bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of the symbiotic and competition phenotypes ofSinorhizobium melilotiPHB synthesis and degradation pathway mutants
Authors: Aneja P , Zachertowska A , Charles T C
Published: September 2005

The competitive abilities of Sinorhizobium meliloti mutant strains containing lesions in the PHB synthesis (phbC) and degradation (bdhA) pathways were compared. While the bdhA mutant showed no noticeable symbiotic defects on alfalfa host plants when inoculated alone, in mixed inoculation experiments it was found to be less competitive than the wild type for nodule occupancy. Long-term survival of the bdhA mutant on a carbon-limiting medium was not affected. However, when subjected to competition with the wild-type strain in periodic subculturing through alternating carbon-limiting and carbon-excess conditions, the bdhA mutant performed poorly. A more severe defect in competition for growth and nodule occupancy was observed with a mutant unable to synthesize PHB (phbC). These results indicate that the ability to efficiently deposit cellular PHB stores is a key factor influencing competitive survival under conditions of fluctuating nutrient carbon availability, whereas the ability to use these stores is less important.Key words: Sinorhizobium meliloti, PHB metabolism, competition.
Antigenic and genetic characterization of serogroup C meningococci isolated from invasive meningococcal disease cases in Canada from 1999 to 2003
Authors: Law Dennis K.S , Stoltz Jan , Henderson Averil M , Tsang Raymond S.W
Published: September 2005

Four hundred and forty-two serogroup C Neisseria meningitidis isolates from individual invasive meningococcal disease (IMD) patients in Canada during the period 1999 to 2003 were analyzed. The majority (84%) of the serogroup C meningococci were characterized by the serotype antigen 2a and belonged to the clonal complex of electrophoretic type ET-15. However, after more than a decade of endemic disease as well as a number of outbreaks and many vaccination campaigns, both genetic and antigenic variants of the serogroup C serotype 2a meningococci were noted. Such variants include strains characterized as C:2a:P1.5 and C:2a:P1.7,1 as well as a non-serotypeable phenotype due to a mutational hot spot on the serotype 2a PorB outer-membrane protein. Meningococci characterized by the antigen formula B:2a:P1.5,2 and B:2a:P1.7,1 have also been found, which suggests capsule switching. Besides the clonal group of ET-15/ET-37, small numbers of serogroup C isolates were found to belong to the clonal complexes of ST-8 (Cluster A4), ST-41/44 (Lineage 3), ST-35, and ST-269.Key words: serogroup C, meningococci, genetic, antigenic, variants.
A STUDY ON SELF-INSERTION OF PEPTIDES INTO SINGLE-WALLED CARBON NANOTUBES BASED ON MOLECULAR DYNAMICS SIMULATION
Authors: LIU G. R. , CHENG Y. , MI DONG , LI Z. R.
Published: September 2005

Molecular dynamics simulation is performed to investigate self-insertion behaviors of peptides into single-walled carbon nanotubes (SWCNTs) in water environment. Peptides of different hydrophobicities and varied lengths are tested to show that the propensities of peptides to self-insert into SWCNTs differ drastically. Our results indicate that there exists a potential well for the system of SWCNT and peptide that is able to self-insert into the nanotube. Further investigations of energy components demonstrate that electrostatic interactions, combined with van der Waals interactions, play dominant roles in the self-insertion of peptides into nanotubes. In addition, we also observe a significant correlation between the propensity of a peptide to insert into nanotube and its hydrophobicity. Such results provide valuable information on the potential applications of carbon nanotubes in the fields of drug delivery, drug design and protein control, etc.
QUANTUM SECURE CONDITIONAL DIRECT COMMUNICATION VIA EPR PAIRS
Authors: GAO TING , YAN FENGLI , WANG ZHIXI
Published: September 2005

Two schemes for quantum secure conditional direct communication are proposed, where a set of EPR pairs of maximally entangled particles in Bell states, initially made by the supervisor Charlie, but shared by the sender Alice and the receiver Bob, functions as quantum information channels for faithful transmission. After insuring the security of the quantum channel and obtaining the permission of Charlie (i.e., Charlie is trustworthy and cooperative, which means the "conditional" in the two schemes), Alice and Bob begin their private communication under the control of Charlie. In the first scheme, Alice transmits secret message to Bob in a deterministic manner with the help of Charlie by means of Alice's local unitary transformations, both Alice and Bob's local measurements, and both of Alice and Charlie's public classical communication. In the second scheme, the secure communication between Alice and Bob can be achieved via public classical communication of Charlie and Alice, and the local measurements of both Alice and Bob. The common feature of these protocols is that the communications between two communication parties Alice and Bob depend on the agreement of the third side Charlie. Moreover, transmitting one bit secret message, the sender Alice only needs to apply a local operation on her one qubit and send one bit classical information. We also show that the two schemes are completely secure if quantum channels are perfect.
CO–NO CATALYTIC SURFACE REACTION ON BODY-CENTERED CUBIC STRUCTURE: MONTE CARLO STUDY
Authors: KHALID M. , QAISRANI A. U. , KHAN M. K.
Published: September 2005

A Monte Carlo Simulation study of the monomer dimer ( CO–NO ) heterogeneous catalytic reaction on body-centered cubic structure (BCC) is presented. The effect of Eley–Rideal (ER), diffusion of nitrogen and carbon monoxide on the phase diagram is investigated. The steady reactive state is observed while using Langmuir–Hinsehelwood (LH) mechanism. Whenever the ER mechanism is included in our simulation, the production of CO 2 starts as soon as y CO departs from zero, which is consistent with the experimental results. The ER mechanism does not affect the production of N 2. The effect of diffusion of CO and N are found very little on the steady state reactive region where the concentration of CO is very high.
CHARACTERISTICS OF DEFECT STATES IN ONE-DIMENSIONAL PHOTONIC CRYSTALS CONTAINING MULTIPLE PHOTONIC QUANTUM-WELLS
Authors: ZHAO LI-MING , ZHOU YUN-SONG , GU BEN-YUAN , LIU CHUNG-PING
Published: September 2005

