and local inflammation in rabbits with atherosclerosis aggravated by chronic arthritis. Atherosclerosis was induced in rabbits by maintaining them on a hyperlipidemic diet after producing an endothelial lesion in the femoral arteries. Simultaneously, chronic arthritis was induced in these animals by repeated intra-articular injections of ovalbumin in previously immunized rabbits. A group of these rabbits was treated prophylactically with oral GS (500 mg·kg−1·day−1), and, when the animals were killed, serum was extracted and peripheral blood mononuclear cells (PBMC) were isolated. Furthermore, the femoral arteries, thoracic aorta, and synovial membranes were examined in gene expression studies and histologically. GS administration reduced circulating levels of the C-reactive protein and of interleukin-6. GS also lowered nuclear factor-κB activation in PBMC, and it downregulated the expression of both the CCL2 (monocyte chemoattractant protein) and cyclooxygenase-2 genes in these cells. Lesions at the femoral wall were milder after GS treatment, as reflected by the intimal-to-media thickened ratio and the absence of aortic lesions. Indeed, GS also attenuated the histological lesions in synovial tissue. In a combined rabbit model of chronic arthritis and atherosclerosis, orally administered GS reduced the markers of inflammation in peripheral blood, as well as the femoral and synovial membrane lesions. GS also prevented the development of inflammation-associated aortic lesions. These results suggest an atheroprotective effect of GS.
Cyclohexanone contamination from extracorporeal circuits impairs cardiovascular function
Authors: Thompson-Torgerson Caitlin S. , Champion Hunter C. , Santhanam Lakshmi , Harris Z. Leah , Shoukas Artin A.
Published: May 2009

Extracorporeal circulation provides critical life support in the face of cardiopulmonary or renal failure, but it also introduces a host of unique morbidities characterized by edema formation, cardiac insufficiency, autonomic dysfunction, and altered vasomotor function. We tested the hypothesis that cyclohexanone (CHX), a solvent used in production of extracorporeal circuits and intravenous (IV) bags, leaches into the contained fluids and can replicate these clinical morbidities. Crystalloid fluid samples from circuits and IV bags were analyzed by gas chromatography-mass spectrometry to provide a range of clinical CHX exposure levels, revealing CHX contamination of sampled fluids (9.63–3,694 μg/l). In vivo rat studies were conducted ( n = 49) to investigate the effects of a bolus IV infusion of CHX vs. saline alone on cardiovascular function, baroreflex responsiveness, and edema formation. Cardiovascular function was evaluated by cardiac output, heart rate, stroke volume, vascular resistance, arterial pressure, and ventricular contractility. Baroreflex function was assessed by mean femoral arterial pressure responses to bilateral carotid occlusion. Edema formation was assessed by the ratio of wet to dry organ weights for lungs, liver, kidneys, and skin. CHX infusion led to systemic hypotension; pulmonary hypertension; depressed contractility, heart rate, stroke volume, and cardiac output; and elevated vascular resistance ( P < 0.05). Mean arterial pressure responsiveness to carotid occlusion was dampened after CHX infusion (from +17.25 ± 1.8 to +5.61 ± 3.2 mmHg; P < 0.05). CHX infusion led to significantly higher wet-to-dry weight ratios vs. saline only (3.8 ± 0.06 vs. 3.5 ± 0.05; P < 0.05). CHX can reproduce clinical cardiovascular, neurological, and edema morbidities associated with extracorporeal circulatory treatment.
Loss of cerebrovascularShaker-type K+channels: a shared vasodilator defect of genetic and renal hypertensive rats
Authors: Tobin Ann A. , Joseph Biny K. , Al-Kindi Hamood N. , Albarwani Sulayma , Madden Jane A. , Nemetz Leah T. , Rusch Nancy J. , Rhee Sung W.
Published: May 2009

