bluuebunny/crossref_metadata_2025 huggingface dataset:
A CELLULAR AUTOMATA MODEL OF LEARNING BASED ON BIT-STRING WITH INTELLIGENCE
Authors: HE MINGFENG , PAN QIU-HUI , WANG ZHIRUI
Published: May 2006

A cellular automata model of learning in a close ecosystem on the basis of Penna model with intelligence is set up. We use the Penna model with intelligence to describe the individual. The individuals are set in a lattice of L × L and the rules of learning is expressed by cellular automata. Then, we present the results of our simulations and discuss the evolution of intelligence and knowledge respectively. From the results we find that the intelligence for the living individuals is more than that for the dead individuals. It can be concluded the effect of natural selection on the evolution of intelligence.
LATTICE BOLTZMANN METHOD IN SIMULATION OF THERMAL MICRO-FLOW WITH TEMPERATURE JUMP
Authors: TIAN ZHI-WEI , ZOU CHUN , LIU ZHAO-HUI , GUO ZHAO-LI , LIU HONG-JUAN , ZHENG CHU-GUANG
Published: May 2006

We simulate the gas flow and heat transfer in micro-Couette flow by the lattice Boltzmann method (LBM). A new boundary treatment is adopted in the numerical experiment in order to capture the velocity slip and the temperature jump of the wall boundary. Velocity and temperature profiles are in good agreement with the analytic results, which exhibits the availability of this model and boundary treatment in describing thermal micro-flow with viscous heat dissipation. We also find the upper boundary's temperature jump is zero at the critical Ec, which is around 3.0 with different Kn.
A PHASE-FITTED AND AMPLIFICATION-FITTED EXPLICIT TWO-STEP HYBRID METHOD FOR SECOND-ORDER PERIODIC INITIAL VALUE PROBLEMS
Authors: VAN DE VYVER HANS
Published: May 2006

In this paper a phase-fitted and amplification-fitted explicit two-step hybrid method is introduced. The construction is based on a modification of a fifth-order dissipative method recently developed by Franco.19 Two free parameters are added in order to nullify the phase-lag and the amplification. Numerical results obtained for well-known test problems show the efficiency of the new method when it is compared with other existing codes.
A PHYSICAL REALIZATION OF THE GENERALIZED PT-, C-, AND CPT-SYMMETRIES AND THE POSITION OPERATOR FOR KLEIN–GORDON FIELDS
Authors: MOSTAFAZADEH ALI
Published: May 2006

Generalized parity [Formula: see text], time-reversal [Formula: see text], and charge-conjugation [Formula: see text] operators were initially defined in the study of the pseudo-Hermitian Hamiltonians. We construct a concrete realization of these operators for Klein–Gordon fields and show that in this realization [Formula: see text] and [Formula: see text] operators respectively correspond to the ordinary time-reversal and charge-grading operations. Furthermore, we present a complete description of the quantum mechanics of Klein–Gordon fields that is based on the construction of a Hilbert space with a relativistically invariant, positive-definite, and conserved inner product. In particular we offer a natural construction of a position operator and the corresponding localized and coherent states. The restriction of this position operator to the positive-frequency fields coincides with the Newton–Wigner operator. Our approach does not rely on the conventional restriction to positive-frequency fields. Yet it provides a consistent quantum mechanical description of Klein–Gordon fields with a genuine probabilistic interpretation.
RECONSTRUCTING THE STRING FIELD VACUUM
Authors: ILDERTON A.
Published: May 2006

The vacuum state functional of both open closed string field theories may be perturbatively reconstructed from the vacuum expectation values it must generate. We give the calculation of the first tree and one loop terms explicitly.
A STUDY ON THE LANGMUIR–BLODGETT (LB) FILMS OF C60/POLY (N-VINYLCARBAZOLE) (PVK) POLYMERS
Authors: JIANG XIAOHONG , ZHANG XINGTANG , HUANG YABIN , DU ZULIANG
Published: May 2006

The Langmuir–Blodgett (LB) films of Poly (N-vinylcarbazole) (PVK) Polymers and its hybrid films with arachidic acid (AA) and C 60 were prepared by a vertical deposition method. Atomic Force Microscopy (AFM) and UV-Vis absorption spectroscopy were used to investigate the assembly of PVK/AA and PVK/ C 60/AA LB films. It was found that the C 60 molecules could be aggregated into smaller particles on the base of PVK polymers. The photoluminescence (PL) of PVK was dramatically quenched resulting from the electron transfer from PVK to C 60 in their composite films.
EFFECTS OF GRAIN BOUNDARY WIDTH ON TRANSFER CHARACTERISTICS OF A POLYSILICON THIN-FILM TRANSISTOR
Authors: GUPTA NAVNEET , TYAGI B. P.
Published: May 2006

The grain boundary scattering effects on carrier transport were studied analytically by considering the grains and grain boundaries that act as the series resistance in the channel of a polycrystalline silicon (poly- Si ) thin-film transistor (TFT). Effective carrier mobility (μ*) and drain current (ID) variations were analyzed using the model by changing the grain boundary width (DGB) in the channel as a function of the gate voltage, in the linear region of the poly- Si TFT characteristic at room temperature. μ* and ID were computed for DGB ranging from 1 nm to 10 nm. It was found that for different values of the gate voltage, μ* and ID increased with a decrease in grain boundary width (DGB). A remarkable improvement was observed in device characteristics as DGB was decreased below 2 nm. The predicted results using the present model are in a reasonably good agreement with experimental results, hence confirming the validity of the model.
LEARNING GENE NETWORK USING TIME-DELAYED BAYESIAN NETWORK
Authors: LIU TIE-FEI , SUNG WING-KIN , MITTAL ANKUSH
Published: May 2006