We calculate the omnidirectional dispersion spectrum for one-dimensional (1D) photonic crystals (PCs) inserting multiple photonic quantum-wells (PQWs) with the use of the plane-wave expansion method in combination with a supercell technique. We find that the localized defect modes significantly depend on the number of the PQWs and the configuration. This may provide a new way to engineer the dispersions of the composite PCs to meet the requirements of optical or microwave devices.
POSITIONAL ORDER OF THE PINNED ABRIKOSOV FLUX LINE LATTICE IN SAMPLES OF FINITE THICKNESS
Authors: ETTOUHAMI A. M.
Published: September 2005

We study translational correlations of the vortex center of mass positions of the Abrikosov flux line lattice in superconducting samples of finite thickness L (along the direction of flux lines). The Larkin correlation lengths for the center of mass mode of the flux lines in the presence of point and correlated disorder are computed, and we find that in the case of point disorder the average (i.e. center of mass) position of flux lines maintains positional order on length scales which scale like [Formula: see text] in 2+1 dimensions. On still longer length scales, however, we find using a replica Gaussian variational approach that center of mass correlations cross over to a power law growth of the form r⊥/L, which should be observable in superconducting thin films.
ELECTRICAL BEHAVIOR OF SOME LANTHANUM-BASED RARE EARTH CMR MATERIALS
Authors: KUMARI V. RAJA , VENKATAIAH G. , REDDY P. VENUGOPAL
Published: September 2005

A lanthanum-based mixed rare earth manganite system with general composition formula La 0.33 Ln 0.34 Sr 0.33 MnO 3, (where Ln is a rare earth ion) has been prepared by the solid state reaction method. After usual characterization of these materials, a systematic study of the electrical resistivity both as a function of temperature (80–300 K) and magnetic field up to 7 Tesla was undertaken mainly to understand the conduction mechanism. On analyzing the experimental results, it has been concluded that the metallic (ferromagnetic) part of the resistivity (ρ) (below TP) fits with the equation ρ(T)=ρ0+ρ2T2+ρ4.5T4.5, indicating the importance of grain/domain boundary effects (ρ0), the electron-electron scattering process (ρ2T2) and the two magnon scattering process (ρ4.5T4.5). On the other hand, the paramagnetic insulating regime may be explained by using adiabatic small polaron hopping and variable range hopping mechanisms, thereby indicating that polaron hopping might be responsible for the conduction mechanism.
COMPARISONS OF NEGATIVE REFRACTION IN LEFT-HANDED MATERIALS AND PHOTONIC CRYSTALS
Authors: FENG LIANG , LIU XIAO-PING , REN JIE , CHEN YAN-FENG , ZHU YONG-YUAN
Published: September 2005

Using the equifrequency surfaces (EFS) to describe negative refractions in left-handed materials (LHMs) and photonic crystals (PCs), negative phase and negative group refractive indexes in LHMs were compared with positive phase and negative group refractive indexes in PCs. The refractive indexes in PCs were dependent on frequencies and incident angles of electromagnetic wave, while indexes in LHMs were constant in the left-handed region. Furthermore, the phase compensating effect resulting from the negative phase refractive index was addressed to distinguish the perfect lens made of LHMs from the superlens realized in the all angle negative refraction (AANR) region of PCs.
TIME SERIES ANALYSIS OF GENE EXPRESSION AND LOCATION DATA
Authors: YEANG CHEN-HSIANG , JAAKKOLA TOMMI
Published: September 2005

We develop a method for integrating time series expression profiles and factor-gene binding data to quantify dynamic aspects of gene regulation. We estimate latencies for transcription activation by explaining time correlations between gene expression profiles through available factor-gene binding information. The resulting aligned expression profiles are subsequently clustered and again combined with binding information to determine groups or subgroups of co-regulated genes. The predictions derived from this approach are consistent with existing results.1,2Our analysis also provides several hypotheses not implicated in previous studies.
AN IMPROVED BICLUSTERING METHOD FOR ANALYZING GENE EXPRESSION PROFILES
Authors: YANG JIONG , WANG HAIXUN , WANG WEI , YU PHILIP S.
Published: September 2005

Microarrays are one of the latest breakthroughs in experimental molecular biology, which provide a powerful tool by which the expression patterns of thousands of genes can be monitored simultaneously and are already producing huge amount of valuable data. The concept of bicluster was introduced by Cheng and Church1 to capture the coherence of a subset of genes and a subset of conditions. A set of heuristic algorithms were also designed to either find one bicluster or a set of biclusters, which consist of iterations of masking null values and discovered biclusters, coarse and fine node deletion, node addition, and the inclusion of inverted data. These heuristics inevitably suffer from some serious drawback. The masking of null values and discovered biclusters with random numbers may result in the phenomenon of random interference which in turn impacts the discovery of high quality biclusters. To address this issue and to further accelerate the biclustering process, we generalize the model of bicluster to incorporate null values and propose a probabilistic algorithm (FLOC) that can discover a set of k possibly overlapping biclusters simultaneously. Furthermore, this algorithm can easily be extended to support additional features that suit different requirements at virtually little cost. Experimental study on the yeast gene expression data2 shows that the FLOC algorithm can offer substantial improvements over the previously proposed algorithm.
HIERARCHICAL CLUSTERING FOR COMPLEX DATA
Authors: KHAN LATIFUR , LUO FENG
Published: September 2005

