bluuebunny/crossref_metadata_2025 huggingface dataset:
EXACT SOLUTION OF THE CONTINUOUS STATES FOR GENERALIZED ASYMMETRICAL HARTMANN POTENTIALS UNDER THE CONDITION OF PSEUDOSPIN SYMMETRY
Authors: GUO JIAN-YOU , ZHOU FANG , GUO FENG-LIANG , ZHOU JIAN-HONG
Published: November 2007

Under the condition of pseudospin symmetry, the exact solution of Dirac equation is studied and that no bound solutions are observed for generalized asymmetrical Hartmann potential, which is in agreement with that for Coulomb potential. With the analytic continuation method, the unbound solutions are presented by mapping the wave functions of bound states in the complex momentum plane. Furthermore, the scattering phase shifts are obtained from the radial wave function by analyzing the asymptotic behavior of the confluent hypergeometric functions.
ANALYSIS OF THE TRANSVERSE EFFECT OF EINSTEIN'S GRAVITATIONAL WAVES
Authors: CORDA CHRISTIAN
Published: November 2007

The investigation of the transverse effect of gravitational waves (GW's) could constitute a further tool to discriminate among several relativistic theories of gravity on the ground. After a review of the TT gauge, the transverse effect of GW's arising by standard general relativity (called Einstein's GW's in this paper) is reanalyzed with a different choice of coordinates. In the chosen gauge, test masses have an apparent motion in the direction of propagation of the wave, while in the transverse direction they appear at rest. Of course, this is only a gauge artefact. In fact, from careful investigation of this particular gauge, it is shown that the tidal forces associated with GW's act along the directions orthogonal to the direction of propagation of waves. In the analysis it is also shown, in a heuristic way, that the transverse effect of Einstein's GW's arises from the propagation of the waves at the speed of the light, thus only massless GW's are purely transverse. But, because the physics of gravitational waves has to be investigated by studying the tidal forces as appearing in the geodesic deviation equation and directly in a laboratory environment on Earth, an analysis of these tidal forces and of the transverse effect in the frame of the local observer is also performed. After this, for a further better understanding of the transverse effect, an example of a wave, which arises from scalar tensor gravity, with both transverse and genuinely longitudinal modes is given and discussed. In the example the connection between the longitudinal component and the velocity of the wave is mathematically shown. At the end of this paper, the review of the TT gauge is completed, recovering the gauge invariance between the presented gauge and the TT gauge.
CANONICAL FORMULATION OF A BOSONIC MATTER FIELD IN (1 + 1)-DIMENSIONAL CURVED SPACE
Authors: GHALATI R. N. , MCKEON D. G. C. , SHERRY T. N.
Published: November 2007

We study a bosonic scalar in (1 + 1)-dimensional curved space that is coupled to a dynamical metric field. This metric, along with the affine connection, also appears in the Einstein–Hilbert action [Formula: see text] when written in first-order form. After applying the Dirac constraint formalism to the Einstein–Hilbert action and the action of the bosonic scalar field separately, we apply it to these actions when they are combined. Only in the latter case does a dynamical degree of freedom emerge.
A NEW CHAOTIC SYSTEM AND CONTROL
Authors: WANG XINGYUAN , WU XIANGJUN , LANG YAHUI
Published: November 2007

In this paper a chaotic system is proposed via modifying hyperchaotic Chen system. Some basic dynamical properties, such as Lyapunov exponents, fractal dimension, chaotic behaviors of this system are studied. The conventional feedback, linear function feedback, nonlinear hyperbolic function feedback control methods are applied to control chaos to unstable equilibrium point. The conditions of stability to control the system is derived according to the Routh–Hurwitz criteria. Numerical results have shown the validity of the proposed schemes.
BOOSTED GAUSSIAN CLASSIFIER WITH INTEGRAL HISTOGRAM FOR FACE DETECTION
Authors: WANG HAIJING , LI PEIHUA , ZHANG TIANWEN
Published: November 2007

Novel features and weak classifiers are proposed for face detection within the AdaBoost learning framework. Features are histograms computed from a set of spatial templates in filtered images. The filter banks consist of Intensity, Laplacian of Gaussian (Difference of Gaussians), and Gabor filters, aiming to capture spatial and frequency properties of faces at different scales and orientations. Features selected by AdaBoost learning, each of which corresponds to a histogram with a pair of filter and template, can thus be interpreted as boosted marginal distributions of faces. We fit the Gaussian distribution of each histogram feature only for positives (faces) in the sample set as the weak classifier. The results of the experiment demonstrate that classifiers with corresponding features are more powerful in describing the face pattern than haar-like rectangle features introduced by Viola and Jones.
SEIFERT SURFACES IN KNOT COMPLEMENTS
Authors: KANG ENSIL
Published: November 2007

In the ordinary normal surface for a compact 3-manifold, any incompressible, ∂-incompressible, compact surface can be moved by an isotopy to a normal surface [9]. But in a non-compact 3-manifold with an ideal triangulation, the existence of a normal surface representing an incompressible surface cannot be guaranteed. The figure-8 knot complement is presented in a counterexample in [12]. In this paper, we show the existence of normal Seifert surface under some restriction for a given ideal triangulation of the knot complement.
A GEOMETRIC PROOF THAT THE SINGULAR BRAID GROUP IS TORSION FREE
Authors: JORDAN-SANTANA MERCEDES
Published: November 2007

In this paper combinatorial means and results from bands in singular braids are used to prove that the singular braid group is torsion free.
BOUNDS ON THE CROSSCAP NUMBER OF TORUS KNOTS
Authors: MATTMAN THOMAS W. , SIZEMORE OWEN
Published: November 2007

