bluuebunny/crossref_metadata_2025 huggingface dataset:
DISPERSIVE SWITCHING IN BISTABLE MODELS
Authors: BATARFI H. A.
Published: October 2008

Novel switching processes in optical bistable models of homogeneously or inhomogeneously broadened 2-level atoms placed in ring cavity with atoms in contact with normal or squeezed vacuum reservoirs are investigated. This is done through computational examination of the relevant input-output relationship by simultaneously varying the atomic and cavity detuning parameters for fixed values of the input laser field.
ELECTRICAL RESISTANCE OF CRACK-FREE GaN/AlN HETEROSTRUCTURE GROWN ON Si(111)
Authors: CHUAH L. S. , HASSAN Z. , HASSAN H. ABU
Published: October 2008

This paper presents the electrical resistance of crack-free n-GaN/AlN/n-Si(111) diodes in relation to the temperature of the Al effusion cell for the growth of AlN intermediate layer (348 nm thickness) using radio-frequency molecular beam epitaxy (RF-MBE). The thickness of the unintentionally doped n-type GaN thin film is in the range of 63–100 nm. Aluminium (300 nm thickness) was sputtered onto the n-type GaN through a metal mask, followed by the 100 nm thick titanium (Ti) capping layer to obtain an ohmic contact. The back contact was created on the back surface of the Si substrate by evaporating indium (In) followed by thermal annealing at 400°C. We will consider the above as a device on an n-type Si(111) substrate, where the electron current flows from the Si substrate to the n-type GaN top layer. It was found that the current–voltage (I–V) characteristics depend on the various deposition temperature of the Al effusion cell for the growth of the AlN intermediate layer. In the forward bias region, where the electrons flow from Si(111) to the GaN top layer, we observe a threshold voltage of approximately 0.5 V for turning on a high current. The order of differential resistance magnitude was nearly a constant in the voltage range of 1.0 to 3.0 V.
SYMBOLIC COMPUTATION STUDY OF BRIGHT SOLITONIC PULSES IN THE NORMAL DISPERSION REGION
Authors: LIU WEN-JUN , TIAN BO , XU TAO
Published: October 2008

New types of solitonic pulses are obtained theoretically based on the solutions for the nonlinear Schrödinger (NLS) equation. Unlike the earlier results, in the normal dispersion region, the novel bright solitonic pulses are observed. Depending on the parameters' values, the properties of both bright and dark solitonic pulses are described in the same expression. Furthermore, those solitonic pulses are found to be evolved into bright and dark ones under certain conditions. This might be a potential application in optical communication systems which can produce bright and dark solitonic pulses simultaneously.
FAULT DIAGNOSIS OF AN INDUSTRIAL MACHINE THROUGH SENSOR FUSION
Authors: LANG HAOXIANG , DE SILVA CLARENCE W.
Published: October 2008

In this paper, a four layer neuro-fuzzy architecture of multi-sensor fusion is developed for a fault diagnosis system which is applied to an industrial fish cutting machine. An important characteristic of the fault diagnosis approach developed in this paper is to make an accurate decision of the machine condition by fusing information acquired from three types of sensors: Accelerometer, microphone and charge-coupled device (CCD) camera. Feature vectors for vibration and sound signals from their fast Fourier transform (FFT) frequency spectra are defined and extracted from the acquired information. A feature-based vision method is applied for object tracking in the machine, to detect and track the fish moving on the conveyor. A four-layer neural network including a fuzzy hidden layer is developed in the paper to analyze and diagnose existing faults. Feature vectors of vibration, sound and vision are provided as inputs to the neuro-fuzzy network for fault detection and diagnosis. By proper training of the neural network using data samples for typical faults, six crucial faults in the fish cutting machine are detected with high reliability and robustness. On this basis, not only the condition of the machine can be determined for possible retuning and maintenance, but also alarms to warn about impending faults may be generated during the machine operation.
A PROPOSAL FOR A MULTI-DRIVE HETEROGENEOUS MODULAR PIPE-INSPECTION MICRO-ROBOT
Authors: BRUNETE ALBERTO , TORRES JOSE EMILIO , HERNANDO MIGUEL , GAMBAO ERNESTO
Published: October 2008