In this paper we introduce a new tree-structured self-organizing neural network called a dynamical growing self-organizing tree (DGSOT). This DGSOT algorithm constructs a hierarchy from top to bottom by division. At each hierarchical level, the DGSOT optimizes the number of clusters, from which the proper hierarchical structure of the underlying data set can be found. We propose a K-level up distribution (KLD) mechanism. This KLD scheme increases the scope for data distribution in the hierarchy, which allows the data mis-clustered in the early stages to be re-evaluated at a later stage increasing the accuracy of the final clustering result. The DGSOT algorithm, combined with the KLD mechanism, overcomes the drawbacks of traditional hierarchical clustering algorithms (e.g., hierarchical agglomerative clustering). The DGSOT algorithm has been tested on two benchmark data sets including gene expression complex data set and we observe that our algorithm extracts patterns with different levels of abstraction. Furthermore, our approach is useful on recognizing features in complex gene expression data. As a dendrogram, these results can be easily displayed for visualization.
CRYOGENIC HEMT NOISE MODELING BY ARTIFICIAL NEURAL NETWORKS
Authors: CADDEMI A. , CATALFAMO F. , DONATO N.
Published: September 2005

In this paper we report the development of an artificial neural network to extract a 17-element small-signal circuit model of high electron mobility transistors (HEMTs) and one associated noise temperature value. By this procedure, we are able to reproduce the small-signal and noise performance of several device types from only one measured scattering parameter set, one frequency point and one noise figure value. The employed noise figure is measured in input matched conditions (i.e. 50 Ω source impedance), namely F 50. The output noise temperature is associated to the drain-source resistance in the HEMT equivalent circuit according to the noise temperature model by Pospieszalski. The noise parameters of the device under test are then calculated by CAD simulation of the circuit and compared with measurement results. The trained network outputs were used by means of a commercial CAD tool, to simulate and fit measurements performed down to cryogenic temperatures with very good agreement. We observed that the difference that occurs between the expected value of the noise temperature and the average value calculated by the neural network leads to negligible variations in the behavior of the simulated noise parameters.
ASYMPTOTIC BEHAVIOR OF SPATIALLY INHOMOGENEOUS BALANCE LAWS
Authors: EHRT JULIA , HÄRTERICH JÖRG
Published: September 2005

We study the longtime behavior of spatially inhomogeneous scalar balance laws with periodic initial data and a convex flux. Our main result states that for a large class of initial data the entropy solution will either converge uniformly to some steady state or to a discontinuous time-periodic solution. This extends results of Lyberopoulos, Sinestrari and Fan and Hale obtained in the spatially homogeneous case. The proof is based on the method of generalized characteristics together with ideas from dynamical systems theory.

A major difficulty consists of finding the periodic solutions which determine the asymptotic behavior. To this end we introduce a new tool, the Rankine–Hugoniot vector field, which describes the motion of a (hypothetical) shock with certain prescribed left and right states. We then show the existence of periodic solutions of the Rankine–Hugoniot vector field and prove that the actual shock curves converge to these periodic solutions.
COMPENSATED COMPACTNESS FOR 2D CONSERVATION LAWS
Authors: TADMOR EITAN , RASCLE MICHEL , BAGNERINI PATRIZIA
Published: September 2005

We introduce a new framework for studying two-dimensional conservation laws by compensated compactness arguments. Our main result deals with 2D conservation laws which are nonlinear in the sense that their velocity fields are a.e. not co-linear. We prove that if uε is a family of uniformly bounded approximate solutions of such equations with H-1-compact entropy production and with (a minimal amount of) uniform time regularity, then (a subsequence of) uε convergences strongly to a weak solution. We note that no translation invariance in space — and in particular, no spatial regularity of u(·, t) is required. Our new approach avoids the use of a large family of entropies; by a judicious choice of entropies, we show that only two entropy production bounds will suffice. We demonstrate these convergence results in the context of vanishing viscosity, kinetic BGK and finite volume approximations. Finally, the intimate connection between our 2D compensated compactness arguments and the notion of multi-dimensional nonlinearity based on kinetic formulation is clarified.
THE RIEMANN PROBLEM FOR THE MULTI-PRESSURE EULER SYSTEM
Authors: CHALONS C. , COQUEL F.
Published: September 2005

We prove the existence and uniqueness of the Riemann solutions to the Euler equations closed by N independent constitutive pressure laws. This model stands as a natural asymptotic system for the multi-pressure Navier–Stokes equations in the regime of infinite Reynolds number. Due to the inherent lack of conservation form in the viscous regularization, the limit system exhibits measure-valued source terms concentrated on shock discontinuities. These non-positive bounded measures, called kinetic relations, are known to provide a suitable tool to encode the small-scale sensitivity in the singular limit. Considering N independent polytropic pressure laws, we show that these kinetic relations can be derived by solving a simple algebraic problem which governs the endpoints of the underlying viscous shock profiles, for any given but prescribed ratio of viscosity coefficient in the viscous perturbation. The analysis based on traveling wave solutions allows us to introduce the asymptotic Euler system in the setting of piecewise Lipschitz continuous functions and to study the Riemann problem.
VEGF-dependent plasticity of fenestrated capillaries in the normal adult microvasculature
Authors: Kamba Tomomi , Tam Betty Y. Y. , Hashizume Hiroya , Haskell Amy , Sennino Barbara , Mancuso Michael R. , Norberg Scott M. , O'Brien Shaun M. , Davis Rachel B. , Gowen Lori C. , Anderson Keith D. , Thurston Gavin , Joho Shuji , Springer Matthew L. , Kuo Calvin J. , McDonald Donald M.
Published: September 2005