The cerebral arteries of hypertensive rats are depolarized and highly myogenic, suggesting a loss of K+channels in the vascular smooth muscle cells (VSMCs). The present study evaluated whether the dilator function of the prominent Shaker-type voltage-gated K+(KV1) channels is attenuated in middle cerebral arteries from two rat models of hypertension. Block of KV1 channels by correolide (1 μmol/l) or psora-4 (100 nmol/l) reduced the resting diameter of pressurized (80 mmHg) cerebral arteries from normotensive rats by an average of 28 ± 3% or 26 ± 3%, respectively. In contrast, arteries from spontaneously hypertensive rats (SHR) and aortic-banded (Ao-B) rats with chronic hypertension showed enhanced Ca2+-dependent tone and failed to significantly constrict to correolide or psora-4, implying a loss of KV1 channel-mediated vasodilation. Patch-clamp studies in the VSMCs of SHR confirmed that the peak K+current density attributed to KV1 channels averaged only 5.47 ± 1.03 pA/pF, compared with 9.58 ± 0.82 pA/pF in VSMCs of control Wistar-Kyoto rats. Subsequently, Western blots revealed a 49 ± 7% to 66 ± 7% loss of the pore-forming α1.2- and α1.5-subunits that compose KV1 channels in cerebral arteries of SHR and Ao-B rats compared with control animals. In each case, the deficiency of KV1 channels was associated with reduced mRNA levels encoding either or both α-subunits. Collectively, these findings demonstrate that a deficit of α1.2- and α1.5-subunits results in a reduced contribution of KV1 channels to the resting diameters of cerebral arteries from two rat models of hypertension that originate from different etiologies.
Postmyocardial infarction remodeling and coronary reserve: effects of ivabradine and beta blockade therapy
Authors: Christensen Lance P. , Zhang Ron-ling , Zheng Wei , Campanelli Joseph J. , Dedkov Eduard I. , Weiss Robert M. , Tomanek Robert J.
Published: May 2009

We compared the effects of heart rate reduction (HRR) by the hyperpolarization-activated pacemaker current ( If) channel inhibitor ivabradine (MI+Iva) and the β1-blocker atenolol (MI+Aten) on ventricular remodeling and perfusion after myocardial infarction (MI) in middle-aged (12 mo) Sprague-Dawley rats. Mean HRR was virtually identical in the two treated groups (19%). Four weeks after coronary artery ligation, maximal myocardial perfusion fell in the MI group but was preserved in infarcted rats treated with either Iva or Aten. However, coronary reserve in the remodeled hearts was preserved only with Iva, since Aten treatment elevated baseline perfusion in response to a higher wall stress. The higher maximal perfusion noted in the two treated groups was not due to arteriogenesis or angiogenesis. Plasma levels of angiotensin (ANG) II and myocardial ANG type 1 (AT1) receptor and transforming growth factor (TGF)-β1 were reduced during the first week of treatment by both Iva and Aten. Moreover, treatment also reduced arteriolar perivascular collagen density. Despite these similar effects of Iva and Aten on vascularity and ANG II, Iva, but not Aten, attenuated the decline in ejection fraction and lowered left ventricular (LV) end-diastolic volume (LVEDV)-to-LV mass ratio, determined by echocardiography. In conclusion, 1) Iva has advantages over Aten in postinfarction therapy that are not due to differential effects of the drugs on heart rate, and 2) age limits growth factor upregulation, angiogenesis, and arteriogenesis in the postinfarcted heart.
Ectodomain shedding of angiotensin converting enzyme 2 in human airway epithelia
Authors: Jia Hong Peng , Look Dwight C. , Tan Ping , Shi Lei , Hickey Melissa , Gakhar Lokesh , Chappell Mark C. , Wohlford-Lenane Christine , McCray Paul B.
Published: May 2009

Angiotensin-converting enzyme 2 (ACE2) is a terminal carboxypeptidase and the receptor for the SARS and NL63 coronaviruses (CoV). Loss of ACE2 function is implicated in severe acute respiratory syndrome (SARS) pathogenesis, but little is known about ACE2 biogenesis and activity in the airways. We report that ACE2 is shed from human airway epithelia, a site of SARS-CoV infection. The regulation of ACE2 release was investigated in polarized human airway epithelia. Constitutive generation of soluble ACE2 was inhibited by DPC 333, implicating a disintegrin and metalloprotease 17 (ADAM17). Phorbol ester, ionomycin, endotoxin, and IL-1β and TNFα acutely induced ACE2 release, further supporting that ADAM17 and ADAM10 regulate ACE2 cleavage. Soluble ACE2 was enzymatically active and partially inhibited virus entry into target cells. We determined that the ACE2 cleavage site resides between amino acid 716 and the putative transmembrane domain starting at amino acid 741. To reveal structural determinants underlying ACE2 release, several mutant and chimeric ACE2 proteins were engineered. Neither the juxtamembrane stalk region, transmembrane domain, nor the cytosolic domain was needed for constitutive ACE2 release. Interestingly, a point mutation in the ACE2 ectodomain, L584A, markedly attenuated shedding. The resultant ACE2-L584A mutant trafficked to the cell membrane and facilitated SARS-CoV entry into target cells, suggesting that the ACE2 ectodomain regulates its release and that residue L584 might be part of a putative sheddase “recognition motif.” Thus ACE2 must be cell associated to serve as a CoV receptor and soluble ACE2 might play a role in modifying inflammatory processes at the airway mucosal surface.
Urokinase receptor mediates lung fibroblast attachment and migration toward provisional matrix proteins through interaction with multiple integrins
Authors: Zhu Sha , Gladson Candece L. , White Kimberly E. , Ding Qiang , Stewart Jerry , Jin Tong H. , Chapman Harold A. , Olman Mitchell A.
Published: May 2009