For a torus knot K, we bound the crosscap number c(K) in terms of the genus g(K) and crossing number n(K) : c(K) ≤ ⌊(g(K)+9)/6⌋ and c(K) ≤ ⌊(n(K) + 16)/12⌋. The (6n - 2,3) torus knots show that these bounds are sharp.
A SPACE LOWER BOUND FOR NAME-INDEPENDENT COMPACT ROUTING IN TREES
Authors: LAING KOFI A. , RAJARAMAN RAJMOHAN
Published: November 2007

Given a rooted n-node tree with arbitrary positive edge weights, and arbitrarily assigned node names, what is the minimum amount of space that a single-source compact routing algorithm could use in its largest routing table while achieving stretch 3? We show that the space requirements is [Formula: see text] bits in a port model that is more general than the fixed-port model, and note that this result also applies for all-pairs routing in trees.
STUDY OF SOME NONLINEAR SELF-SIMILAR DISTRIBUTIONS
Authors: BEN MABROUK ANOUAR
Published: November 2007

We study some properties of some self-similar distributions constructed on a nonlinear way. We use wavelets to characterize such properties and to check the validity of the multifractal formalism in some cases.
QUANTUM CIRCUITS FOR PROBABILISTIC ENTANGLEMENT TELEPORTATION VIA A PARTIALLY ENTANGLED PAIR
Authors: CHEN XIU-BO , WEN QIAO-YAN , ZHU FU-CHEN
Published: November 2007

It deserves mentioning that the quantum circuit, i.e. quantum logic network, is essential to the practical realization of teleportation in experiment. Using only one partially entangled pair, we first propose two novel strategies for probabilistically teleporting any partially entangled state of a bipartite system. The feature of the present protocol is to weaken the requirement for the quantum channel, and also to cut down the number of entangled particles initially shared by the sender and receiver. On the other hand, we explicitly construct the generalized measurement described by the positive operator-valued measure (POVM). Two kinds of efficient quantum circuits for implementing the teleportation are offered. In addition, we generalize the two-particle probabilistic teleportation to the system of many particles.
ON FUZZY OPTIMAL CONTROLS IN THE WEAKLY STRUCTURABLE CONTINUOUS DYNAMIC SYSTEMS (WSCDS)
Authors: SIRBILADZE G.
Published: November 2007

We pose problems of the WSCDS optimal control and discuss the results developed by G. Sirbiladze in Ref. 7. Sufficient and necessary conditions are presented for the existence of an extremal fuzzy optimal control process, for which we use R. Bellman's optimality principle and take into consideration the gain-loss fuzzy process. An example of constructing the continuous extremal fuzzy dynamic systems optimal control is presented.
APPLICATION OF ANT COLONY OPTIMIZATION TO CREDIT RISK ASSESSMENT
Authors: MARINAKIS YANNIS , MARINAKI MAGDALENE , ZOPOUNIDIS CONSTANTIN
Published: November 2007

This paper presents a novel approach to solve feature subset selection problems using an Ant Colony Optimization (ACO) algorithm. ACO is one of the important naturally inspired intelligent techniques. It is based on the foraging behavior of real ants in nature. The proposed ACO is combined with a number of nearest neighbor classifiers. The resulting ACO algorithm is applied to classify credit risk using data belonging to 1,411 firms obtained from a leading Greek commercial bank. The objective is to classify subject firms into several groups representing different levels of credit risk. The results of the proposed algorithm are compared with those of others including SVM, CART, and with two other metaheuristic algorithms using tabu search and genetic algorithms, both of which use nearest neighbor classifiers in the classification phase. The results suggest that the proposed method is more accurate than others that have been tested in classifying credit risk.
USING GRAPHEME n-GRAMS IN SPELLING CORRECTION AND AUGMENTATIVE TYPING SYSTEMS
Authors: MEMUSHAJ ALKET , SOBH TAREK M.
Published: November 2007

Probabilistic language models have gained popularity in Natural Language Processing due to their ability to successfully capture language structures and constraints with computational efficiency. Probabilistic language models are flexible and easily adapted to language changes over time as well as to some new languages. Probabilistic language models can be trained and their accuracy strongly related to the availability of large text corpora.

In this paper, we investigate the usability of grapheme probabilistic models, specifically grapheme n-grams models in spellchecking as well as augmentative typing systems. Grapheme n-gram models require substantially smaller training corpora and that is one of the main drivers for this thesis in which we build grapheme n-gram language models for the Albanian language. There are presently no available Albanian language corpora to be used for probabilistic language modeling.

Our technique attempts to augment spellchecking and typing systems by utilizing grapheme n-gram language models in improving suggestion accuracy in spellchecking and augmentative typing systems. Our technique can be implemented in a standalone tool or incorporated in another tool to offer additional selection/scoring criteria.
EXPERIMENTAL NANOMECHANICS OF ONE-DIMENSIONAL NANOMATERIALS BY IN SITU MICROSCOPY
Authors: HAN XIAODONG , ZHANG ZE , WANG ZHONG LIN
Published: November 2007

This paper provides a comprehensive review on the methodological development and technical applications of in situ microscopy, including transmission electron microscopy (TEM), scanning electron microscopy (SEM) and atomic force microscopy (AFM), developed in the last decade for investigating the structure-mechanical-property relationship of a single one-dimensional nanomaterial, such as nanotube, nanowire and nanobelt. The paper covers both the fundamental methods and detailed applications, including AFM-based static elastic and plastic measurements of a carbon nanotube, external field-induced resonance dynamic measurement of elastic modulus of a nanotube/nanowire, nano-indentation, and in situ plastic deformation process of a nanowire. Details are presented on the elastic property measurements and direct imaging of plastic to superplastic behavior of semiconductor nanowires at atomic resolution, providing quantitative information on the mechanical behavior of nanomaterials. The studies on the Si and SiC nanowires clearly demonstrated their distinct, "unexpected" and superior plastic mechanical properties. Finally, a perspective is given on the future of nanomechanics.
SYNTHESIS AND SPECTROSCOPIC CHARACTERIZATION OF SALMON DNA-WRAPPED SINGLE-WALL CARBON NANOTUBES
Authors: ASADA YUKI , DOHI HIROFUMI , KUWAHARA SHOTA , SUGAI TOSHIKI , KITAURA RYO , SHINOHARA HISANORI
Published: November 2007