This paper presents the architecture used to develop a micro-robot for narrow pipes inspection. Both the electromechanical design and the control scheme will be described. In pipe environments it is very useful to have a method to retrieve information of the state of the inner part of the pipes in order to detect damages, leaks and holes. Due to the different types of existing pipes, a modular approach with different types of modules has been chosen in order to be able to adapt to the shape of the pipe and to chose the most appropriate gait. The micro-robot has been designed for narrow pipes, a field in which there are not many prototypes. The micro-robot incorporates a camera module for visual inspection and several drive modules for locomotion and turn (helicoidal, inchworm, two degrees of freedom rotation). The control scheme is based on semi-distributed behavior control and is also described. A simulation environment is also presented for prototype testing.
INTEROPERABILITY VERIFICATION FOR WEB SERVICE BASED ROBOT COMMUNICATION PLATFORMS AND CONTRIBUTION TO THE INTERNATIONAL STANDARDS
Authors: NARITA MASAHIKO , SHIMAMURA MAKIKO , IWASA KAZUNORI , YAMAGUCHI TORU
Published: October 2008

The common robot communication platform using Web Service is well accepted and becoming popular gradually. One of the key components for robot communication platform is the reliable messaging which provides reliable high performance message transfer. Both conforming to standard specifications and interoperability among multiple implementations are critical requirements for the platform, because different robots and different services should be able to connect and communicate each other on the platform. However, there is no conformance/interoperability testing tool for the reliable message component of Web Services. This paper describes requirements for the conformance and interoperability testing for Web Service technologies, and how we developed the verification suit that satisfies the requirements by automated error case verification model. This paper also reports the interoperability verification results for emerging reliable message components of Web Services and our contribution to the international standardization group based on this verification results.
A REAL TIME TRAFFIC LIGHT RECOGNITION SYSTEM
Authors: YANG XIAOLI , ZHAO ZHENPENG , KIM YOUN K.
Published: October 2008

Driving is a challenging task, especially for those with color vision deficiencies. Intelligent Transport Systems (ITS) can provide useful information and make driving safe and convenient. A real time traffic light recognition system is presented in this paper for improving public safety and facilitating color deficient drivers. It may also be included as a part of ITS. The presented system consists of a digital video camera to record traffic lights and a portable PC to process images in real time. It uses various techniques of color detection, feature matching with normalized cross-correlation (NCC), and mathematical shape analysis for the traffic light recognition. For color detection, we obtained an initial solution by using RGB component adjustment, thresholding algorithm, and median filter. In dealing with illumination changes with weather and time, a simple adaptation method was developed. Feature matching with NCC was used after color detection to further detect and recognize the traffic lights. To improve the system's tolerance and robustness, a mathematical shape analysis was undertaken to obtain the final results. Numerous experiments were conducted to demonstrate the effectiveness and practicability of the system with images under different weather conditions. The average recognition ratio is higher than 95% from the testing results. The average processing time is 30 ms per frame, making the system suitable in real time conditions. Audio alert is added to the current system as an integral part of a portable system to be developed.
LOW-COST AND ROBUST POSITIONING SYSTEM FOR INDOOR GROUP OF FORKLIFTS UTILIZING PROBABILITY ESTIMATION AND SENSOR NETWORK
Authors: CHOU TSAI-LIN , FUJII NORISUKE , OTA JUN , TANAKA MASAYUKI , SHINOZAKI AKIKO
Published: October 2008

A position management system for forklifts involved in a warehouse storage task is proposed. With a simple, low-cost laser beam sensor and reflective stickers, the position of the forklift can be established. Furthermore, by combining probability estimation algorithms, the possible location of forklifts can be managed, and the accuracy of positioning can be improved through the exchange of information on a sensor network. Finally, the layout, which has a better system performance, is also discussed and proposed. With this system, forklift operations are easier, and the cost of a warehouse navigation system decreases.
KNOWLEDGE EXTRACTION FROM RISE-TIME AUTO-CORRELATED PATTERNS
Authors: ELFADIL NAZAR
Published: October 2008

In this paper, the author presents an approach for automated knowledge extraction from rise time auto-correlated patterns by using self-organizing maps and k-means clustering. The extracted knowledge in terms of rules will be used as knowledge base for an expert system. Rise-time auto-correlated data patterns are used as a learning data set. The produced knowledge based was verified by using a conventional expert system.
EMPIRICAL MODE DECOMPOSITION: APPLICATIONS ON SIGNAL AND IMAGE PROCESSING
Authors: NUNES JEAN-CLAUDE , DELÉCHELLE ÉRIC
Published: October 2008

In this paper, we propose some recent works on data analysis and synthesis based on Empirical Mode Decomposition (EMD). Firstly, a direct 2D extension of original Huang EMD algorithm with application to texture analysis, and fractional Brownian motion synthesis. Secondly, an analytical version of EMD based on PDE in 1D-space is presented.