Exact determination of a gene network is required to discover the higher-order structures of an organism and to interpret its behavior. Most research work in learning gene networks either assumes that there is no time delay in gene expression or that there is a constant time delay. This paper shows how Bayesian Networks can be applied to represent multi-time delay relationships as well as directed loops. The intractability of the network learning algorithm is handled by using an improved mutual information criterion. Also, a new structure learning algorithm, "Learning By Modification", is proposed to learn the sparse structure of a gene network. The experimental results on synthetic data and real data show that our method is more accurate in determining the gene structure as compared to the traditional methods. Even transcriptional loops spanning over the whole cell can be detected by our algorithm.
STATE-SPACE PLANNING WITH VARIANTS OF A*
Authors: MALI AMOL DATTATRAYA , TANG MINH
Published: May 2006

Significant advances have occurred in heuristic search for planning in the last eleven years. Many of these planners use A*-style search. We report on five sound and complete domain-independent forward state-space STRIPS planners in this paper. The planners are AWA* (Adjusted Weighted A*), MAWA* (Modified AWA*), AWA*-AC (AWA* with action conflict-based adjustment), AWA*-PD (AWA* with deleted preconditions-based adjustment), and AWA*-AC-LE (AWA*-AC with lazy evaluation). AWA* is the first planner to use node-dependent weighting in A*. MAWA*, AWA*-AC, AWA*-PD, and AWA*-AC-LE use conditional two-phase heuristic evaluation. MAWA* applies node-dependent weighting to a subset of the nodes in the fringe, after the two-phase evaluation. One novel idea in AWA*-AC-LE is lazy heuristic evaluation which does not construct relaxed plans to compute heuristic values for all nodes. We report on an empirical comparison of AWA*, MAWA*, AWA*-AC, AWA*-PD, and AWA*-AC-LE with classical planners AltAlt, FF, HSP-2 and STAN 4. Our variants of A* outperform these planners on several problems. The empirical evaluation shows that heuristic search planning is significantly benefitted by node-dependent weighting, conditional two-phase heuristic evaluation and lazy evaluation. We report on the insights about inferior performance of our planners in some domains using the notion of waiting time. We discuss many other variants of A*, state-space planners and directions for future work.
USING A LAGRANGIAN HEURISTIC FOR A COMBINATORIAL AUCTION PROBLEM
Authors: GUO YUNSONG , LIM ANDREW , RODRIGUES BRIAN , TANG JIQING
Published: May 2006

Combinatorial auctions allow bidders to bid for items leading to more efficient allocations, but determining winners in auctions is [Formula: see text]-complete. In this work, a simple yet effective Lagrangian relaxation based heuristic algorithm is presented. Extensive computational experiments using standard benchmark data (CATS) as well as newly generated more realistic test sets were conducted which showed the heuristic was able to provide optimal solutions for most test cases and is within 1% from the optimums for the rest within very short times. Experiements comparing CPLEX 8.0, the fastest current algorithm, showed the heuristic was able to provide equally godd or better solutions often requring less than 1% of the time required by CPLEX 8.0.
STUDY ON RELATIONSHIP BETWEEN CONDENSED PARTICLES AND STRUCTURE OF CONDENSATION JET USING 2D IMAGE AND DISCRETE WAVELETS MULTIRESOLUTION
Authors: KIMURA MOTOAKI , TAKEI MASAHIRO , SAITO YOSHIFURU , HORII KIYOSHI
Published: May 2006

This paper describes the application of discrete wavelet transforms to the analysis of condensation jets in order to clarify the associated fluid and heat transfer phenomena. An experimentally-obtained, two-dimensional image of the condensation particle density around the jet was decomposed into 7 levels of resolution with their respective wavelengths. Based on the known physical characteristics of turbulent flow around the jet, levels 0 and 1 were shown to represent the large-scale components of the condensation particle density and the higher levels represent the small-scale components. From the wavelet-analyzed images, the width of the condensation zone was obtained and this compared well with the width inferred from temperature measurements. Thus, the method was verified and also provided data not available experimentally.
EXTRACTION OF PARTICLE CONCENTRATION DISTRIBUTION FROM PLUG FLOW CT IMAGES USING 3D WAVELET MULTIRESOLUTION
Authors: TAKEI M. , OCHI M. , SAITO Y. , HORII K.
Published: May 2006

Particle concentration distribution images of a dense solid-air two-phase (plug) flow have been obtained at 10 ms intervals at a bend pipe upstream in a horizontal pipeline by means of a capacitance computed tomography. The three-dimensional images (time and two-dimensional space images) have been decomposed to the wavelet time levels to extract the dominant particle concentration distribution using three-dimensional discrete wavelet multiresolution. As a result, the time dominant particle distribution with specific time frequency level is visualized in a cross-section. In detail, the high concentration of the particle spatial distribution at the dense flow front, which composes high-time frequency levels 6 and 7, is located at the center above the stationary layer.
DATA HANDLING METHODOLOGY FOR DISCRETE WAVELETS AND ITS APPLICATIONS TO THE DYNAMIC VECTOR FIELDS
Authors: MATSUYAMA SAWA , MATSUYAMA SHIHO , SAITO YOSHIFURU
Published: May 2006