Unlike during development, blood vessels in the adult are generally thought not to require VEGF for normal function. However, VEGF is a survival factor for many tumor vessels, and there are clues that some normal blood vessels may also depend on VEGF. In this study, we sought to identify which, if any, vascular beds in adult mice depend on VEGF for survival. Mice were treated with a small-molecule VEGF receptor (VEGFR) tyrosine kinase inhibitor or soluble VEGFRs for 1–3 wk. Blood vessels were assessed using immunohistochemistry or scanning or transmission electron microscopy. In a study of 17 normal organs after VEGF inhibition, we found significant capillary regression in pancreatic islets, thyroid, adrenal cortex, pituitary, choroid plexus, small-intestinal villi, and epididymal adipose tissue. The amount of regression was dose dependent and varied from organ to organ, with a maximum of 68% in thyroid, but was less in normal organs than in tumors in RIP-Tag2-transgenic mice or in Lewis lung carcinoma. VEGF-dependent capillaries were fenestrated, expressed high levels of both VEGFR-2 and VEGFR-3, and had normal pericyte coverage. Surviving capillaries in affected organs had fewer fenestrations and less VEGFR expression. All mice appeared healthy, but distinct physiological changes, including more efficient blood glucose handling, accompanied some regimens of VEGF inhibition. Strikingly, most capillaries in the thyroid grew back within 2 wk after cessation of treatment for 1 wk. Our findings of VEGF dependency of normal fenestrated capillaries and rapid regrowth after regression demonstrate the plasticity of the adult microvasculature.
β-Myosin heavy chain myocytes are more resistant to changes in power output induced by ischemic conditions
Authors: Hinken Aaron C. , McDonald Kerry S.
Published: September 2005

During ischemia intracellular concentrations of Piand H+increase. Also, changes in myosin heavy chain (MHC) isoform toward β-MHC have been reported after ischemia and infarction associated with coronary artery disease. The purpose of this study was to investigate the effects of myoplasmic changes of Piand H+on the loaded shortening velocity and power output of cardiac myocytes expressing either α- or β-MHC. Skinned cardiac myocyte preparations were obtained from adult male Sprague-Dawley rats (control or treated with 5- n-propyl-2-thiouracil to induce β-MHC) and mounted between a force transducer and servomotor system. Myocyte preparations were subjected to a series of isotonic force clamps to determine shortening velocity and power output during Ca2+activations in each of the following solutions: 1) pCa 4.5 and pH 7.0; 2) pCa 4.5, pH 7.0, and 5 mM Pi; 3) pCa 4.5 and pH 6.6; and 4) pCa 4.5, pH 6.6, and 5 mM Pi. Added Piand lowered pH each caused isometric force to decline to the same extent in α-MHC and β-MHC myocytes; however, β-MHC myocytes were more resistant to changes in absolute power output. For example, peak absolute power output fell 53% in α-MHC myocytes, whereas power fell only 38% in β-MHC myocytes in response to elevated Piand lowered pH (i.e., solution 4). The reduced effect on power output was the result of a greater increase in loaded shortening velocity induced by Piin β-MHC myocytes and an increase in loaded shortening velocity at pH 6.6 that occurred only in β-MHC myocytes. We conclude that the functional response to elevated Piand lowered pH during ischemia is MHC isoform-dependent with β-MHC myocytes being more resistant to declines in power output.
Involvement of ROCK-mediated endothelial tension development in neutrophil-stimulated microvascular leakage
Authors: Breslin Jerome W. , Sun Hengrui , Xu Wenjuan , Rodarte Charles , Moy Alan B. , Wu Mack H. , Yuan Sarah Y.
Published: September 2005

Neutrophil-induced coronary microvascular barrier dysfunction is an important pathophysiological event in heart disease. Currently, the precise cellular and molecular mechanisms of neutrophil-induced microvascular leakage are not clear. The aim of this study was to test the hypothesis that rho kinase (ROCK) increases coronary venular permeability in association with elevated endothelial tension. We assessed permeability to albumin ( Pa) in isolated porcine coronary venules and in coronary venular endothelial cell (CVEC) monolayers. Endothelial barrier function was also evaluated by measuring transendothelial electrical resistance (TER) of CVEC monolayers. In parallel, we measured isometric tension of CVECs grown on collagen gels. Transference of constitutively active (ca)-ROCK protein into isolated coronary venules or CVEC monolayers caused a significant increase in Paand decreased TER in CVECs. The ROCK inhibitor Y-27632 blocked the ca-ROCK-induced changes. C5a-activated neutrophils (106/ml) also significantly elevated venular Pa, which was dose-dependently inhibited by Y-27632 and a structurally distinct ROCK inhibitor, H-1152. In CVEC monolayers, activated neutrophils increased permeability with a concomitant elevation in isometric tension, both of which were inhibited by Y-27632 or H-1152. Treatment with ca-ROCK also significantly increased CVEC monolayer permeability and isometric tension, coupled with actin polymerization and elevated phosphorylation of myosin regulatory light chain on Thr18/Ser19. The data suggest that during neutrophil activation, ROCK promotes microvascular leakage in association with actin-myosin-mediated tension development in endothelial cells.
Tailoring cardiac resynchronization therapy using interventricular asynchrony. Validation of a simple model
Authors: Verbeek Xander A. A. M. , Auricchio Angelo , Yu Yinghong , Ding Jiang , Pochet Thierry , Vernooy Kevin , Kramer Andrew , Spinelli Julio , Prinzen Frits W.
Published: September 2005