We proposed an extension in 2D-case of the so-called "sifting process" used in the original Huang's EMD. The 2D-sifting process is performed in two steps: extrema detection (by neighboring window or morphological operators) and surface interpolation by splines (thin plate splines or multigrid B-splines). We propose a multiscale segmentation approach by using the zero-crossings from each 2D-intrinsic mode function (IMF) obtained by 2D-EMD.

We apply the Hilbert–Huang transform (which consists of two parts: (a) Empirical mode decomposition, and (b) the Hilbert spectral analysis) to texture analysis. We analyze each 2D-IMF obtained by 2D-EMD by studying local properties (amplitude, phase, isotropy, and orientation) extracted from the monogenic signal of each one of them. The monogenic signal proposed by Felsberg et al. is a 2D-generalization of the analytic signal, where the Riesz transform replaces the Hilbert transform. These local properties are obtained by the structure multivector such as proposed by Felsberg and Sommer.

We present numerical simulations of fractional Brownian textures. Recent works published by Flandrin et al. relate that, in the case of fractional Gaussian noise (fGn), EMD acts essentially as a dyadic filter bank that can be compared to wavelet decompositions. Moreover, in the context of fGn identification, Flandrin et al. show that variance progression across IMFs is related to Hurst exponent H through a scaling law. Starting with these results, we proposed an algorithm to generate fGn, and fractional Brownian motion (fBm) of Hurst exponent H from IMFs obtained from EMD of a White noise, i.e., ordinary Gaussian noise (fGn with H = 1/2).

Deléchelle et al. proposed an analytical approach (formulated as a partial differential equation (PDE)) for sifting process. This PDE-based approach is applied on signals. The analytical approach has a behavior similar to that of the EMD proposed by Huang.
Systematic Mapping of Genetic Interaction Networks
Authors: Dixon Scott J. , Costanzo Michael , Baryshnikova Anastasia , Andrews Brenda , Boone Charles
Published: October 2008

Genetic interactions influencing a phenotype of interest can be identified systematically using libraries of genetic tools that perturb biological systems in a defined manner. Systematic screens conducted in the yeast Saccharomyces cerevisiae have identified thousands of genetic interactions and provided insight into the global structure of biological networks. Techniques enabling systematic genetic interaction mapping have been extended to other single-celled organisms, the bacteria Escherichia coli and the yeast Schizosaccharomyces pombe, opening the way to comparative investigations of interaction networks. Genetic interaction screens in Caenorhabditis elegans, Drosophila melanogaster, and mammalian models are helping to improve our understanding of metazoan-specific signaling pathways. Together, our emerging knowledge of the genetic wiring diagrams of eukaryotic and prokaryotic cells is providing a new understanding of the relationship between genotype and phenotype.
Genomic Insights into Marine Microalgae
Authors: Parker Micaela S. , Mock Thomas , Armbrust E. Virginia
Published: October 2008

Marine eukaryotic photosynthesis is dominated by a diverse group of unicellular organisms collectively called microalgae. Microalgae include cells derived from a primary endosymbiotic event (similar to land plants) and cells derived from subsequent secondary and/or tertiary endosymbiotic events. These latter cells are chimeras of several genomes and dominate primary production in the marine environment. Two consequences of multiple endosymbiotic events include complex targeting mechanisms to allow nuclear-encoded proteins to be imported into the plastid and coordination of enzymes, potentially from disparate originator cells, to form complete metabolic pathways. In this review, we discuss the forces that shaped the genomes of marine microalgae and then discuss some of the metabolic consequences of such a complex evolutionary history. We focus our metabolic discussion on carbon, nitrogen, and iron. We then discuss biomineralization and new evidence for programmed cell death in microalgae. We conclude with a short summary on advances in genetic manipulation of microalgae and thoughts on the future directions of marine algal genomics.
Selection on Codon Bias
Authors: Hershberg Ruth , Petrov Dmitri A.
Published: October 2008