Single-wall carbon nanotubes (SWNTs) can be well-dispersed in water by wrapping with short segments of natural DNA from salmon sperm. We report here the isolated DNA-wrapped SWNT hybrids. Measurements were carried out using UV-vis-NIR, near-infrared photoluminescence (PL) spectrum and atomic force microscopy (AFM). A possible charge transport between SWNTs and salmon-DNA is discussed in terms of observed spectral shifts in the photoluminescence spectra.
Cell culture alters Ca2+entry pathways activated by store-depletion or hypoxia in canine pulmonary arterial smooth muscle cells
Authors: Ng Lih Chyuan , Kyle Barry D. , Lennox Alison R. , Shen Xiao-Ming , Hatton William J. , Hume Joseph R.
Published: November 2007

Previous studies have shown that, in acutely dispersed canine pulmonary artery smooth muscle cells (PASMCs), depletion of both functionally independent inositol 1,4,5-trisphosphate (IP3)- and ryanodine-sensitive Ca2+stores activates capacitative Ca2+entry (CCE). The present study aimed to determine if cell culture modifies intracellular Ca2+stores and alters Ca2+entry pathways caused by store depletion and hypoxia in canine PASMCs. Intracellular Ca2+concentration ([Ca2+]i) was measured in fura 2-loaded cells. Mn2+quench of fura 2 signal was performed to study divalent cation entry, and the effects of hypoxia were examined under oxygen tension of 15–18 mmHg. In acutely isolated PASMCs, depletion of IP3-sensitive Ca2+stores with cyclopiazonic acid (CPA) did not affect initial caffeine-induced intracellular Ca2+transients but abolished 5-HT-induced Ca2+transients. In contrast, CPA significantly reduced caffeine- and 5-HT-induced Ca2+transients in cultured PASMCs. In cultured PASMCs, store depletion or hypoxia caused a transient followed by a sustained rise in [Ca2+]i. The transient rise in [Ca2+]iwas partially inhibited by nifedipine, whereas the nifedipine-insensitive transient rise in [Ca2+]iwas inhibited by KB-R7943, a selective inhibitor of reverse mode Na+/Ca2+exchanger (NCX). The nifedipine-insensitive sustained rise in [Ca2+]iwas inhibited by SKF-96365, Ni2+, La3+, and Gd3+. In addition, store depletion or hypoxia increased the rate of Mn2+quench of fura 2 fluorescence that was also inhibited by these blockers, exhibiting pharmacological properties characteristic of CCE. We conclude that cell culture of canine PASMCs reorganizes IP3and ryanodine receptors into a common intracellular Ca2+compartment, and depletion of this store or hypoxia activates voltage-operated Ca2+entry, reverse mode NCX, and CCE.
Osmotic cell shrinkage activates ezrin/radixin/moesin (ERM) proteins: activation mechanisms and physiological implications
Authors: Rasmussen Maria , Alexander R. Todd , Darborg Barbara V. , Møbjerg Nadja , Hoffmann Else K. , Kapus András , Pedersen Stine F.
Published: November 2007

Hyperosmotic shrinkage induces multiple cellular responses, including activation of volume-regulatory ion transport, cytoskeletal reorganization, and cell death. Here we investigated the possible roles of ezrin/radixin/moesin (ERM) proteins in these events. Osmotic shrinkage of Ehrlich Lettre ascites cells elicited the formation of long microvillus-like protrusions, rapid translocation of endogenous ERM proteins and green fluorescent protein-tagged ezrin to the cortical region including these protrusions, and Thr567/564/558 (ezrin/radixin/moesin) phosphorylation of cortical ERM proteins. Reduced cell volume appeared to be the critical parameter in hypertonicity-induced ERM protein activation, whereas alterations in extracellular ionic strength or intracellular pH were not involved. A shrinkage-induced increase in the level of membrane-associated phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] appeared to play an important role in ERM protein activation, which was prevented after PtdIns(4,5)P2 depletion by expression of the synaptojanin-2 phosphatase domain. While expression of constitutively active RhoA increased basal ERM phosphorylation, the Rho-Rho kinase pathway did not appear to be involved in shrinkage-induced ERM protein phosphorylation, which was also unaffected by the inhibition or absence of Na+/H+ exchanger isoform (NHE1). Ezrin knockdown by small interfering RNA increased shrinkage-induced NHE1 activity, reduced basal and shrinkage-induced Rho activity, and attenuated the shrinkage-induced formation of microvillus-like protrusions. Hyperosmolarity-induced cell death was unaltered by ezrin knockdown or after phosphatidylinositol 3-kinase (PI3K) inhibition. In conclusion, ERM proteins are activated by osmotic shrinkage in a PtdIns(4,5)P2-dependent, NHE1-independent manner. This in turn mitigates the shrinkage-induced activation of NHE1, augments Rho activity, and may also contribute to F-actin rearrangement. In contrast, no evidence was found for the involvement of an NHE1-ezrin-PI3K-PKB pathway in counteracting shrinkage-induced cell death.
Physiological hydrostatic pressure protects endothelial monolayer integrity
Authors: Müller-Marschhausen K. , Waschke J. , Drenckhahn D.
Published: November 2007