This study explores the use of interventricular asynchrony (interVA) for optimizing cardiac resynchronization therapy (CRT), an idea emerging from a simple pathway model of conduction in the ventricles. Measurements were performed in six dogs with chronic left bundle branch block (LBBB) and in 29 patients of the Pacing Therapies for Congestive Heart Failure (PATH-CHF)-I study. In the dogs, intraventricular asynchrony (intraVA) was determined using left ventricular (LV) endocardial activation maps. In dogs and patients, the maximum rate of rise of LV pressure (LV dP/d tmax) and the pulse pressure (PP) and interVA [time delay between upslope of LV and right ventricular (RV) pressure curves] were measured during LV, RV, and biventricular (BiV) pacing with various atrioventricular (AV) delays. Measurements in the canine hearts supported the pathway model in that optimal resynchronization occurred at ∼50% reduction of intraVA and at an interVA value halfway that during LBBB and LV pacing. In patients with significant hemodynamic response during pacing ( n = 22), intrinsic interVA and interVA at peak improvement (interVAp) varied widely between patients (from −83 to −15 ms and from −42 to +31 ms, respectively). However, the model predicted individual interVAp accurately (SD of ±6 ms and ±12 ms for LV dP/d tmax and PP, respectively). At equal interVA, LV and BiV pacing produced equal hemodynamic response, but in 11 of 22 responders, BiV pacing reduced interVA insufficiently to reach the maximum hemodynamic response. LV pacing at short AV delay proved to result in better hemodynamics than predicted by the model, indicating that additional factors determine hemodynamics during LV preexcitation. Guided by a simple pathway model, interVA measurements accurately predict optimal hemodynamic performance in individual CRT patients.
Gene therapy with iNOS provides long-term protection against myocardial infarction without adverse functional consequences
Authors: Li Qianhong , Guo Yiru , Tan Wei , Stein Adam B. , Dawn Buddhadeb , Wu Wen-Jian , Zhu Xiaoping , Lu Xiaoqin , Xu Xiaoming , Siddiqui Tariq , Tiwari Sumit , Bolli Roberto
Published: September 2005

Previous studies have shown that gene therapy with inducible nitric oxide synthase (iNOS) protects against myocardial infarction at 3 days after gene transfer. However, the long-term effects of iNOS gene therapy on myocardial ischemic injury and cardiac function are unknown. To address this issue, we used a recombinant adenovirus 5 (Ad5) vector (Av3) with deletions of the E1, E2a, and E3 regions, which enables long-lasting recombinant gene expression for at least 2 mo due to lack of inflammation. Mice received intramyocardial injections in the left ventricular (LV) anterior wall of Av3/LacZ (LacZ group) or Av3/iNOS (iNOS group); 1 or 2 mo later, they were subjected to myocardial infarction (30-min coronary occlusion followed by 4 h of reperfusion). Cardiac iNOS gene expression was confirmed by immunoblotting and activity assays at 1 and 2 mo after gene transfer. In the iNOS group, infarct size (percentage of risk region) was significantly reduced ( P < 0.05) both at 1 mo (24.2 ± 3.4%, n = 6, vs. 48.0 ± 3.6%, n = 8, in the LacZ group) and at 2 mo (23.4 ± 3.1%, n = 8, vs. 36.6 ± 2.4%, n = 7). The infarct-sparing effects of iNOS gene therapy were as powerful as those observed 24 h after ischemic preconditioning (23.1 ± 3.4%, n = 10). iNOS gene transfer had no effect on LV function or dimensions up to 8 wk later (echocardiography). These data demonstrate that iNOS gene therapy mediated by the Av3 vector affords long-term (2 mo) cardioprotection without inflammation or adverse functional consequences, a finding that provides a rationale for further preclinical testing of this therapy.
Molecular Pathways Leading to Cancer Cachexia
Authors: Tisdale Michael J.
Published: September 2005

Loss of body weight in cancer patients strongly influences morbidity and mortality. Recent studies have suggested that both tumor and host factors play a major role in tissue catabolism in cachexia, leading to upregulation of degradative pathways in both skeletal muscle and adipose tissue.
Cardiovascular phenotyping of fetal mice by noninvasive high-frequency ultrasound facilitates recovery of ENU-induced mutations causing congenital cardiac and extracardiac defects
Authors: Shen Yuan , Leatherbury L. , Rosenthal J. , Yu Qing , Pappas M. A. , Wessels A. , Lucas J. , Siegfried B. , Chatterjee B. , Svenson Karen , Lo C. W.
Published: September 2005