In a wide variety of organisms, synonymous codons are used with different frequencies, a phenomenon known as codon bias. Population genetic studies have shown that synonymous sites are under weak selection and that codon bias is maintained by a balance between selection, mutation, and genetic drift. It appears that the major cause for selection on codon bias is that certain preferred codons are translated more accurately and/or efficiently. However, additional and sometimes maybe even contradictory selective forces appear to affect codon usage as well. In this review, we discuss the current understanding of the ways in which natural selection participates in the creation and maintenance of codon bias. We also raise several open questions: (i) Is natural selection weak independently of the level of codon bias? It is possible that selection for preferred codons is weak only when codon bias approaches equilibrium and may be quite strong on genes with codon bias levels that are much lower and/or above equilibrium. (ii) What determines the identity of the major codons? (iii) How do shifts in codon bias occur? (iv) What is the exact nature of selection on codon bias? We discuss these questions in depth and offer some ideas on how they can be addressed using a combination of computational and experimental analyses.
The Dynamics of Photosynthesis
Authors: Eberhard Stephan , Finazzi Giovanni , Wollman Francis-André
Published: October 2008

Despite recent elucidation of the three-dimensional structure of major photosynthetic complexes, our understanding of light energy conversion in plant chloroplasts and microalgae under physiological conditions requires exploring the dynamics of photosynthesis. The photosynthetic apparatus is a flexible molecular machine that can acclimate to metabolic and light fluctuations in a matter of seconds and minutes. On a longer time scale, changes in environmental cues trigger acclimation responses that elicit intracellular signaling between the nucleo-cytosol and chloroplast resulting in modification of the biogenesis of the photosynthetic machinery. Here we attempt to integrate well-established knowledge on the functional flexibility of light-harvesting and electron transfer processes, which has greatly benefited from genetic approaches, with data derived from the wealth of recent transcriptomic and proteomic studies of acclimation responses in photosynthetic eukaroytes.
The Origins of Multicellularity and the Early History of the Genetic Toolkit For Animal Development
Authors: Rokas Antonis
Published: October 2008

Multicellularity appeared early and repeatedly in life's history; its instantiations presumably required the confluence of environmental, ecological, and genetic factors. Comparisons of several independently evolved pairs of multicellular and unicellular relatives indicate that transitions to multicellularity are typically associated with increases in the numbers of genes involved in cell differentiation, cell-cell communication, and adhesion. Further examination of the DNA record suggests that these increases in gene complexity are the product of evolutionary innovation, tinkering, and expansion of genetic material. Arguably, the most decisive multicellular transition was the emergence of animals. Decades of developmental work have demarcated the genetic toolkit for animal multicellularity, a select set of a few hundred genes from a few dozen gene families involved in adhesion, communication, and differentiation. Examination of the DNA records of the earliest-branching animal phyla and their closest protist relatives has begun to shed light on the origins and assembly of this toolkit. Emerging data favor a model of gradual assembly, with components originating and diversifying at different time points prior to or shortly after the origin of animals.
Evolutionary Genetics of Genome Merger and Doubling in Plants
Authors: Doyle Jeff J. , Flagel Lex E. , Paterson Andrew H. , Rapp Ryan A. , Soltis Douglas E. , Soltis Pamela S. , Wendel Jonathan F.
Published: October 2008

Polyploidy is a common mode of evolution in flowering plants. The profound effects of polyploidy on gene expression appear to be caused more by hybridity than by genome doubling. Epigenetic mechanisms underlying genome-wide changes in expression are as yet poorly understood; only methylation has received much study, and its importance varies among polyploids. Genetic diploidization begins with the earliest responses to genome merger and doubling; less is known about chromosomal diploidization. Polyploidy duplicates every gene in the genome, providing the raw material for divergence or partitioning of function in homoeologous copies. Preferential retention or loss of genes occurs in a wide range of taxa, suggesting that there is an underlying set of principles governing the fates of duplicated genes. Further studies are required for general patterns to be elucidated, involving different plant families, kinds of polyploidy, and polyploids of different ages.
Weird Animal Genomes and the Evolution of Vertebrate Sex and Sex Chromosomes
Authors: Graves Jennifer A. Marshall
Published: October 2008

Humans, mice, and even kangaroos have an XX female:XY male system of sex determination, in which the Y harbors a male-dominant sex-determining gene SRY. Birds have the opposite, ZZ males and ZW females, and may use a dosage-sensitive Z-borne gene. Other reptiles have genetic sex but no visible sex chromosomes, or determine sex by temperature of egg incubation. How can we make sense of so much variation? How do systems change in evolution? Studies of some unlikely animals—platypus and dragon lizards, frogs and fish—confirm that evolutionary transitions have occurred between TSD and GSD systems, between XY and ZW systems, and even between male and female heterogametic systems. Here I explore nonmodel systems that offer some new perspectives on some venerable questions of sex and sex chromosomes.
Bisphosphonate-Related Osteonecrosis of the Jaw: Diagnosis, Prevention, and Management
Authors: Ruggiero Salvatore L. , Mehrotra Bhoomi
Published: October 2008