Fibroblasts from patients with pulmonary fibrosis express higher levels of the receptor for urokinase, and the extent of fibrosis in some animal models exhibits a dependence on the urokinase receptor. Recent observations have identified the urokinase receptor as a trans-interacting receptor with consequences on signaling and cell responses that vary depending on its interacting partner, the relative levels of expression, and the state of cellular transformation. We undertook this study to define the urokinase-type plasminogen activator cellular receptor (u-PAR)-integrin interactions and to determine the functional consequences of such interactions on normal human lung fibroblast attachment and migration. u-PAR colocalizes in lammelipodia/filopodia with relevant integrins that mediate fibroblast attachment and spreading on the provisional matrix proteins vitronectin, fibronectin, and collagens. Inhibitory antibody studies have revealed that human lung fibroblasts utilize αvβ5to attach to vitronectin, predominantly α5β1(and αvβ3) to attach to fibronectin, and α1β1, α2β1, and α3β1to attach to collagen. Blocking studies with α-integrin subunit decoy peptides and u-PAR neutralizing antibodies indicate that u-PAR modulates the integrin-mediated attachment to purified provisional matrix proteins, to anti-integrin antibodies, or to fibroproliferative lesions from fibrotic lungs. Furthermore, these decoy peptides blunt fibroblast spreading and migration. We show that u-PAR can interact with multiple α-integrins but with a preference for α3. Taken together, these data demonstrate that u-PAR may interact with multiple integrins in normal human lung fibroblasts thereby promoting attachment, spreading, and migration. Modulation of fibroblast invasion would be expected to lead to amelioration of fibroproliferative diseases of the lung.
Loss of CFTR results in reduction of histone deacetylase 2 in airway epithelial cells
Authors: Bartling Toni R. , Drumm Mitchell L.
Published: May 2009

Inflammatory cytokines, particularly the neutrophil chemoattractant IL-8, are elevated in the cystic fibrosis (CF) airway, even in the absence of detectable infection. The transcriptional regulation of many inflammatory genes, including IL8 ( CXCL8), involves chromatin remodeling through histone acetylation. NF-κB is known to facilitate histone acetylation of IL8 and other proinflammatory gene promoters, but we find that increased NF-κB activation cannot explain the elevated IL8 expression and promoter acetylation seen in CFTR-deficient cells. Recognized components of the NF-κB-coactivator complex, acetyltransferase CBP, p300, and the histone deacetylase HDAC1, are unchanged by CFTR activity. However, we find that the histone acetyltransferase (HAT)/HDAC balance is sensitive to CFTR function, as cells with reduced or absent CFTR function have decreased HDAC2 protein, resulting in hyperacetylation of the IL8 promoter and increased IL8 transcription. Reduced HDAC2 and HDAC2 activity, but not HDAC2 mRNA, is observed in cells deficient in CFTR. Suppressing HDAC2 expression with HDAC2 short hairpin RNA (shRNA) results in increased IL8 expression and promoter acetylation comparable with CFTR-deficient cells. Treating CFTR-deficient cells with N-acetyl-cysteine (NAC) increases HDAC2 expression to near control levels. Our data suggest that there is an intrinsic alteration in the HAT/HDAC balance in cells lacking CFTR function in vitro and in native CF tissue and that oxidative stress is likely contributing to this alteration. This mechanism, found in other inflammatory airway diseases, provides an explanation for the apparent dysregulation of inflammatory mediators seen in the CF airway, as reduced histone deacetylation would potentially influence many genes.
Receptor for advanced glycation end-products (RAGE) is an indicator of direct lung injury in models of experimental lung injury
Authors: Su Xiao , Looney Mark R. , Gupta Naveen , Matthay Michael A.
Published: May 2009