As part of a large-scale noninvasive fetal ultrasound screen to recover ethylnitrosourea (ENU)-induced mutations causing congenital heart defects in mice, we established a high-throughput ultrasound scanning strategy for interrogating fetal mice in utero utilizing three orthogonal imaging planes defined by the fetus’ vertebral column and body axes, structures readily seen by ultrasound. This contrasts with the difficulty of acquiring clinical ultrasound imaging planes which are defined by the fetal heart. By use of the three orthogonal imaging planes for two-dimensional (2D) imaging together with color flow, spectral Doppler, and M-mode imaging, all of the major elements of the heart can be evaluated. In this manner, 10,091 ENU-mutagenized mouse fetuses were ultrasound scanned between embryonic days 12.5 and 19.5, with 324 fetuses found to die prenatally and 425 exhibiting cardiovascular defects. Further analysis by necropsy and histology showed heart defects that included conotruncal anomalies, obstructive lesions, and shunt lesions as well as other complex heart diseases. Ultrasound imaging also identified craniofacial/head defects and body wall closure defects, which necropsy revealed as encephalocele, holoprosencephaly, omphalocele, or gastroschisis. Genome scanning mapped one ENU-induced mutation associated with persistence truncus arteriosus and holoprosencephaly to mouse chromosome 2, while another mutation associated with cardiac defects and omphalocele was mapped to mouse chromosome 17. These studies show the efficacy of this novel ultrasound scanning strategy for noninvasive ultrasound phenotyping to facilitate the recovery of ENU-induced mutations causing congenital heart defects and other extracardiac anomalies.
On Mx/(G1G2)/1/G(BS)/Vs vacation queue with two types of
general heterogeneous service
Authors: Madan Kailash C. , Al-Rawi Z. R. , Al-Nasser Amjad D.
Published: September 2005

We analyze a batch arrival queue with a single server
providing two kinds of general heterogeneous service. Just before
his service starts, a customer may choose one of the services and
as soon as a service (of any kind) gets completed, the server may
take a vacation or may continue staying in the system. The
vacation times are assumed to be general and the server vacations
are based on Bernoulli schedules under a single vacation policy.
We obtain explicit queue size distribution at a random epoch as
well as at a departure epoch and also the mean busy period of the
server under the steady state. In addition, some important
performance measures such as the expected queue size and the
expected waiting time of a customer are obtained. Further, some
interesting particular cases are also discussed.
Involvement of Rel/Nuclear Factor-κB Transcription Factors in Keratinocyte Senescence
Authors: Bernard David , Gosselin Karo , Monte Didier , Vercamer Chantal , Bouali Fatima , Pourtier Albin , Vandenbunder Bernard , Abbadie Corinne
Published: September 2005

After a finite doubling number, normal cells become senescent, i.e., nonproliferating and apoptosis resistant. Because Rel/nuclear factor (NF)-κB transcription factors regulate both proliferation and apoptosis, we have investigated their involvement in senescence. cRel overexpression in young normal keratinocytes results in premature senescence, as defined by proliferation blockage, apoptosis resistance, enlargement, and appearance of senescence-associated β-galactosidase (SA-β-Gal) activity. Normal senescent keratinocytes display a greater endogenous Rel/NF-κB DNA binding activity than young cells; inhibiting this activity in presenescent cells decreases the number of cells expressing the SA-β-Gal marker. Normal senescent keratinocytes and cRel-induced premature senescent keratinocytes overexpressed manganese superoxide dismutase (MnSOD), a redox enzyme encoded by a Rel/NF-κB target gene. MnSOD transforms the toxic O2 into H2O2, whereas catalase and glutathione peroxidase convert H2O2 into H2O. Neither catalase nor glutathione peroxidase is up-regulated during cRel-induced premature senescence or during normal senescence, suggesting that H2O2 accumulates. Quenching H2O2 by catalase delays the occurrence of both normal and premature cRel-induced senescence. Conversely, adding a nontoxic dose of H2O2 to the culture medium of young normal keratinocytes induces a premature senescence-like state. All these results indicate that Rel/NF-κB factors could take part in the occurrence of senescence by generating an oxidative stress via the induction of MnSOD.
Identification of HRPAP20
Authors: Karp Cristina M. , Pan Huiqui , Zhang Mingyu , Buckley Donna J. , Schuler Linda A. , Buckley Arthur R.
Published: September 2005

The prolactin (PRL)-dependent rat Nb2 T lymphoma is a valuable model for investigation of molecular mechanisms that underlie tumor progression in hormone-dependent cancers. mRNA differential display was used to screen for novel gene products expressed in hormone-stimulated or differentiating agent-treated Nb2 sublines. From numerous transcripts identified, DNA sequencing and GenBank analysis revealed a novel 289-bp fragment. Using 5′-rapid amplification of complementary ends-PCR, this fragment was used to clone a unique 2117-bp cDNA, designated HRPAP20 (hormone-regulated proliferation-associated protein), in rat lymphoma cells. Computer-assisted sequence analysis revealed a single open reading frame that encoded a putative 20.2-kDa protein. The effect of hormone stimulation to alter expression of HRPAP20 was evaluated by Northern blot analysis of total RNA obtained from PRL-stimulated, lactogen-dependent Nb2-11 cells. Quiescent cells, synchronized in the G0-G1 phase of cell cycle, exhibited reduced HRPAP20 expression compared with exponentially proliferating cultures. The addition of mitogenic concentrations of PRL to stationary cells increased HRPAP20 mRNA accumulation within 4–6 h, corresponding to G1 cell cycle progression. Immunoblot analysis showed that PRL also increased HRPAP20 protein levels within 4 h. In addition, PRL stimulated serine phosphorylation of the HRPAP20 protein with a similar kinetic pattern. Stable transfection of the HRPAP20 cDNA into Nb2-11 cells significantly (P < 0.01) increased proliferation in the absence of hormonal stimulation and inhibited apoptosis induced by lactogen deprivation (P < 0.001). In the hormone-independent and highly malignant Nb2-SFJCD1 subline, the constitutive expression of HRPAP20 was markedly reduced by exposure of the cells to dietary differentiating agents (butyrate, retinoic acid, and vitamin D3). After removal of these substances, PRL stimulated its expression in a manner similar to that observed in PRL-dependent Nb2-11 cells. HRPAP20 expression was also evaluated in MCF-7 cells. Its expression was detectable in quiescent cultures; addition of PRL significantly (P < 0.05) increased HRPAP20 during G1 cell cycle progression. Exposure of the cells to butyrate or retinoic acid reduced HRPAP20 expression, similar to the effects of these substances in the malignant rat lymphoma. Stable transfection of HRPAP20 into MCF-7 cells significantly (P < 0.006) increased proliferation in the absence of hormone stimulation and augmented survival in the absence of serum (P < 0.05). We conclude that HRPAP20 is a phosphoprotein that is required for proliferation and survival of hormone-dependent tumor cells.
Nur77 Activated by Hypoxia-Inducible Factor-1α Overproduces Proopiomelanocortin in von Hippel-Lindau-Mutated Renal Cell Carcinoma
Authors: Choi Ji-Woong , Park Sang Chul , Kang Gyeong Hoon , Liu Jun O. , Youn Hong-Duk
Published: September 2005