Endothelial monolayer integrity is required to maintain endothelial barrier functions and has found to be impaired in several disorders like inflammatory edema, allergic shock, or artherosclerosis. Under physiologic conditions in vivo, endothelial cells are exposed to mechanical forces such as hydrostatic pressure, shear stress, and cyclic stretch. However, insight into the effects of hydrostatic pressure on endothelial cell biology is very limited at present. Therefore, in this study, we tested the hypothesis that physiological hydrostatic pressure protects endothelial monolayer integrity in vitro. We investigated the protective efficacy of hydrostatic pressure in microvascular myocardial endothelial (MyEnd) cells and macrovascular pulmonary artery endothelial cells (PAECs) by the application of selected pharmacological agents known to alter monolayer integrity in the absence or presence of hydrostatic pressure. In both endothelial cell lines, extracellular Ca2+depletion by EGTA was followed by a loss of vascular-endothelial cadherin (VE-caherin) immunostaining at cell junctions. However, hydrostatic pressure (15 cmH2O) blocked this effect of EGTA. Similarly, cytochalasin D-induced actin depolymerization and intercellular gap formation and cell detachment in response to the Ca2+/calmodulin antagonist trifluperazine (TFP) as well as thrombin-induced cell dissociation were also reduced by hydrostatic pressure. Moreover, hydrostatic pressure significantly reduced the loss of VE-cadherin-mediated adhesion in response to EGTA, cytochalasin D, and TFP in MyEnd cells as determined by laser tweezer trapping using VE-cadherin-coated microbeads. In caveolin-1-deficient MyEnd cells, which lack caveolae, hydrostatic pressure did not protect monolayer integrity compromised by EGTA, indicating that caveolae-dependent mechanisms are involved in hydrostatic pressure sensing and signaling.
Dorsal motor nucleus of the vagus: a site for evoking simultaneous changes in crural diaphragm activity, lower esophageal sphincter pressure, and fundus tone
Authors: Niedringhaus Mark , Jackson Patrick G. , Evans Stephen R. T. , Verbalis Joseph G. , Gillis Richard A. , Sahibzada Niaz
Published: November 2007

The sphincter mechanism at the esophagogastric junction includes smooth muscle of the lower esophagus and skeletal muscle of the crural diaphragm (CD). Smooth muscle is known to be under the control of the dorsal motor nucleus of the vagus (DMV), while central nervous system (CNS) control of the CD is unknown. The main purposes of our study were to determine the CNS site that controls the CD and whether simultaneous changes in lower esophageal sphincter (LES) pressure and CD activity occur when this site is activated. Experiments were performed on anesthetized male ferrets whose LES pressure, CD activity, and fundus tone were monitored. To activate DMV neurons, l-glutamate was microinjected unilaterally into the DMV at three areas: intermediate, rostral, and caudal. Stimulation of the intermediate DMV decreased CD activity (−4.8 ± 0.1 bursts/min and −0.3 ± 0.01 mV) and LES pressure (−13.2 ± 2.0 mmHg; n = 9). Stimulation of this brain site also produced an increase in fundus tone. Stimulation of the rostral DMV elicited increases in the activity of all three target organs ( n = 5). Stimulation of the caudal DMV had no effect on the CD but did decrease both LES pressure and fundus tone ( n = 5). All changes in LES pressure, fundus tone, and some DMV-induced changes in CD activity (i.e., bursts/min) were prevented by ipsilateral vagotomy. Our data indicate that simultaneous changes in activity of esophagogastric sphincters and fundus tone occur from rostral and intermediate areas of the DMV and that these changes are largely mediated by efferent vagus nerves.
ACE2 and ANG-(1-7) in the rat uterus during early and late gestation
Authors: Neves Liomar A. A. , Stovall Kathryn , Joyner JaNae , Valdés Gloria , Gallagher Patricia E. , Ferrario Carlos M. , Merrill David C. , Brosnihan K. Bridget
Published: November 2007

The present study was designed to determine ANG peptide content [ANG I, ANG II, ANG-(1-7)], ACE2 mRNA, and the immunocytochemical distribution of ANG-(1-7) and ACE2 in the uteroembryonic unit during early and late gestation in Sprague-Dawley rats and in a rat model of pregnancy-induced hypertension, the reduced uterine perfusion pressure (RUPP) model. At early pregnancy ANG-(1-7) and ACE2 staining were localized in the primary and secondary decidual zone and luminal and glandular epithelial cells. During late gestation, ANG-(1-7) and ACE2 staining was visualized in the labyrinth placenta and amniotic and yolk sac epithelium. Uterine ANG II concentration at early pregnancy was significantly decreased by 21–55% in the implantation and interimplantation sites compared with virgin rats, whereas ANG-(1-7) levels were maintained at prepregnancy levels. At late gestation, uterine concentrations of ANG I and ANG II were significantly increased (30% and 25%, respectively). In RUPP animals, ANG-(1-7) concentration is significantly reduced in the uterus (181 ± 16 vs. 372 ± 74 fmol/g of tissue) and placenta (143 ± 26 vs. 197 ± 20 fmol/g of tissue). ACE2 mRNA increased in the uterus of early pregnant compared with virgin rats, yet within the implantation site it was downregulated. At late pregnancy, ACE2 mRNA is elevated by 58% in the uterus and decreased by 59% in RUPP animals. The regulation of ANG-(1-7) and ACE2 in early and late pregnancy supports the hypothesis that ANG-(1-7) and ACE2 may act as a local autocrine/paracrine regulator throughout pregnancy, participating in the early (angiogenesis, apoptosis, and growth) and late (uteroplacental blood flow) events of pregnancy.
Renoprotective effects of neuronal NOS-derived nitric oxide and cyclooxygenase-2 metabolites in transgenic rats with inducible malignant hypertension
Authors: Patterson Matthew E. , Mullins John J. , Mitchell Kenneth D.
Published: November 2007