Receptor for advanced glycation end-products (RAGE) is a marker of alveolar type I cells and is elevated in the pulmonary edema fluid of patients with acute lung injury (ALI). We tested the hypothesis that RAGE in the bronchoalveolar lavage (BAL) would be elevated in experimental models of direct ALI characterized by alveolar epithelial cell injury. We developed ELISA measurements for RAGE and studied ALI (direct and indirect) mouse models and collected BAL at specified endpoints to measure RAGE. We also tested whether levels of BAL RAGE correlated 1) with the severity of lung injury in acid and hyperoxia-induced ALI and 2) with the beneficial effect of a novel treatment, mesenchymal stem cells (MSC), in LPS-induced ALI. In ALI models of direct lung injury induced by intratracheal instillation of acid, LPS, or Escherichia coli, the BAL RAGE was 58-, 22-, and 13-fold elevated, respectively. In contrast, BAL RAGE was not detectable in indirect models of ALI induced by an intraperitoneal injection of thiourea or by an intravenous injection of MHC I monoclonal antibody that produces a mouse model of transfusion-related ALI. BAL RAGE did correlate with the severity of lung injury in acid and hyperoxia-induced ALI. In addition, with LPS-induced ALI, BAL RAGE was markedly reduced with MSC treatment. In summary, BAL RAGE is an indicator of ALI, and it may be useful in distinguishing direct from indirect models of ALI as well as assessing the response to specific therapies.
Pleural mesothelial cell transformation into myofibroblasts and haptotactic migration in response to TGF-β1 in vitro
Authors: Nasreen Najmunnisa , Mohammed Kamal A. , Mubarak Kamal K. , Baz Maher A. , Akindipe Olufemi A. , Fernandez-Bussy Sebastian , Antony Veena B.
Published: May 2009

Idiopathic pulmonary fibrosis (IPF) is a disease of unknown etiology characterized by the development of subpleural foci of myofibroblasts that contribute to the exuberant fibrosis noted in the pulmonary parenchyma. Pleural mesothelial cells (PMC) are metabolically dynamic cells that cover the lung and chest wall as a monolayer and are in intimate proximity to the underlying lung parenchyma. The precise role of PMC in the pathogenesis of pulmonary parenchymal fibrosis remains to be identified. Transforming growth factor (TGF)-β1, a cytokine known for its capacity to induce proliferative and transformative changes in lung cells, is found in significantly higher quantities in the lungs of patients with IPF. High levels of TGF-β1 in the subpleural milieu may play a key role in the transition of normal PMC to myofibroblasts. Here we demonstrate that PMC activated by TGF-β1 undergo epithelial-mesenchymal transition (EMT) and respond with haptotactic migration to a gradient of TGF-β1 and that the transition of PMC to myofibroblasts is dependent on smad-2 signaling. The EMT of PMC was marked by upregulation of α-smooth muscle actin (α-SMA), fibroblast specific protein-1 (FSP-1), and collagen type I expression. Cytokeratin-8 and E-cadherin expression decreased whereas vimentin remained unchanged over time in transforming PMC. Knockdown of smad-2 gene by silencing small interfering RNA significantly suppressed the transition of PMC to myofibroblasts and significantly inhibited the PMC haptotaxis. We conclude that PMC undergo EMT when exposed to TGF-β1, involving smad-2 signaling, and PMC may be a possible source of myofibroblasts in IPF.
A Code for Spatial Alternation During Fixation in Rat Hippocampal CA1 Neurons
Authors: Takahashi Muneyoshi , Lauwereyns Johan , Sakurai Yoshio , Tsukada Minoru
Published: May 2009