Mutation in the von Hippel-Lindau (VHL) protein associated with renal cell carcinoma causes hypoxia-inducible factor (HIF) to stabilize and consequently to induce various HIF-targeting proteins. In this study, we found that proopiomelanocortin (POMC), an adrenocorticotropic hormone precursor, is up-regulated constitutively in VHL-mutated renal cell carcinoma. A critical transcription factor responsible for POMC overproduction was identified as Nur77, a member of the orphan steroid receptor superfamily. Little is known about how VHL mutation leads to activation of Nur77. We report that Nur77 is directly regulated by HIF. We show that HIF-1α, but not HIF-2α, binds to a putative HIF responsive element in the Nur77 promoter, activating the expression of Nur77. Mutation or deletion of the HIF binding site in the Nur77 promoter abrogates activation of a luciferase reporter gene under the control of Nur77 promoter by HIF-1α. The treatment of Nur77 antisense oligonucleotide reduces POMC transcription under hypoxic conditions. We confirmed that Nur77 and POMC are up-regulated in VHL-mutated renal cell carcinoma. In this study, we provide the first molecular evidence that Nur77 activated by HIF under hypoxic conditions regulates production of the peptide hormone precursor POMC.
Hypermethylation and Silencing of the Putative Tumor SuppressorTazarotene-Induced Gene 1in Human Cancers
Authors: Youssef Emile M. , Chen Xu-qi , Higuchi Eisaku , Kondo Yutaka , Garcia-Manero Guillermo , Lotan Reuben , Issa Jean-Pierre J.
Published: September 2005

A variety of tumor suppressor genes are down-regulated by hypermethylation during carcinogenesis. Using methylated CpG amplification-representation difference analysis, we identified a DNA fragment corresponding to the Tazarotene-induced gene 1 (TIG1) promoter-associated CpG island as one of the genes hypermethylated in the leukemia cell line K562. Because TIG1 has been proposed to act as a tumor suppressor, we tested the hypothesis that cytosine methylation of the TIG1 promoter suppresses its expression and causes a loss of responsiveness to retinoic acid in some neoplastic cells. We examined TIG1 methylation and expression status in 53 human cancer cell lines and 74 primary tumors, including leukemia and head and neck, breast, colon, skin, brain, lung, and prostate cancer. Loss of TIG1 expression was strongly associated with TIG1 promoter hypermethylation (P < 0.001). There was no correlation between TIG1 promoter methylation and that of retinoid acid receptor β2 (RARβ2), another retinoic-induced putative tumor suppressor gene (P = 0.78). Treatment with the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine for 5 days restored TIG1 expression in all eight silenced cell lines tested. TIG1 expression was also inducible by treatment with 1 μm all-trans-retinoic acid for 3 days except in densely methylated cell lines. Treatment of the K562 leukemia cells with demethylating agent combined with all-trans-retinoic acid induced apoptosis. These findings indicate that silencing of TIG1 promoter by hypermethylation is common in human cancers and may contribute to the loss of retinoic acid responsiveness in some neoplastic cells.
Decreased Expression of Early Growth Response-1 and Its Role in Uterine Leiomyoma Growth
Authors: Shozu Makio , Murakami Kouichi , Segawa Tomoya , Kasai Tadayuki , Ishikawa Hiroshi , Shinohara Kazunori , Okada Masahiko , Inoue Masaki
Published: September 2005

Expression of early growth response (Egr)-1, a transcriptional factor implicated in growth regulation, is suppressed in several malignant tumors. The present study investigated the expression of Egr-1 and related genes in uterine leiomyoma and normal myometrium to determine possible contributions of Egr-1 to neoplastic growth in leiomyoma cells. Levels of Egr-1 transcripts were decreased in all leiomyomas (n = 20) to approximately 10% of levels in corresponding myometrium, where basal expression was high. Preoperative leuprorelin acetate therapy increased levels of Egr-1 mRNA in normal myometrium only. Northern blot analysis using additional sample sets (n = 5) revealed the full-length Egr-1 transcript. Western blot analysis (n = 5) confirmed decreased expression of Egr-1 protein. Southern blot analysis of the Egr-1 gene and microsatellite analysis of the chromosomal location at 5q31 (D5S414, D5S500, and D5S476) revealed neither DNA recombination nor loss of heterozygosity in leiomyomas. Moreover, Egr-1 retained identical responsiveness to phorbol 12-myristate 13-acetate in primary cultures derived from both leiomyoma and normal tissues. Electrophoretic mobility shift analysis revealed that phorbol 12-myristate 13-acetate-induced Egr-1 in leiomyoma cells retained DNA binding ability. Egr-1 thus appears functionally intact in leiomyoma cells. Finally, consistent with the role of Egr-1 in growth inhibition, transfection of Egr-1 expression vector into a myometrial cell line (KW) that expresses low levels of Egr-1 and displays rapid growth inhibited thymidine uptake in these cells. Egr-1 may display tumor-suppressing activity and offers a potential target for leiomyoma management.
Radiation Improves the Distribution and Uptake of Liposomal Doxorubicin (Caelyx) in Human Osteosarcoma Xenografts
Authors: Davies Catharina de L. , Lundstrøm Lisa M. , Frengen Jomar , Eikenes Live , Bruland Øyvind S. , Kaalhus Olav , Hjelstuen Mari H. B. , Brekken Christian
Published: September 2005