The present study was performed to determine the effects of neuronal nitric oxide synthase (nNOS) and cyclooxygenase-2 (COX-2) inhibition on blood pressure and renal hemodynamics in transgenic rats with inducible ANG II-dependent malignant hypertension [strain name: TGR(Cyp1a1Ren2)]. Male Cyp1a1-Ren2 rats ( n = 7) were fed a normal diet containing indole-3-carbinol (I3C; 0.3%) for 6–9 days to induce malignant hypertension. Mean arterial pressure (MAP) and renal hemodynamics were assessed in pentobarbital sodium-anesthetized Cyp1a1-Ren2 rats before and during intravenous infusion of the nNOS inhibitor S-methyl-l-thiocitrulline (l-SMTC; 1 mg/h). In hypertensive Cyp1a1-Ren2 rats, l-SMTC increased MAP from 169 ± 3 to 188 ± 4 mmHg ( P < 0.01), which was a smaller increase than in noninduced rats (124 ± 9 to 149 ± 9 mmHg, P < 0.01, n = 5). Additionally, l-SMTC decreased renal plasma flow (RPF) to a similar extent (−34 ± 13 vs. −35 ± 12%) in the hypertensive and normotensive rats (4.1 ± 0.2 to 2.7 ± 0.5 and 3.1 ± 0.3 to 2.0 ± 0.3 ml·min−1·g−1, respectively, P < 0.01) but did not alter glomerular filtration rate (GFR) in either group. In additional experiments, administration of the COX-2 inhibitor, nimesulide (3 mg/kg iv), during simultaneous infusion of l-SMTC decreased MAP in both hypertensive and noninduced rats (182 ± 2 to 170 ± 3 mmHg and 153 ± 3 to 140 ± 3 mmHg, respectively, P < 0.01). Nimesulide also decreased RPF (1.9 ± 0.2 to 0.8 ± 0.1 ml·min−1·g−1, P < 0.01) and GFR (0.9 ± 0.1 to 0.4 ± 0.1 ml·min−1·g−1, P < 0.01) in hypertensive rats but did not alter RPF or GFR in noninduced rats. The present findings demonstrate that both nNOS-derived NO and COX-2 metabolites exert pronounced renal vasodilator influences in hypertensive Cyp1a1-Ren2 rats. The data also indicate that the renal vasodilator effects of COX-2-derived prostanoids in hypertensive Cyp1a1-Ren2 rats are not dependent on nNOS activity.
P2 receptors in the regulation of renal transport mechanisms
Authors: Vallon Volker
Published: November 2007

Extracellular nucleotides (e.g., ATP) regulate physiological and pathophysiological processes through activation of nucleotide P2 receptors in the plasma membrane. Examples include such diverse processes as communication from taste buds to gustatory nerves, platelet aggregation, nociception, or neutrophil chemotaxis. Over approximately the last 15 years, evidence has also accumulated that cells in renal epithelia release nucleotides in response to physiological stimuli and that these nucleotides act in a paracrine and autocrine way to activate P2 receptors and play a significant role in the regulation of transport mechanisms and cell volume regulation. This review discusses potential stimuli and mechanisms involved in nucleotide release in renal epithelia and summarizes the available data on the expression and function of nucleotide P2 receptors along the native mammalian tubular and collecting duct system. Using established agonist profiles for P2 receptor subtypes, significant insights have been gained particularly into a potential role for P2Y2-like receptors in the regulation of transport mechanisms in the collecting duct. Due to the lack of receptor subtype-specific antagonists, however, the in vivo relevance of P2 receptor subtypes is unclear. Studies in gene knockout mice provided first insights including an antihypertensive activity of P2Y2receptors that is linked to an inhibitory influence on renal Na+and water reabsorption. We are only beginning to unravel the important roles of extracellular nucleotides and P2 receptors in the regulation of the diverse transport mechanisms of the kidney.
Locomotor Pattern in the Adult Zebrafish Spinal Cord In Vitro
Authors: Gabriel Jens Peter , Mahmood Riyadh , Walter Alexander M. , Kyriakatos Alexandros , Hauptmann Giselbert , Calabrese Ronald L. , El Manira Abdeljabbar
Published: November 2007

The zebrafish is an attractive model system for studying the function of the spinal locomotor network by combining electrophysiological, imaging, and genetic approaches. Thus far, most studies have been focusing on embryonic and larval stages. In this study we have developed an in vitro preparation of the isolated spinal cord from adult zebrafish in which locomotor activity can be induced while the activity of single neurons can be monitored using whole cell recording techniques. Application of NMDA elicited rhythmic locomotor activity that was monitored by recording from muscles or ventral roots in semi-intact or isolated spinal cord preparations, respectively. This rhythmic activity displayed a left–right alternation and a rostrocaudal delay. Blockade of glycinergic synaptic transmission by strychnine switched the alternating activity into synchronous bursting in the left and right sides as well as along the rostrocaudal axis. Whole cell recordings from motoneurons showed that they receive phasic synaptic inputs that were correlated with the locomotor activity recorded in ventral roots. This newly developed in vitro preparation of the adult zebrafish spinal cord will allow examination of the organization of the spinal locomotor network in an adult system to complement studies in zebrafish larvae and new born rodents.
Cortical-Like Functional Organization of the Pheromone-Processing Circuits in the Medial Amygdala
Authors: Bian Xiling , Yanagawa Yuchio , Chen Wei R. , Luo Minmin
Published: November 2007