The classical notion of hippocampal CA1 “place cells,” whose activity tracks physical locations, has undergone substantial revision in recent years. Here, we provide further evidence of an abstract spatial code in hippocampal CA1, which relies on memory and adds complexity to the basic “place cell.” Using a nose-poking paradigm with four male Wistar rats, we specifically concentrated on activity during fixation, when the rat was immobile and waiting for the next task event in a memory-guided spatial alternation task. The rat had to alternate between choosing the right and left holes on a trial-by-trial basis, without any sensory cue, and relying on an internal representation of the sequence of trials. Twelve tetrodes were chronically implanted for single-unit recording in the right CA1 of each rat. We focus on 76 single neurons that showed significant activation during the fixation period compared with baseline activity between trials. Among these 76 fixation neurons, we observed 38 neurons that systematically changed their fixation activity as a function of the alternation sequence. That is, even though these rats were immobile during the fixation period, the neurons fired differently for trials in which the next spatial choice should be left (i.e., RIGHT-TO-LEFT trials) compared with trials in which the next spatial choice should be right (i.e., LEFT-TO-RIGHT trials), or vice versa. Our results imply that these neurons maintain a sequential code of the required spatial response during the alternation task and thus provide abstract information, derived from memory, that can be used for efficient navigation.
Comparisons of the Generalized Potential Temperature in Moist Atmosphere with the Equivalent Potential Temperature in Saturated Moist Atmosphere
Authors: Zhou Yushu , Liu Liping , Deng Guo
Published: May 2009

The real tropospheric atmosphere is neither absolutely dry nor completely saturated. It is in general moist but not saturated. Here the generalized potential temperature (GPT) was introduced to describe this humid feature of real moist atmosphere. GPT's conservation property in moist adiabatic process was discussed and proved. Comparisons of GPT in moist atmosphere with the equivalent potential temperature (EPT) in saturated moist atmosphere were made by analyzing three torrential rain cases occurring over Jianghuai Valleys in 2003, the north China in 2004, and with the typhoon Fung-Wong in 2008, respectively. Results showed that the relative humidity is not up to 100% even in torrential rain systems, the saturated condition for EPT is not always held, and thus GPT can describe the moisture concentration and moisture gradient better than EPT. The GPT's definition includes the process that the air changes from dry to moist, then up to saturated. Therefore, potential temperature (PT) and EPT can be considered as its two special status. Similar as PT and EPT, GPT can be used to study atmospheric dynamic and thermodynamic processes more generally because of its conservation property in moist adiabatic process.
Evolutionary Selection of Features for Neural Sleep/Wake Discrimination
Authors: Dürr Peter , Karlen Walter , Guignard Jérémie , Mattiussi Claudio , Floreano Dario
Published: May 2009

In biomedical signal analysis, artificial neural networks are often used for pattern classification because of their capability for nonlinear class separation and the possibility to efficiently implement them on a microcontroller.
Typically, the network topology is designed by hand, and a gradient-based search algorithm is used to find a set of
suitable parameters for the given classification task. In many cases, however, the choice of the network architecture
is a critical and difficult task. For example, hand-designed networks often require more computational resources than
necessary because they rely on input features that provide no information or are redundant. In the case of mobile
applications, where computational resources and energy are limited, this is especially detrimental. Neuroevolutionary
methods which allow for the automatic synthesis of network topology and parameters offer a solution to these
problems. In this paper, we use analog genetic encoding (AGE) for the evolutionary synthesis of a neural classifier
for a mobile sleep/wake discrimination system. The comparison with a hand-designed classifier trained with back propagation
shows that the evolved neural classifiers display similar performance to the hand-designed networks, but
using a greatly reduced set of inputs, thus reducing computation time and improving the energy efficiency of the
mobile system.
Loss of the SMRT/NCoR2 Corepressor Correlates with JAG2 Overexpression in Multiple Myeloma
Authors: Ghoshal Pushpankur , Nganga Alain J. , Moran-Giuati Joseph , Szafranek Angela , Johnson Timothy R. , Bigelow Ashley J. , Houde Christiane M. , Avet-Loiseau Herve , Smiraglia Dominic J. , Ersing Noreen , Chanan-Khan Asher A. , Coignet Lionel J.
Published: May 2009