Liposomal drug delivery appears to improve the antitumor effect and reduce toxicity compared with the free drug. The therapeutic index may be improved further by combining cytotoxic drugs and radiotherapy. Successful therapy requires that the cytotoxic agents reach the tumor cells. Therefore, we studied tumor growth and the microdistribution of liposomal doxorubicin (Caelyx) with and without additional ionizing radiation in human osteosarcoma xenografts in athymic mice. Caelyx was injected i.v. 1 day before single or fractionated radiotherapy. Both chemoirradiation regimens induced significant tumor growth delays and worked synergistically. Confocal laser scanning microscopy showed that intact liposomes were located in close proximity to endothelial cells, and the distribution of released doxorubicin was heterogeneous. Before radiotherapy, hardly any doxorubicin was localized in the central parts of the tumor. Radiotherapy increased the tumor uptake of doxorubicin by a factor of two to four, with drug being redistributed farther from the vessels in the tumor periphery and located around vessels in the central parts of the tumor. Colocalization of doxorubicin and hypoxic cells showed no distribution of drug into hypoxic areas. Dynamic contrast-enhanced magnetic resonance imaging (MRI) 1 day before the injection of Caelyx and 2 days after treatment start showed that the combined treatment reduced the vascular volume and the vascular transfer rate of the MRI tracer. The results show that chemoirradiation with Caelyx induces synergistic treatment effects. Improved intratumoral drug uptake and distribution are responsible to some extent for the enhanced antitumor effect.
Molecular Detection of Noninvasive and Invasive Bladder Tumor Tissues and Exfoliated Cells by Aberrant Promoter Methylation of Laminin-5 Encoding Genes
Authors: Sathyanarayana Ubaradka G. , Maruyama Riichiroh , Padar Asha , Suzuki Makoto , Bondaruk Jolanta , Sagalowsky Arthur , Minna John D. , Frenkel Eugene P. , Grossman H. Barton , Czerniak Bogdan , Gazdar Adi F.
Published: September 2005

Laminin-5 (LN5) anchors epithelial cells to the underlying basement membrane, and it is encoded by three distinct genes: LAMA3, LAMB3, and LAMC2. To metastasize and grow, cancer cells must invade and destroy the basement membrane. Our previous work has shown that epigenetic inactivation is a major mechanism of silencing LN5 genes in lung cancers. We extended our methylation studies to resected bladder tumors (n = 128) and exfoliated cell samples (bladder washes and voided urine; n = 71) and correlated the data with clinicopathologic findings. Nonmalignant urothelium had uniform expression of LN5 genes and lacked methylation. The methylation frequencies for LN5 genes in tumors were 21–45%, and there was excellent concordance between methylation in tumors and corresponding exfoliated cells. Methylation of LAMA3 and LAMB3 and the methylation index were correlated significantly with several parameters of poor prognosis (tumor grade, growth pattern, muscle invasion, tumor stage, and ploidy pattern), whereas methylation of LAMC2 and methylation index were associated with shortened patient survival. Of particular interest, methylation frequencies of LAMA3 helped to distinguish invasive (72%) from noninvasive (12%) tumors. These results suggest that methylation of LN5 genes has potential clinical applications in bladder cancers.
Senescence-initiated Reversal of Drug Resistance
Authors: Zheng Xin , Chou Pauline M. , Mirkin Bernard L. , Rebbaa Abdelhadi
Published: September 2005

The present study was undertaken to verify whether induction of senescence could be sufficient to reverse drug resistance and, if so, to determine the underlying mechanism(s). Our findings indicated that cotreatment of drug-resistant neuroblastoma cells with doxorubicin, at sublethal concentrations, in combination with the pan-caspase inhibitor, Q-VD-OPH, elicited a strong reduction of cell viability that occurred in a caspase-independent manner. This was accompanied by the appearance of a senescence phenotype, as evidenced by increased p21/WAF1 expression and senescence-associated β-galactosidase activity. Experiments using specific inhibitors of major cellular proteases other than caspases have shown that inhibition of cathepsin L, but not proteasome or cathepsin B, was responsible for the senescence-initiated reversal of drug resistance. This phenomenon appeared to be general because it was valid for other drugs and drug-resistant cell lines. A nonchemical approach, through cell transfection with cathepsin L small interfering RNA, also strongly reversed drug resistance. Further investigation of the underlying mechanism revealed that cathepsin L inhibition resulted in the alteration of intracellular drug distribution. In addition, in vitro experiments have demonstrated that p21/WAF1 is a substrate for cathepsin L, suggesting that inhibition of this enzyme may result in p21/WAF1 stabilization and its increased accumulation. All together, these findings suggest that cathepsin L inhibition in drug-resistant cells facilitates induction of senescence and reversal of drug resistance. This may represent the basis for a novel function of cathepsin L as a cell survival molecule responsible for initiation of resistance to chemotherapy.