Bisphosphonate therapy has been considered standard therapy in the management and care of cancer patients with metastatic bone disease and patients with osteoporosis. The efficacy of these drugs is due to their ability to inhibit osteoclast-mediated bone resorption. However, the postmarketing experience with intravenous and, to a much lesser extent, oral bisphosphonates has raised concerns about potential side effects related to profound bone remodeling inhibition and osteonecrosis isolated to the jaws. We review the risk factors, incidence, pathogenesis, prevention strategies, and management of this new complication.
Tumor Suppressors, Chromosomal Instability, and Hepatitis C Virus–Associated Liver Cancer
Authors: McGivern David R. , Lemon Stanley M.
Published: October 2008

Hepatitis C virus (HCV) is the only known RNA virus with an exclusively cytoplasmic life cycle that is associated with cancer. The mechanisms by which it causes cancer are unclear, but chronic immune-mediated inflammation and associated oxidative chromosomal DNA damage probably play a role. Compelling data suggest that the path to hepatocellular carcinoma in chronic hepatitis C shares some important features with the mechanisms of transformation employed by DNA tumor viruses. Interactions of viral proteins with key regulators of the cell cycle, the retinoblastoma-susceptibility protein, p53, and possibly DDX5 and DDX3 lead to enhanced cellular proliferation and may also compromise multiple cell-cycle checkpoints that maintain genomic integrity, thus setting the stage for carcinogenesis. Dysfunctional DNA damage and mitotic spindle checkpoints resulting from these interactions may promote chromosomal instability and leave the hepatocyte unable to control DNA damage caused by oxidative stress mediated by HCV proteins, alcohol, and immune-mediated inflammation.
NOD-Like Receptors: Role in Innate Immunity and Inflammatory Disease
Authors: Chen Grace , Shaw Michael H. , Kim Yun-Gi , Nuñez Gabriel
Published: October 2008

The NOD-like receptors (NLRs) are a specialized group of intracellular receptors that represent a key component of the host innate immune system. Since the discovery of the first NLR almost 10 years ago, the study of this special class of microbial sensors has burgeoned; consequently, a better understanding of the mechanism by which these receptors recognize microbes and other danger signals and of how they activate inflammatory signaling pathways has emerged. Moreover, in addition to their primary role in host defense against invading pathogens, their ability to regulate nuclear factor–kappa B (NF-κB) signaling, interleukin-1-beta (IL-1β) production, and cell death indicates that they are crucial to the pathogenesis of a variety of inflammatory human diseases.
The COXIB Experience: A Look in the Rearview Mirror
Authors: Marnett Lawrence J.
Published: October 2008

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used prescription and nonprescription drugs in the world. The discovery of cyclooxygenase (COX) as the target of NSAIDs, the subsequent identification of two isoforms of COX (COX-1 and COX-2), and studies of their regulation and sites of expression led to the hypothesis that COX-2 is the molecular target for the anti-inflammatory and analgesic effects of NSAIDs. A corollary was that COX-2-selective inhibitors (COXIBs) would retain the desirable effects of NSAIDs without some of their liabilities (e.g., gastrointestinal toxicity, which was ascribed to COX-1 inhibition). The first marketed COXIBs exhibited reduced gastrointestinal side effects relative to traditional NSAIDs and were enormous commercial successes. However, clinical trials testing the hypothesis that COXIBs prevent recurrence of premalignant colon polyps uncovered adverse cardiovascular effects that are mechanism based. This review provides an overview of the discovery, development, and difficulties of the COXIBs, a perspective on what has been learned, and speculation on the way forward.
Second Harmonic Generation, Sum Frequency Generation, and χ(3): Dissecting Environmental Interfaces with a Nonlinear Optical Swiss Army Knife
Authors: Geiger Franz M.
Published: October 2008