A discrete wavelet transform is one of the effective methodologies for compressing the image data and extracting the major characteristics from various data, but it always requires a number of target data composed of a power of 2. To overcome this difficulty without losing any original data information, we propose here a novel approach based on the Fourier transform. The key idea is simple but effective because it keeps all of the frequency components comprising the target data exactly. The raw data is firstly transformed to the Fourier coefficients by Fourier transform. Then, the inverse Fourier transform makes it possible to the number of data comprising a power of 2. We have applied this interpolation for the wind vector image data, and we have tried to compress the data by the multiresolution analysis by using the three-dimensional discrete wavelet transform. Several examples demonstrate the usefulness of our new method to work out the graphical communication tools.
APPLICATION OF WAVELET-BASED SINGULARITY DETECTION TECHNIQUE IN AUTOMATIC INSPECTION SYSTEM
Authors: JIANG HUIQIN , MA LING , JIANG HONGYU , RINOSHIKA AKIRA
Published: May 2006

This paper describes an application of the wavelet transform in in-line solder paste inspection. In the development of a three-dimensional (3D) automatic inspection device of solder paste, it is necessary to detect the characteristic positions in images. In this paper, on the basis of the property of local wavelet transform modulus maximum (WTMM) and the deference filter, a practical algorithm is proposed for the detection of the characteristic positions. The proposed algorithm is applied to more than 20 actual images obtained from the 3D automatic inspection device. The detected errors are smaller than the maximum permissible error of 5 pixels. Also, the proposed algorithm is verified in-line. The experimental results show that the quality of solder paste can be successfully judged in-line. The proposed algorithm is superior to other possible techniques reported so far because of its implementation in assembly lines.
CHARACTERISTIC SCALES IN A SPRAY FROM A DIESEL INJECTOR STUDIED WITH WAVELET MULTIRESOLUTION ANALYSIS
Authors: FÖRSTH MICHAEL , RINOSHIKA AKIRA (HUI LI)
Published: May 2006

Wavelet multiresolution analysis has been applied to digital images of ethanol sprays injected into air at atmospheric pressure and at room temperature. The imaging was performed with laser-sheet imaging using the 308 nm light from a XeCl excimer laser. Image capturing was performed with a CCD camera. The importance of different scales in the turbulent structure of the sprays was easily recognized using wavelet multiresolution analysis. It was observed that the intermediate and small scale levels contained information of such important phenomena as the spray break-up. This was not easily recognized in the original images, due to averaging over all scales.
Decreased cation channel activity and blunted channel-dependent eryptosis in neonatal erythrocytes
Authors: Hermle Tobias , Shumilina Ekaterina , Attanasio Philipp , Akel Ahmad , Kempe Daniela S. , Lang Philipp A. , Podolski Marlies , Gatz Sabine , Bachmann Robert , Bachmann Cornelia , Abele Harald , Huber Stephan , Wieder Thomas , Lang Florian
Published: May 2006

Eryptosis or apoptosis-like death of erythrocytes is characterized by phosphatidylserine exposure and erythrocyte shrinkage, both typical features of nucleated apoptotic cells. Eryptosis is triggered by activation of nonselective Ca2+-permeable cation channels with subsequent entry of Ca2+ and stimulation of Ca2+-sensitive scrambling of the cell membrane. The channels are activated and thus eryptosis is triggered by Cl− removal, osmotic shock, oxidative stress, or glucose deprivation. The present study has been performed to compare cation channel activity and susceptibility to eryptosis in neonatal and adult erythrocytes. Channel activity was determined by patch-clamp analysis, cytosolic Ca2+ activity by fluo-3 fluorescence, phosphatidylserine exposure by FITC-labeled annexin V binding, and cell shrinkage by decrease in forward scatter in fluorescence-activated cell sorting analysis. Prostaglandin E2 (PGE2) formation, cation channel activity, Ca2+ entry, annexin V binding, and decreased forward scatter were triggered by removal of Cl− in both adult and neonatal erythrocytes. The effects were, however, significantly blunted in neonatal erythrocytes. Osmotic shock, PGE2, and platelet-activating factor similarly increased annexin V binding and decreased forward scatter, effects again significantly reduced in neonatal erythrocytes. On the other hand, spontaneous and oxidative (addition of tert-butylperoxide) stress-induced eryptosis was significantly larger in neonatal erythrocytes. In conclusion, cation channel activity, Ca2+ leakage, and thus channel-dependent triggering of eryptosis are blunted, whereas spontaneous and oxidative stress-induced eryptosis is more pronounced in neonatal erythrocytes.
Colocalization of the α-subunit of gustducin with PYY and GLP-1 in L cells of human colon
Authors: Rozengurt Nora , Wu S. Vincent , Chen Monica C. , Huang Carlos , Sternini Catia , Rozengurt Enrique
Published: May 2006

In view of the importance of molecular sensing in the function of the gastrointestinal (GI) tract, we assessed whether signal transduction proteins that mediate taste signaling are expressed in cells of the human gut. Here, we demonstrated that the α-subunit of the taste-specific G protein gustducin (Gαgust) is expressed prominently in cells of the human colon that also contain chromogranin A, an established marker of endocrine cells. Double-labeling immunofluorescence and staining of serial sections demonstrated that Gαgust localized to enteroendocrine L cells that express peptide YY and glucagon-like peptide-1 in the human colonic mucosa. We also found expression of transcripts encoding human type 2 receptor (hT2R) family members, hT1R3, and Gαgust in the human colon and in the human intestinal endocrine cell lines (HuTu-80 and NCI-H716 cells). Stimulation of HuTu-80 or NCI-H716 cells with the bitter-tasting compound phenylthiocarbamide, which binds hT2R38, induced a rapid increase in the intracellular Ca2+ concentration in these cells. The identification of Gαgust and chemosensory receptors that perceive chemical components of ingested substances, including drugs and toxins, in open enteroendocrine L cells has important implications for understanding molecular sensing in the human GI tract and for developing novel therapeutic compounds that modify the function of these receptors in the gut.
Phenotypic characterization of gastric sensory neurons in mice
Authors: Bielefeldt Klaus , Zhong Fang , Koerber H. Richard , Davis Brian M.
Published: May 2006