Multiple myeloma (MM) is a clonal B-cell neoplasm that accounts for 10% of all malignant hematologic neoplasms and that affects terminally differentiated B cells (i.e., plasma cells). It is now well recognized that the cytokine interleukin-6 (IL-6) is a major cytokine that promotes the proliferation of malignant plasma cells in MM. The IL-6 gene can be regulated by the NOTCH genes products. We have previously shown that the NOTCH ligand, JAG2, is overexpressed in MM. To investigate the mechanism(s) leading to JAG2 overexpression in MM, we assessed potential epigenetic modifications of the JAG2 promoter. We showed that the JAG2 promoter region is aberrantly acetylated in MM cell lines and patient samples. The acetylation state of histones is regulated by the recruitment of histone deacetylases (HDAC). HDACs are typically recruited to promoter regions through interaction with nuclear corepressors such as SMRT. SMRT levels were therefore investigated. Interestingly, MM cell lines and patient samples presented significantly reduced SMRT levels. The experiments suggest a correlation between constitutive acetylation of the JAG2 core promoter in the MM cell lines and reduced levels of the SMRT corepressor that recruits HDAC to promoter regions. Finally, SMRT function restoration induced JAG2 down-regulation as well as MM cell apoptosis. [Cancer Res 2009;69(10):4380–7]
Association between Transcriptional Activity, Local Chromatin Structure, and the Efficiencies of Both Subpathways of Nucleotide Excision Repair of Melphalan Adducts
Authors: Episkopou Hara , Kyrtopoulos Soterios A. , Sfikakis Petros P. , Fousteri Maria , Dimopoulos Meletios A. , Mullenders Leon H.F. , Souliotis Vassilis L.
Published: May 2009

The repair of melphalan-induced N-alkylpurine monoadducts and interstrand cross-links was examined in different repair backgrounds, focusing on four genes (β-actin, p53, N-ras, and δ-globin) with dissimilar transcription activities. Adducts were found to be substrates for both global genome repair (GGR) and transcription-coupled repair (TCR), with TCR being less efficient than GGR. In nucleotide excision repair–deficient cells, adducts accumulated to similar levels in all four genes. The repair efficiency in different gene loci varied in a qualitatively and quantitatively similar way in both GGR-deficient and TCR-deficient backgrounds and correlated with transcriptional activity and local chromatin condensation. No strand-specific repair was found in GGR+/TCR+ cells, implying that GGR dominated. Adducts were lost over two sharply demarcated phases: a rapid phase resulting in the removal within 1 hour of up to ∼80% of the adducts, and a subsequent phase with t1/2 ∼36 to 48 hours. Following pretreatment of cells with α-amanitin, the rate of transcription, the state of chromatin condensation, and the repair efficiencies (both TCR and GGR) of the transcribed β-actin, p53, and N-ras genes became similar to those of the nontranscribed δ-globin gene. In conclusion, a continuous, parallel variation of the state of transcription and local chromatin condensation, on one hand, and the rates of both GGR and TCR, on the other hand, have been shown. [Cancer Res 2009;69(10):4424–33]
Sunitinib Inhibits Tumor Growth and Synergizes with Cisplatin in Orthotopic Models of Cisplatin-Sensitive and Cisplatin-Resistant Human Testicular Germ Cell Tumors
Authors: Castillo-Ávila Wilmar , Piulats Josep Maria , Garcia del Muro Xavier , Vidal August , Condom Enric , Casanovas Oriol , Mora Josefina , Germà Josep Ramon , Capellà Gabriel , Villanueva Alberto , Viñals Francesc
Published: May 2009

Purpose: Germ cell tumors (GCT) of the testis are highly curable, but those patients who are refractory to cisplatin (CDDP)-based combination chemotherapy have a poor prognosis. Therefore, identifying new alternatives for treatment remains a priority. Several studies support an important role for angiogenesis in GCTs, suggesting that antiangiogenic treatment might be a good alternative. Sunitinib is an oral multitarget tyrosine kinase receptor inhibitor with antiangiogenic and antitumor activities. In the present study, we evaluated the effect of sunitinib, CDDP, or the combination of both drugs using an orthotopic model of human testicular GCT.

Experimental Design: Mice were implanted with four different testicular tumors: a yolk sac, two choriocarcinomas, and a CDDP-resistant choriocarcinoma variant induced in mice by continuous exposure to CDDP. Mice were treated with vehicle, CDDP, sunitinib, or the combination of both drugs and their effects on tumors were analyzed.

Results: We observed a significant inhibition in tumor growth accompanied by longer survival after sunitinib treatment. Combination therapy with CDDP significantly enhanced these effects. Sunitinib induced apoptosis, reduced tumor cell proliferation and tumor vasculature, and inhibited vascular endothelial growth factor receptor 1, 2, and 3 and platelet-derived growth factor receptor α phosphorylation without affecting phosphorylation of other tyrosine kinase receptors. More importantly, tumor growth inhibition induced by sunitinib was also observed in the induced CDDP-resistant choriocarcinoma model.