The medial amygdala (MeA) is a critical center for processing pheromonal signals that regulate social and reproductive behaviors, but the fundamental cellular mechanisms underlying signal processing in the MeA have remained largely unknown. Some studies suggest that the MeA belongs to the striatum and provides inhibitory output to hypothalamic areas including the ventromedial hypothalamus (VMH). By combining tract tracing, genetic labeling of GABAergic neurons, and immunostaining against markers for glutamatergic synapses, we found that a majority of MeA neurons projecting to the VMH are glutamatergic. Whole cell patch-clamp recordings revealed that VMH-projecting neurons form a homogeneous population in terms of morphological and intrinsic properties. Nearly all cells possess Ih and IT and in some cases they can give rise to postinhibitory rebound spikes. Morphological analysis of neurobiotin-filled cells revealed neurons with long dendritic arbors that extend to the MeA external layer and within the amygdala. Thus the VMH-projecting neurons in the MeA differ from the medium spiny neurons, the principal neurons of striatum, in terms of intrinsic physiological properties and morphology. In contrast, they resemble a subset of pyramidal cells in deep piriform cortex. Similar to pyramidal cells in piriform cortex, the VMH-projecting neurons in the MeA received direct excitatory input from their upstream sensory areas and inhibitory input from local GABAergic neurons. We conclude that pheromonal signals relayed to the VMH are processed by unique cortical, but not striatal, circuitry in the MeA.
Responses to Moving Visual Stimuli in Pretectal Neurons of the Small-Spotted Dogfish (Scyliorhinus canicula)
Authors: Masseck Olivia Andrea , Hoffmann Klaus-Peter
Published: November 2007

Single-unit recordings were performed from a retinorecipient pretectal area (corpus geniculatum laterale) in Scyliorhinus canicula. The function and homology of this nucleus has not been clarified so far. During visual stimulation with a random dot pattern, 45 (35%) neurons were found to be direction selective, 10 (8%) were axis selective (best neuronal responses to rotations in both directions around one particular stimulus axis), and 75 (58%) were movement sensitive. Direction-selective responses were found to the following stimulus directions (in retinal coordinates): temporonasal and nasotemporal horizontal movements, up- and downward vertical movements, and oblique movements. All directions of motion were represented equally by our sample of pretectal neurons. Additionally we tested the responses of 58 of the 130 neurons to random dot patterns rotating around the semicircular canal or body axes to investigate whether direction-selective visual information is mapped into vestibular coordinates in pretectal neurons of this chondrichthyan species. Again all rotational directions were represented equally, which argues against a direct transformation from a retinal to a vestibular reference frame. If a complete transformation had occurred, responses to rotational axes corresponding to the axes of the semicircular canals should have been overrepresented. In conclusion, the recorded direction-selective neurons in the Cgl are plausible detectors for retinal slip created by body rotations in all directions.
The Collagen Receptor Endo180 (CD280) Is Expressed on Basal-like Breast Tumor Cells and Promotes Tumor Growth In vivo
Authors: Wienke Dirk , Davies Gareth C. , Johnson Damian A. , Sturge Justin , Lambros Maryou B.K. , Savage Kay , Elsheikh Somaia Elbauomy , Green Andrew R. , Ellis Ian O. , Robertson David , Reis-Filho Jorge S. , Isacke Clare M.
Published: November 2007

Tumor cell invasion into the surrounding stroma requires increased cell motility and extensive remodeling of the extracellular matrix. Endo180 (CD280, MRC2, urokinase-type plasminogen activator receptor-associated protein) is a recycling endocytic receptor that functions in both these cellular activities by promoting cell migration and uptake of collagens for intracellular degradation. In the normal breast, Endo180 is predominantly expressed by stromal fibroblasts. The contrary observation that Endo180 is expressed on epithelial tumor cell lines that display a high invasive capacity suggested that up-regulation of this receptor may be an associated and functional component in the acquisition of a more aggressive phenotype by tumor cells in vivo. Here, we show that high levels of Endo180 are found in a subset of basal-like breast cancers and that this expression is an independent prognostic marker for shorter disease-free survival. Two potential mechanisms for Endo180 up-regulation were uncovered. First, it was shown that Endo180 can be transcriptionally up-regulated in vitro following transforming growth factor-β treatment of breast cancer cells. Second, a proportion of Endo180+ tumors were shown to have Endo180 gene copy number gains and amplifications. To investigate the functional consequence of Endo180 up-regulation, MCF7 cells transfected with Endo180 were inoculated into immunocompromised mice. Expression of wild-type Endo180, but not an internalization-defective Endo180 mutant, resulted in enhanced tumor growth together with a reduction in tumor collagen content. Together, these data argue that elevated expression of this receptor in tumor cells could have important consequences in subsets of basal-like carcinomas for which there is a current lack of effective treatment. [Cancer Res 2007;67(21):10230–11]
Human Pregnane X Receptor and Resistance to Chemotherapy in Prostate Cancer
Authors: Chen Yakun , Tang Yong , Wang Man-Tzu , Zeng Su , Nie Daotai
Published: November 2007

Resistance to chemotherapy is a significant barrier to the effective management of prostate cancer. Human pregnane X receptor (hPXR), an orphan nuclear receptor known for its activation by many important clinical drugs, interacts with many cellular signaling pathways during carcinogenesis and is a major transcription factor regulating the expression of drug metabolism enzymes, including transporters. It is unknown whether hPXR is a determinant of drug resistance in prostate cancer. In this study, we first detected the expression of hPXR in both normal and cancerous prostate tissues. Pretreatment with SR12813, a potent and selective agonist of hPXR, led to nuclear translocation of PXR in PC-3 cells and increased expression of cytochrome P450 3A4 (CYP3A4) and multidrug resistance 1 (MDR1). SR12813 pretreatment increased resistance of PC-3 cells to Taxol and vinblastine, as assessed by viability and clonogenic survival. To further study the role of hPXR in prostate cancer drug resistance, hPXR expression was knocked down using PXR-targeting short hairpin RNAs. The activities of hPXR toward the promoter of CYP3A4 in hPXR-ablated clones decreased when compared with that of wild-type PC-3 cells. Their sensitivities to Taxol and vinblastine were enhanced by hPXR ablation. Our data here suggest that hPXR may play an important role in prostate cancer resistance to chemotherapeutics. [Cancer Res 2007;67(21):10361–7]
Activation of Toll-like Receptor 4 on Tumor CellsIn vitroInhibits Subsequent Tumor GrowthIn vivo
Authors: Andreani Virginia , Gatti Gerardo , Simonella Lucio , Rivero Virginia , Maccioni Mariana
Published: November 2007