Recent studies suggest that the capsaicin receptor [transient receptor potential vanilloid (TRPV)1] may play a role in visceral mechanosensation. To address the potential role of TRPV1 in vagal sensory neurons, we developed a new in vitro technique allowing us to determine TRPV1 expression directly in physiologically characterized gastric sensory neurons. Stomach, esophagus, and intact vagus nerve up to the central terminations were carefully dissected and placed in a perfusion chamber. Intracellular recordings were made from the soma of nodose neurons during mechanical stimulation of the stomach. Physiologically characterized neurons were labeled iontophoretically with neurobiotin and processed for immunohistochemical experiments. As shown by action potential responses triggered by stimulation of the upper thoracic vagus with a suction electrode, essentially all abdominal vagal afferents in mice conduct in the C-fiber range. Mechanosensitive gastric afferents encode stimulus intensities over a wide range without apparent saturation when punctate stimuli are used. Nine of 37 mechanosensitive vagal afferents expressed TRPV1 immunoreactivity, with 8 of the TRPV1-positive cells responding to stretch. A small number of mechanosensitive gastric vagal afferents express neurofilament heavy chains and did not respond to stretch. By maintaining the structural and functional integrity of vagal afferents up to the nodose ganglion, physiological and immunohistochemical properties of mechanosensory gastric sensory neurons can be studied in vitro. Using this novel technique, we identified TRPV1 immunoreactivity in only one-fourth of gastric mechanosensitive neurons, arguing against a major role of this ion channel in sensation of mechanical stimuli under physiological conditions.
Contrasting inotropic responses to α1-adrenergic receptor stimulation in left versus right ventricular myocardium
Authors: Wang Guan-Ying , McCloskey Diana T. , Turcato Sally , Swigart Philip M. , Simpson Paul C. , Baker Anthony J.
Published: May 2006

The left ventricle (LV) and right ventricle (RV) have differing hemodynamics and embryological origins, but it is unclear whether they are regulated differently. In particular, no previous studies have directly compared the LV versus RV myocardial inotropic responses to α1-adrenergic receptor (α1-AR) stimulation. We compared α1-AR inotropy of cardiac trabeculae from the LV versus RV of adult mouse hearts. As previously reported, for mouse RV trabeculae, α1-AR stimulation with phenylephrine (PE) caused a triphasic contractile response with overall negative inotropy. In marked contrast, LV trabeculae had an overall positive inotropic response to PE. Stimulation of a single subtype (α1A-AR) with A-61603 also mediated contrasting LV/RV inotropy, suggesting differential activation of multiple α1-AR-subtypes was not involved. Contrasting LV/RV α1-AR inotropy was not abolished by inhibiting protein kinase C, suggesting differential activation of PKC isoforms was not involved. However, contrasting LV/RV α1-AR inotropic responses did involve different effects on myofilament Ca2+ sensitivity: submaximal force of skinned trabeculae was increased by PE pretreatment for LV but was decreased by PE for RV. For LV myocardium, α1-AR-induced net positive inotropy was abolished by the myosin light chain kinase inhibitor ML-9. This study suggests that LV and RV myocardium have fundamentally different inotropic responses to α1-AR stimulation, involving different effects on myofilament function and myosin light chain phosphorylation.
Adverse effects of atrioventricular synchronous right ventricular pacing on left ventricular sympathetic activity, efficiency, and hemodynamic status
Authors: Al-Hesayen Abdul , Parker John D.
Published: May 2006

Right ventricular (RV) pacing is now recognized to play a role in the development of heart failure in patients with and without underlying left ventricular (LV) dysfunction. We used the cardiac norepinephrine spillover method to test the hypothesis that RV pacing is associated with cardiac sympathetic activation. We studied 8 patients with normal LV function using temporary right atrial and ventricular pacing wires. All measurements were carried out during a fixed atrial pacing rate. The radiotracer norepinephrine spillover technique was employed to measure total body and cardiac sympathetic activity while changes in LV performance were evaluated with a high-fidelity manometer catheter. Atrioventricular synchronous RV pacing, compared with atrial pacing alone, was associated with a 65% increase in cardiac norepinephrine spillover, an increase in LV end-diastolic pressure, and a reduction in myocardial efficiency. These responses may play a role in the development of heart failure and poor outcomes that are associated with chronic RV pacing.
Effects of sympathetically induced vasomotion on tissue-capillary fluid exchange
Authors: Sakurai Terumi , Terui Naohito
Published: May 2006

The spontaneous and rhythmic constriction of peripheral arterioles, which is not associated with the cardiac or respiratory cycles, is called vasomotion. Vasomotion is observed in various tissues of various species, but the physiological role of vasomotion has not been clarified because of the difficulty in controlling the appearance of vasomotion in in vivo preparations. We developed a method of controlling vasomotion in in vivo experiments. The electrical stimulation of the cervical sympathetic nerve could reproducibly evoke vasomotion in rabbit ear skin. The frequencies of the evoked vasomotion were 0.04–0.07 Hz, which corresponded to spontaneously occurring vasomotion that has been reported before. Vasomotion was always evoked between 25 and 35°C. At lower than 17°C or higher than 37°C, vasomotion was not evoked. With the use of this method of evoking vasomotion in vivo, the role of vasomotion in tissue perfusion was examined. A tracer (Cr-EDTA) was injected into the ear tissue, and tracer fading was then measured by using a camera. The rates of fading (clearance) of the tracer with vasomotion were significantly greater (1.7 to 8.1 times) than those without vasomotion. These results provided evidence that vasomotion enhanced tissue perfusion.
Identification with MRI of the pleura as a major site of the acute inflammatory effects induced by ovalbumin and endotoxin challenge in the airways of the rat
Authors: Quintana Harry Karmouty , Cannet Catherine , Schaeublin Elisabeth , Zurbruegg Stefan , Sugar Rosemary , Mazzoni Lazzaro , Page Clive P. , Fozard John R. , Beckmann Nicolau
Published: May 2006