Conclusions: Taken together, these results suggest that sunitinib might be a new alternative for treatment of CDDP-refractory patients.
Single-Step Antigen Loading and Activation of Dendritic Cells by mRNA Electroporation for the Purpose of Therapeutic Vaccination in Melanoma Patients
Authors: Bonehill Aude , Van Nuffel An M.T. , Corthals Jurgen , Tuyaerts Sandra , Heirman Carlo , François Violaine , Colau Didier , van der Bruggen Pierre , Neyns Bart , Thielemans Kris
Published: May 2009

Purpose: A critical factor determining the effectiveness of currently used dendritic cell (DC)–based vaccines is the DC activation or maturation status. We have recently shown that the T-cell stimulatory capacity of DCs pulsed with tumor-antigen–derived peptides can be considerably increased by activating the DCs through electroporation with mRNA encoding CD40 ligand, CD70, and a constitutively active Toll-like receptor 4 (TriMix DCs). Here, we investigate whether TriMix DCs can be coelectroporated with whole tumor-antigen–encoding mRNA.

Experimental Design: The T-cell stimulatory capacity of TriMix DCs pulsed with the immunodominant MelanA-A2 peptide and that of TriMix DCs coelectroporated with MelanA mRNA were compared in vitro. TriMix DCs were also coelectroporated with mRNA encoding Mage-A3, Mage-C2, tyrosinase, or gp100. The capacity of these DCs to stimulate tumor-antigen–specific T cells in melanoma patients was investigated both in vitro before vaccination and after DC vaccination.

Results: Like peptide-pulsed TriMix DCs, TriMix DCs coelectroporated with MelanA mRNA are very potent in inducing MelanA-specific CD8+ T cells in vitro. These T cells have an activated phenotype, show cytolytic capacity, and produce inflammatory cytokines in response to specific stimulation. TriMix DCs coelectroporated with tyrosinase are able to stimulate tyrosinase-specific CD8+ T cells in vitro from the blood of nonvaccinated melanoma patients. Furthermore, TriMix DCs coelectroporated with Mage-A3, Mage-C2, or tyrosinase are able to induce antigen-specific CD8+ T cells through therapeutic DC vaccination.

Conclusions: TriMix DCs coelectroporated with whole tumor-antigen mRNA stimulate antigen-specific T cells in vitro and induce antigen-specific T-cell responses in melanoma patients through vaccination. Therefore, they represent a promising new approach for antitumor immunotherapy.
Increased Frequency and Suppression by Regulatory T Cells in Patients with Acute Myelogenous Leukemia
Authors: Szczepanski Miroslaw J. , Szajnik Marta , Czystowska Malgorzata , Mandapathil Magis , Strauss Laura , Welsh Ann , Foon Kenneth A. , Whiteside Theresa L. , Boyiadzis Michael
Published: May 2009

Purpose: Regulatory CD4+CD25highFoxp3+ T cells (Treg) control peripheral immune tolerance. Patients with cancer, including those with hematologic malignancies, have elevated numbers of Treg in the peripheral circulation and in tumor tissues. However, mechanisms of suppression and clinical significance of Treg, especially in patients with acute myelogenous leukemia (AML), has not been well defined.

Experimental Design: We prospectively evaluated the phenotype, function, and mechanisms of suppression used by Treg in newly diagnosed untreated AML patients. The relationship between the frequency of circulating Treg and the disease status as well as treatment outcome was also evaluated.

Results: The percentage of circulating Treg was higher (P < 0.0001) and their phenotype was distinct in AML patients relative to normal controls. Suppression mediated by Treg coincubated with proliferating autologous responder cells was also higher (P < 0.001) in AML than that mediated by control Treg. Using Transwell inserts, we showed that interleukin-10 and transforming growth factor-β1 production as well as cell-to-cell contact were necessary for Treg-mediated suppression. Also, the pretreatment Treg frequency predicted response to chemotherapy. Unexpectedly, patients who achieved complete remission still had elevated frequency of Treg, which mediated high levels of suppressor activity.

Conclusions: Treg accumulating in the peripheral circulation of AML patients mediate vigorous suppression via contact-dependent and contact-independent mechanisms. Patients with lower Treg frequency at diagnosis have a better response to induction chemotherapy. During the post-induction period, the Treg frequency and suppressive activity remain elevated in complete remission, suggesting that Treg are resistant to conventional chemotherapy.