Although an eruption of information on the role of Toll-like receptor 4 (TLR4), the main receptor for bacterial lipopolysaccharide, in activating macrophages and dendritic cells has emerged, very little is known about the role of TLR4 present on epithelial cells from sterile environments like tumors. The main goal of this work was to investigate the consequences of TLR4 activation present on tumor cells in two different animal models of cancer: the Dunning rat prostate cancer and the B16 murine melanoma models. We show that (a) activating TLR4 signaling in two different tumor cell lines in vitro modifies the tumor outgrowth in vivo; (b) this effect is not due to a direct consequence of TLR4 signaling on the proliferation/apoptosis balance of the tumor cells; (c) the T-cell compartment is somehow involved in the described phenomenon because the inhibitory effect observed is not seen in athymic nude mice; and (d) tumor-infiltrating lymphocytes purified from tumors induced by TLR4-activated cells show strong induction of IFNγ transcript in detriment of interleukin-10 transcript, suggesting a change in their functionality. We hypothesize that TLR4 signaling in tumor cells in vitro induces the expression of proinflammatory mediators, which could dramatically alter the maturation state of dendritic cells present at the site of inoculation, switching the type of immune response elicited against the tumor. These results open up new avenues for understanding the role of TLR4 in tumor cells and for identifying potential new therapy strategies for cancer. [Cancer Res 2007;67(21):10519–27]
Endoplasmic Reticulum Stress in the Proapoptotic Action of Edelfosine in Solid Tumor Cells
Authors: Nieto-Miguel Teresa , Fonteriz Rosalba I. , Vay Laura , Gajate Consuelo , López-Hernández Silvia , Mollinedo Faustino
Published: November 2007

The endoplasmic reticulum (ER) has been posited as a potential anticancer target. The synthetic antitumor alkyl-lysophospholipid analogue edelfosine accumulates in the ER of solid tumor cells. This ER accumulation of the drug leads to the inhibition of phosphatidylcholine and protein synthesis, G2-M arrest, depletion of ER-stored Ca2+, Bax up-regulation and activation, transcriptional factor growth arrest and DNA damage–inducible gene 153 up-regulation, caspase-4 and caspase-8 activation, and eventually to apoptosis. Edelfosine prompted ER stress apoptotic signaling, but not the survival unfolded protein response. Edelfosine also induced persistent c-Jun NH2-terminal kinase (JNK) activation. Gene transfer–mediated overexpression of apoptosis signal–regulating kinase 1, which plays a crucial role in ER stress, enhanced edelfosine-induced JNK activation and apoptosis. Inhibition of JNK, caspase-4, or caspase-8 activation diminished edelfosine-induced apoptosis. Edelfosine treatment led to the generation of the p20 caspase-8 cleavage fragment of BAP31, directing proapoptotic signals between the ER and the mitochondria. bax−/−bak−/− double-knockout cells fail to undergo edelfosine-induced ER-stored Ca2+ release and apoptosis. Wild-type and bax−/−bak−/− cells showed similar patterns of phosphatidylcholine and protein synthesis inhibition, despite their differences in drug sensitivity. Thus, edelfosine-induced apoptosis is dependent on Bax/Bak-mediated ER-stored Ca2+ release, but phosphatidylcholine and protein synthesis inhibition is not critical. Transfection-enforced expression of Bcl-XL, which localizes specifically in mitochondria, prevented apoptosis without inhibiting ER-stored Ca2+ release. These data reveal that edelfosine induces an ER stress response in solid tumor cells, providing novel insights into the edelfosine-mediated antitumor activity. Our data also indicate that mitochondria are indispensable for this edelfosine-induced cell death initiated by ER stress. [Cancer Res 2007;67(21):10368–78]
Overexpression of Eg5 Causes Genomic Instability and Tumor Formation in Mice
Authors: Castillo Andrew , Morse Herbert C. , Godfrey Virginia L. , Naeem Rizwan , Justice Monica J.
Published: November 2007

Proper chromosome segregation in eukaryotes is driven by a complex superstructure called the mitotic spindle. Assembly, maintenance, and function of the spindle depend on centrosome migration, organization of microtubule arrays, and force generation by microtubule motors. Spindle pole migration and elongation are controlled by the unique balance of forces generated by antagonistic molecular motors that act upon microtubules of the mitotic spindle. Defects in components of this complex structure have been shown to lead to chromosome missegregation and genomic instability. Here, we show that overexpression of Eg5, a member of the Bim-C class of kinesin-related proteins, leads to disruption of normal spindle development, as we observe both monopolar and multipolar spindles in Eg5 transgenic mice. Our findings show that perturbation of the mitotic spindle leads to chromosomal missegregation and the accumulation of tetraploid cells. Aging of these mice revealed a higher incidence of tumor formation with a mixed array of tumor types appearing in mice ages 3 to 30 months with the mean age of 20 months. Analysis of the tumors revealed widespread aneuploidy and genetic instability, both hallmarks of nearly all solid tumors. Together with previous findings, our results indicate that Eg5 overexpression disrupts the unique balance of forces associated with normal spindle assembly and function, and thereby leads to the development of spindle defects, genetic instability, and tumors. [Cancer Res 2007;67(21):1–10] [Cancer Res 2007;67(21):10138–47]
Clusterin Isoforms Differentially Affect Growth and Motility of Prostate Cells: Possible Implications in Prostate Tumorigenesis
Authors: Moretti Roberta M. , Marelli Marina Montagnani , Mai Stefania , Cariboni Anna , Scaltriti Maurizio , Bettuzzi Saverio , Limonta Patrizia
Published: November 2007