Inflammatory effects in the rat lung have been investigated, non-invasively by MRI, at early time points (3 and 6 h) after ovalbumin (OA) or endotoxin (LPS) challenges. Six hours after challenge with OA, a strong, even inflammatory signal was present around the periphery of the lung in a region corresponding to the pleura. Histological analysis confirmed the presence of marked edema associated with the pleural cavity of OA-treated animals. Lower levels of pleural edema were observed in MRI and histological evaluation of LPS-treated animals and no abnormality was observed in actively sensitized and naïve, saline-treated groups. Diffuse edematous signals were detected in the lung 3 and 6 h after challenge with OA or LPS; the signal volumes were larger at both time points following OA instillation. Bronchoalveolar lavage (BAL) fluid analysis performed 6 h after challenge revealed increased levels of protein and greater cellular activation in OA- than in LPS-treated animals. Furthermore, increased levels of peribronchial edema were found by histology 6 h after OA. BAL fluid and histological assessments demonstrated that the inflammatory signals were due to edema and not mucus as no significant changes in BAL mucin concentrations or differences in goblet cells were identified between OA or LPS challenge and their respective vehicle groups. Our data show that MRI is able to detect, non-invasively, inflammatory signals in both the lung and the pleura in spontaneously breathing animals, highlighting its potential to study the consequences of pulmonary insults on both sites.
A3adenosine receptor activation decreases mortality and renal and hepatic injury in murine septic peritonitis
Authors: Lee H. Thomas , Kim Mihwa , Joo Jin Deok , Gallos George , Chen Jiang-Fan , Emala Charles W.
Published: May 2006

The role of A3adenosine receptors (ARs) in sepsis and inflammation is controversial. In this study, we determined the effects of A3AR modulation on mortality and hepatic and renal dysfunction in a murine model of sepsis. To induce sepsis, congenic A3AR knockout mice (A3AR KO) and wild-type control (A3AR WT) mice were subjected to cecal ligation and double puncture (CLP). A3AR KO mice had significantly worse 7-day survival compared with A3AR WT mice. A3AR KO mice also demonstrated significantly higher elevations in plasma creatinine, alanine aminotransferase, aspartate aminotransferase, keratinocyte-derived chemokine, and TNF-α 24 h after induction of sepsis compared with A3AR WT mice. Renal cortices from septic A3AR KO mice exhibited increased mRNA encoding proinflammatory cytokines and enhanced nuclear translocation of NF-kB compared with samples from A3AR WT mice. A3AR WT mice treated with N6-(3-iodobenzyl)ADO-5′ N-methyluronamide (IB-MECA; a selective A3AR agonist) or 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate (MRS-1191; a selective A3AR antagonist) had improved or worsened 7-day survival after induction of sepsis, respectively. Moreover, A3AR WT mice treated with IB-MECA or MRS-1191 showed acutely improved or worsened, respectively, renal and hepatic function following CLP. IB-MECA significantly reduced mortality in mice lacking the A1AR or A2aAR but not the A3AR, demonstrating specificity of IB-MECA in activating A3ARs and mediating protection against sepsis-induced mortality. We conclude that endogenous or exogenous A3AR activation confers significant protection from murine septic peritonitis primarily by attenuating the hyperacute inflammatory response in sepsis.
Oxygen treatment after experimental hypoxia-ischemia in neonatal rats alters the expression of HIF-1α and its downstream target genes
Authors: Calvert John W. , Cahill Julian , Yamaguchi-Okada Mitsuo , Zhang John H.
Published: May 2006

Recently, mounting evidence has emerged to suggest that hyperbaric oxygenation (HBOT)-induced neuroprotection after experimental global ischemia and subarachnoid hemorrhage entails a decrease in the expression of hypoxia-inducible factor-1α (HIF-1α). Therefore, the purpose of this study was to test the hypothesis that oxygen-induced neuroprotection after neonatal hypoxia-ischemia involves alterations in the expression of HIF-1α. Seven-day-old rat pups were subjected to unilateral carotid artery ligation followed by 2 h of hypoxia (8% O2 at 37°C). Pups were then treated with HBOT (2.5 ATA) or normobaric oxygenation treatment (NBOT) for 2 h. The expression and phosphorylation status of HIF-1α was evaluated at intervals up to 24 h after the insult, as was the expression of glucose transporter (GLUT)-1, GLUT-3, lactate dehydrogenase (LDH), aldolase (Ald), and p53. The protein-protein interaction of HIF-1α and p53 was also examined. An elevated expression of HIF-1α, GLUT-1, GLUT-3, Ald, and LDH was observed after the insult. An increase in the dephosphorylated form of HIF-1α was followed by an increase in the association of HIF-1α with p53 and an increase in p53 levels. Both HBOT and NBOT reduced the elevated expression of HIF-1α and decreased its dephosphorylated form. Furthermore, both treatments promoted a transient increase in the expression of GLUT-1, GLUT-3, LDH, and Ald, while decreasing the HIF-1α-p53 interaction and decreasing the expression of p53. Therefore, the alteration of the HIF-1α phenotype by a single oxygen treatment may be one of the underlying mechanisms for the observed oxygen-induced neuroprotection seen when oxygen is administered after a neonatal hypoxic-ischemic insult.
Reflex regulation of airway smooth muscle tone
Authors: Canning Brendan J.
Published: May 2006

Autonomic nerves in most mammalian species mediate both contractions and relaxations of airway smooth muscle. Cholinergic-parasympathetic nerves mediate contractions, whereas adrenergic-sympathetic and/or noncholinergic parasympathetic nerves mediate relaxations. Sympathetic-adrenergic innervation of human airway smooth muscle is sparse or nonexistent based on histological analyses and plays little or no role in regulating airway caliber. Rather, in humans and in many other species, postganglionic noncholinergic parasympathetic nerves provide the only relaxant innervation of airway smooth muscle. These noncholinergic nerves are anatomically and physiologically distinct from the postganglionic cholinergic parasympathetic nerves and differentially regulated by reflexes. Although bronchopulmonary vagal afferent nerves provide the primary afferent input regulating airway autonomic nerve activity, extrapulmonary afferent nerves, both vagal and nonvagal, can also reflexively regulate autonomic tone in airway smooth muscle. Reflexes result in either an enhanced activity in one or more of the autonomic efferent pathways, or a withdrawal of baseline cholinergic tone. These parallel excitatory and inhibitory afferent and efferent pathways add complexity to autonomic control of airway caliber. Dysfunction or dysregulation of these afferent and efferent nerves likely contributes to the pathogenesis of obstructive airways diseases and may account for the pulmonary symptoms associated with extrapulmonary disorders, including gastroesophageal reflux disease, cardiovascular disease, and rhinosinusitis.
Increased pulmonary vascular resistance and reduced stroke volume in association with CO2retention and inferior vena cava dilatation
Authors: Baković Darija , Eterović Davor , Valic Zoran , Saratlija-Novaković Žana , Palada Ivan , Obad Ante , Dujić Željko
Published: May 2006

Changes in cardiovascular parameters elicited during a maximal breath hold are well described. However, the impact of consecutive maximal breath holds on central hemodynamics in the postapneic period is unknown. Eight trained apnea divers and eight control subjects performed five successive maximal apneas, separated by a 2-min resting interval, with face immersion in cold water. Ultrasound examinations of inferior vena cava (IVC) and the heart were carried out at times 0, 10, 20, 40, and 60 min after the last apnea. The arterial oxygen saturation level and blood pressure, heart rate, and transcutaneous partial pressures of CO2and O2were monitored continuously. At 20 min after breath holds, IVC diameter increased (27.6 and 16.8% for apnea divers and controls, respectively). Subsequently, pulmonary vascular resistance increased and cardiac output decreased both in apnea divers (62.8 and 21.4%, respectively) and the control group (74.6 and 17.8%, respectively). Cardiac output decrements were due to reductions in stroke volumes in the presence of reduced end-diastolic ventricular volumes. Transcutaneous partial pressure of CO2increased in all participants during breath holding, returned to baseline between apneas, but remained slightly elevated during the postdive observation period (∼4.5%). Thus increased right ventricular afterload and decreased cardiac output were associated with CO2retention and signs of peripheralization of blood volume. These results indicate that repeated apneas may cause prolonged hemodynamic changes after resumption of normal breathing, which may suggest what happens in sleep apnea syndrome.
Contribution of individual targets to the antitumor efficacy of the multitargeted receptor tyrosine kinase inhibitor SU11248
Authors: Potapova Olga , Laird A. Douglas , Nannini Michelle A. , Barone Angela , Li Guangmin , Moss Katherine G. , Cherrington Julie M. , Mendel Dirk B.
Published: May 2006

Recent achievements in the development of multitargeted molecular inhibitors necessitate a better understanding of the contribution of activity against individual targets to their efficacy. SU11248, a small-molecule inhibitor targeting class III/V receptor tyrosine kinases, including the platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) receptors, KIT and FLT3, exhibits direct effects on cancer cells as well as antiangiogenic activity. Here, we investigated the contributions of inhibiting individual SU11248 target receptors to its overall antitumor efficacy in tumor models representing diverse signaling paradigms. Consistent with previous results, SU11248 was highly efficacious (frequently cytoreductive) in all models tested. To elucidate the specific contributions of inhibition of PDGF and VEGF receptors to the in vivo efficacy of SU11248, we employed two selective inhibitors, SU10944 (VEGF receptor inhibitor) and Gleevec (PDGF receptor inhibitor). SU10944 alone induced a tumor growth delay in all models evaluated, consistent with a primarily antiangiogenic mode of action. In contrast, Gleevec resulted in modest growth inhibition in tumor models in which the cancer cells expressed its targets (PDGFRβ and KIT), but was not efficacious against tumors not driven by these target receptor tyrosine kinases. Strikingly, in all but one tumor model evaluated, the antitumor efficacy of SU10944 combined with Gleevec was similar to that of single-agent SU11248, and was greatly superior to that of each compound alone, indicating that the antitumor potency of SU11248 in these models stems from combined inhibition of both PDGF and VEGF receptors. The one exception was a model driven by an activated mutant of FLT3, in which the activity of SU11248, which targets FLT3, was greater than that of SU10944 plus Gleevec. Moreover, SU10944 combined with Gleevec inhibited tumor neoangiogenesis to an extent comparable to that of SU11248. Thus, the potent efficacy of SU11248 in models representing diverse signaling paradigms results from simultaneous inhibition of individual target receptors expressed both in cancer cells and in the tumor neovasculature, supporting the hypothesis that multitargeted inhibitors have the cumulative antitumor efficacy of combined single-target inhibitors. [Mol Cancer Ther 2006;5(5);1280–9]
Pharmacologic inhibition of cyclin-dependent kinase 4/6 activity arrests proliferation in myoblasts and rhabdomyosarcoma-derived cells
Authors: Saab Raya , Bills Jennifer L. , Miceli Alexander P. , Anderson Colleen M. , Khoury Joseph D. , Fry David W. , Navid Fariba , Houghton Peter J. , Skapek Stephen X.
Published: May 2006