Besides a fully processed, secreted form of clusterin (sCLU), an alternative proapoptotic form of the protein targeting the nucleus (nCLU) was recently described. The possible differential roles played by the two clusterin forms in growth and motility of nonmalignant and malignant prostate cells are investigated here. sCLU or nCLU was transiently transfected in both androgen-independent prostate cancer cells (PC3 and DU 145) and immortalized prostate epithelial cells (PNT1A, a nontumoral control). Then, cell growth, motility, and cytoskeleton organization were studied. We found that (a) in PNT1A cells, both sCLU and nCLU significantly decreased cell proliferation and motility; (b) in PC3 and DU 145 cancer cells, only nCLU inhibited cell growth and migration, with sCLU being ineffective; and (c) the antimotility effect of nCLU was accompanied by a dramatic dismantling of the actin cytoskeleton. Moreover, transfection with “full-length” CLU cDNA produced both sCLU and nCLU in nonmalignant PNT1A cells, whereas only sCLU was found in cancer cells. Thus, CLU gene expression might play a crucial role in prostate tumorigenesis by exerting differential biological effects on normal versus tumor cells through differential processing of CLU isoforms in the two cell systems. We also found that nCLU binds to α-actinin, a key protein for the regulation of actin cytoskeleton, and that nCLU and α-actinin colocalize in the cytoplasm. Thus, the antimotility activity of nCLU and its ability to cause dismantling of the actin cytoskeleton seem to be mediated by its binding to α-actinin. [Cancer Res 2007;67(21):10325–33]
BAG3 Regulates Motility and Adhesion of Epithelial Cancer Cells
Authors: Iwasaki Masahiro , Homma Sachiko , Hishiya Akinori , Dolezal Samuel J. , Reed John C. , Takayama Shinichi
Published: November 2007

BAG3 protein binds to and regulates Hsp70 chaperone activity. The BAG3 protein contains a WW domain and a proline-rich region with SH3-binding motifs, suggesting that it may interact with proteins relevant to signal transduction, recruiting Hsp70 to signaling complexes and altering cell responses. BAG3 overexpression has been observed in human cancers. We show here that homozygous BAG3-deficient mouse embryonic fibroblasts (MEF) exhibit delayed formation of filopodia and focal adhesion complexes when freshly plated. BAG3-deficient MEFs show reduced cell motility in culture. We observed that endogenous BAG3 protein is highly expressed in many human epithelial cancer cell lines, especially adenocarcinomas. Gene transfer–mediated overexpression of BAG3 increased motility of Cos7 cell and several human cancer cell lines, including breast cancer MCF7 and prostate cancer DU145 and ALVA31 cell lines. Conversely, reduction of BAG3 protein by RNA interference (RNAi) decreased cell motility in four of four epithelial tumor lines tested. We observed an influence of BAG3 on cell adhesion in culture. In Cos7 kidney epithelial cells, BAG3 protein partially colocalizes with actin at the leading edge of migrating cells, wherein active actin polymerization and nucleation occur. RNAi-mediated reductions in BAG3 expression were associated with decreased Rac1 activity, suggesting a role for BAG3 in regulating this small GTPase involved in actin-cytoskeleton dynamics. In mice, RNAi-mediated reductions in BAG3 in a human tumor xenograft suppressed invasion and metastasis in vivo. Thus, the high levels of BAG3 protein seen in some epithelial cancer cell lines may be relevant to mechanisms of tumor invasion and metastasis. [Cancer Res 2007;67(21):10252–8]
Resistance to an Irreversible Epidermal Growth Factor Receptor (EGFR) Inhibitor in EGFR-Mutant Lung Cancer Reveals Novel Treatment Strategies
Authors: Yu Zhiwei , Boggon Titus J. , Kobayashi Susumu , Jin Cheng , Ma Patrick C. , Dowlati Afshin , Kern Jeffrey A. , Tenen Daniel G. , Halmos Balázs
Published: November 2007

Patients with epidermal growth factor receptor (EGFR)–mutant non–small cell lung cancer derive significant clinical benefit from treatment with the EGFR tyrosine kinase inhibitors gefitinib and erlotinib. Secondary EGFR mutations such as EGFR T790M commonly lead to resistance to these agents, limiting their long-term efficacy. Irreversible EGFR inhibitors such as CL-387,785 can overcome resistance and are in clinical development, yet acquired resistance against these agents is anticipated. We carried out a cell-based, in vitro random mutagenesis screen to identify EGFR mutations that confer resistance to CL-387,785 using T790M-mutant H1975 lung adenocarcinoma cells. Mutations at several residues occurred repeatedly leading to functional resistance to CL-387,785. These variants showed uninhibited cell growth, reduced apoptosis, and persistent EGFR activation in the presence of CL-387,785 as compared with parental H1975 cells, thus confirming their role in resistance. A screen of alternative agents showed that both an alternative EGFR inhibitor and a cyclin-dependent kinase 4 inhibitor led to significant inhibition of cell growth of the resistant mutants, suggestive of potential alternative treatment strategies. These results identify novel mutations mediating resistance to irreversible EGFR inhibitors and reveal alternative strategies to overcome or prevent the development of resistance in EGFR-mutant non–small cell lung cancers. [Cancer Res 2007;67(21):10417–27]