Myoblast cell cycle exit and differentiation are mediated in part by down-regulation of cyclin D1 and associated cyclin-dependent kinase (Cdk) activity. Because rhabdomyosarcoma may represent a malignant tumor composed of myoblast-like cells failing to exit the cell cycle and differentiate, we considered whether excess Cdk activity might contribute to this biology. Cyclin D–dependent Cdk4 and Cdk6 were expressed in most of a panel of six human rhabdomyosarcoma-derived cell lines. Cdk4 was expressed in 73% of alveolar and embryonal rhabdomyosarcoma tumors evaluated using a human tissue microarray. When challenged to differentiate by mitogen deprivation in vitro, mouse C2C12 myoblasts arrested in G1 phase of the cell cycle, whereas four in the panel of rhabdomyosarcoma cell lines failed to do so. C2C12 myoblasts maintained in mitogen-rich media and exposed to a Cdk4/Cdk6 inhibitor PD 0332991 accumulated in G1 cell cycle phase. Similar treatment of rhabdomyosarcoma cell lines caused G1 arrest and prevented cell accumulation in vitro, and it delayed growth of rhabdomyosarcoma xenografts in vivo. Consistent with a role for Cdk4/Cdk6 activity as a regulator of myogenic differentiation, we observed that PD 0332991 exposure promoted morphologic changes and enhanced the expression of muscle-specific proteins in cultured myoblasts and in the Rh30 cell line. Our findings support the concept that pharmacologic inhibition of Cdk4/Cdk6 may represent a useful therapeutic strategy to control cell proliferation and possibly promote myogenic differentiation in rhabdomyosarcoma. [Mol Cancer Ther 2006;5(5):1299–308]
Exisulind and guanylyl cyclase C induce distinct antineoplastic signaling mechanisms in human colon cancer cells
Authors: Pitari Giovanni Mario , Li Tong , Baksh Ronnie I. , Waldman Scott A.
Published: May 2006

The nonsteroidal anti-inflammatory drug sulindac is metabolized to sulindac sulfone (exisulind), an antineoplastic agent that inhibits growth and induces apoptosis in solid tumors. In colon cancer cells, the antineoplastic effects of exisulind have been attributed, in part, to induction of cyclic guanosine 3′,5′-monophosphate (cGMP) signaling through inhibition of cGMP-specific phosphodiesterases, which elevates intracellular cGMP, and novel expression of cGMP-dependent protein kinase (PKG) Iβ, the presumed downstream effector mediating apoptosis. Here, inhibition of proliferation and induction of cell death by exisulind was dissociated from cGMP signaling in human colon cancer cells. Accumulation of intracellular cGMP produced by an exogenous cell-permeant analogue of cGMP or a potent agonist of guanylyl cyclase C yielded cytostasis without cell death. Surprisingly, the antiproliferative effects of induced cGMP accumulation were paradoxically less than additive, rather than synergistic, when combined with exisulind. Further, although exisulind induced expression of PKG Iβ, it did not elevate intracellular cGMP and its efficacy was not altered by inhibition or activation of PKG I. Rather, PKG I induced by exisulind may mediate desensitization of cytostasis induced by cGMP. Thus, cytotoxic effects of exisulind are independent of cGMP signaling in human colon cancer cells. Moreover, combination therapies, including exisulind and agents that induce cGMP signaling, may require careful evaluation in patients with colon cancer. [Mol Cancer Ther 2006;5(5):1190–6]
Enhancement of the radiosensitivity of cervical cancer cells by overexpressing p73α
Authors: Liu Stephanie Si , Chan Kelvin Yuen-Kwong , Leung Rebecca Ching-Yu , Law Helen Ka-Wai , Leung Tsin-Wah , Ngan Hextan Yuen-Sheung
Published: May 2006

Radiation therapy is the most effective therapy for cervical cancer in advanced stages. p53 plays a critical role in the cellular response to radiation-induced DNA damage. However, p53 function is often impaired in the presence of the oncoprotein E6 from human papillomavirus, which is often associated with the development of cervical cancer. p73, a p53 family member, is highly similar to p53, but is resistant to the degradation by human papillomavirus E6. In this study, we investigated the role of p73α in relation to cellular radiosensitivity in the p53-impaired cervical cancer cells. Radiosensitivity and irradiation-induced apoptotic cell death were examined in the exogenous overexpressed p73α- and p53-impaired cells. Our results showed that the endogenous p73α expressed only in the radiosensitive cervical cancer C4-1 cells, but not in the radioresistant SiHa, Caski, and HeLa cells. Overexpression of exogenous p73α by transfection in the radioresistant cells resulted in a significant increase of cellular sensitivity to radiation. Enhanced radiosensitivity in p73α-transfected cells was attributed by increase of cellular apoptosis. Coactivation of p21 was also observed in the p73α-transfected cells upon radiation treatment. In summary, our findings suggested that p73α is an important determinant of cellular radiosensitivity in the p53-impaired cervical cancer cells. [Mol Cancer Ther 2006;5(5):1209–15]
DNA mismatch repair and p53 function are major determinants of the rate of development of cisplatin resistance
Authors: Lin Xinjian , Howell Stephen B.
Published: May 2006

As opposed to factors that control sensitivity to the acute cytotoxic effect of cisplatin, little is known about the factors that determine the rate at which resistance develops. This study examined how loss of p53 or DNA mismatch repair (MMR) function affected the rate of development of resistance to cisplatin in human colon carcinoma cells during sequential cycles of cisplatin exposure that mimic the way the drug is used in the clinic. We used a panel of sublines molecularly engineered to express either the MMR- and p53-proficient phenotype or singly or doubly deficient phenotypes. Loss of either MMR or p53 alone increased the rate of development of resistance to cisplatin by 1.8- and 2.4-fold, respectively; however, loss of both MMR and p53 increased the rate by 4.8-fold. Inhibition of DNA polymerase ζ by suppression of the expression of its REV3 subunit eliminated the increased rate of development of resistance observed in the MMR-deficient cells. Loss of p53 or MMR increased the steady-state level of REV3 and of REV1 mRNA; loss of both functions increased these levels much further by a factor of 20.2-fold for REV3 and 10.3-fold for REV1. The basal level of homologous recombination measured using a reporter vector was 1.3- to 1.7-fold higher in cells that had lost either p53 or MMR function, and 2.6-fold higher in cells that had lost both. In the p53- and MMR-proficient cells, cisplatin induced a 17-fold increase in homologous recombination even when the recombining sequences that did not contain cisplatin adducts; the magnitude of induction was even greater in cells that had lost either one or both functions. We conclude that separate from effects on sensitivity to the acute cytotoxic effect of cisplatin, loss of MMR, especially when combined with loss of p53, results in rapid evolution of cisplatin resistance during sequential rounds of drug exposure that is likely mediated by enhanced mutagenic translesion synthesis. The DNA damage response activated by cisplatin is accompanied by a p53- and MMR-dependent increase in homologous recombination even between adduct-free sequences. [Mol Cancer Ther 2006;5(5):1239–47]
A novel peroxisome proliferator–activated receptor γ ligand, MCC-555, induces apoptosis via posttranscriptional regulation of NAG-1 in colorectal cancer cells
Authors: Yamaguchi Kiyoshi , Lee Seong-Ho , Eling Thomas E. , Baek Seung Joon
Published: May 2006

Apoptosis and/or differentiation induction caused by the peroxisome proliferator–activated receptor γ (PPARγ) ligand is a promising approach to cancer therapy. The thiazolidinedione derivative MCC-555 has an apoptotic activity in human colorectal cancer cells, accompanied by up-regulation of a proapoptotic nonsteroidal anti-inflammatory drug–activated gene (NAG-1) in a PPARγ-independent manner. Treatment with MCC-555 resulted in the induction of NAG-1 expression and apoptosis in HCT-116 cells. Down-regulation of NAG-1 by small interfering RNA suppressed MCC-555-induced apoptosis. MCC-555 was found to affect NAG-1 mRNA stability. To further define the underlying mechanism of RNA stability affected by MCC-555, we cloned the 3′-untranslated region (3′UTR) of human NAG-1 mRNA, which contains four copies of an AU-rich element (ARE), downstream from the luciferase gene. The reporter activity was reduced to ∼70% by inserting the 3′UTR. In addition, deletion of ARE sequences in the 3′UTR or MCC-555 treatment substantially restored activity. This effect of MCC-555 on the ARE-mediated mRNA degradation was inhibited by extracellular signal–regulated kinase (ERK) pathway inhibitors. Subsequently, rapid phosphorylation of ERK1/2 by MCC-555 treatment was detected. Moreover, ERK small interfering RNA suppressed MCC-555-induced NAG-1 expression. These results suggest that ARE sequences in the 3′UTR of the NAG-1 gene contribute to mRNA degradation and ERK1/2 phosphorylation is responsible for the stabilization of NAG-1 mRNA. These findings may provide a novel explanation for the antitumorigenic and/or proapoptotic action of MCC-555 in human colorectal cancer and the ability of pharmacologic approaches to be used against diseases caused by alterations of RNA stability. [Mol Cancer Ther 2006;5(5):1352–61]
Experimental therapy of malignant gliomas using the inhibitor of histone deacetylase MS-275
Authors: Eyüpoglu Ilker Y. , Hahnen Eric , Tränkle Christian , Savaskan Nicolai E. , Siebzehnrübl Florian A. , Buslei Rolf , Lemke Dieter , Wick Wolfgang , Fahlbusch Rudolf , Blümcke Ingmar
Published: May 2006

Inhibitors of histone deacetylases are promising compounds for the treatment of cancer but have not been systematically explored in malignant brain tumors. Here, we characterize the benzamide MS-275, a class I histone deacetylase inhibitor, as potent drug for experimental therapy of glioblastomas. Treatment of four glioma cell lines (U87MG, C6, F98, and SMA-560) with MS-275 significantly reduced cell growth in a concentration-dependent manner (IC90, 3.75 μmol/L). Its antiproliferative effect was corroborated using a bromodeoxyuridine proliferation assay and was mediated by G0-G1 cell cycle arrest (i.e., up-regulation of p21/WAF) and apoptotic cell death. Implantation of enhanced green fluorescent protein–transfected F98 glioma cells into slice cultures of rat brain confirmed the cytostatic effect of MS-275 without neurotoxic damage to the organotypic neuronal environment in a dose escalation up to 20 μmol/L. A single intratumoral injection of MS-275 7 days after orthotopic implantation of glioma cells in syngeneic rats confirmed the chemotherapeutic efficacy of MS-275 in vivo. Furthermore, its propensity to pass the blood-brain barrier and to increase the protein level of acetylated histone H3 in brain tissue identifies MS-275 as a promising candidate drug in the treatment of malignant gliomas. [Mol Cancer Ther 2006;5(5):1248–55]