This review discusses recent advances in the nonlinear optics of environmental interfaces. We discuss the quantitative aspects of the label-free approaches presented here and demonstrate that nonlinear optics has now assumed the role of a Swiss Army knife that can be used to dissect, with molecular detail, the fundamental and practical aspects of environmental interfaces and heterogeneous geochemical environments. In this work, nonlinear optical methods are applied to complex organic molecules, such as veterinary antibiotics, and to small inorganic anions and cations, such as nitrate and chromate, or cadmium, zinc, and manganese. The environmental implications of the thermodynamic, kinetic, spectroscopic, structural, and electrochemical data are discussed.
Photoelectron Spectroscopy of Multiply Charged Anions
Authors: Wang Xue-Bin , Wang Lai-Sheng
Published: October 2008

Multiply charged anions (MCAs) are common in condensed phases but are challenging to study in the gas phase. An experimental technique, coupling photoelectron spectroscopy (PES) with electrospray ionization (ESI), has been developed to investigate the properties of free MCAs in the gas phase. This article reviews the principles of this technique and some initial findings about the intrinsic properties of MCAs. Examples include the observation of the repulsive Coulomb barrier that exists universally in MCAs and its effects on the dynamic stability and PES of MCAs. The solvation and solvent stabilization of MCAs have been studied in the gas phase and are also discussed. A second-generation low-temperature ESI-PES apparatus has been developed, which allows ion temperatures to be controlled from 10 to 350 K. New results from this low-temperature ESI-PES instrument are also reviewed, including doubly charged fullerene anions, inorganic metal complexes, and temperature-induced conformation changes of complex anions.
Noncontractile Functions of Airway Smooth Muscle Cells in Asthma
Authors: Tliba Omar , Panettieri Reynold A.
Published: October 2008

Although pivotal in regulating bronchomotor tone in asthma, airway smooth muscle (ASM) also modulates airway inflammation and undergoes hypertrophy and hyperplasia, contributing to airway remodeling in asthma. ASM myocytes secrete or express a wide array of immunomodulatory mediators in response to extracellular stimuli, and in chronic severe asthma, increases in ASM mass may render the airway irreversibly obstructed. Although the mechanisms by which ASM secretes cytokines and chemokines are the same as those regulating immune cells, there exist unique ASM signaling pathways that may provide novel therapeutic targets. This review provides an overview of our current understanding of the proliferative as well as the synthetic properties of ASM.
Prejudice Reduction: What Works? A Review and Assessment of Research and Practice
Authors: Paluck Elizabeth Levy , Green Donald P.
Published: October 2008

This article reviews the observational, laboratory, and field experimental literatures on interventions for reducing prejudice. Our review places special emphasis on assessing the methodological rigor of existing research, calling attention to problems of design and measurement that threaten both internal and external validity. Of the hundreds of studies we examine, a small fraction speak convincingly to the questions of whether, why, and under what conditions a given type of intervention works. We conclude that the causal effects of many widespread prejudice-reduction interventions, such as workplace diversity training and media campaigns, remain unknown. Although some intergroup contact and cooperation interventions appear promising, a much more rigorous and broad-ranging empirical assessment of prejudice-reduction strategies is needed to determine what works.
Influence of aging on the in vivo properties of human patellar tendon
Authors: Carroll C. C. , Dickinson J. M. , Haus J. M. , Lee G. A. , Hollon C. J. , Aagaard P. , Magnusson S. P. , Trappe T. A.
Published: October 2008

Tendons are important for optimal muscle force transfer to bone and play a key role in functional ability. Changes in tendon properties with aging could contribute to declines in physical function commonly associated with aging. We investigated the in vivo mechanical properties of the patellar tendon in 37 men and women [11 young (27 ± 1 yr) and 26 old (65 ± 1 yr)] using ultrasonography and magnetic resonance imaging (MRI). Patella displacement relative to the tibia was monitored with ultrasonography during ramped isometric contractions of the knee extensors, and MRI was used to determine tendon cross-sectional area (CSA) and signal intensity. At peak force, patellar tendon deformation, stress, and strain were 13 ( P = 0.05), 19, and 12% less in old compared with young ( P < 0.05). Additionally, deformation, stiffness, stress, CSA, and length were 18, 35, 41, 28, and 11% greater ( P < 0.05), respectively, in men compared with women. After normalization of mechanical properties to a common force, no age differences were apparent; however, stress and strain were 26 and 22% higher, respectively, in women compared with men ( P < 0.05). CSA and signal intensity decreased 12 and 24%, respectively, with aging ( P < 0.05) in the midregion of the tendon. These data suggest that differences in patellar tendon in vivo mechanical properties with aging are more related to force output rather than an age effect. In contrast, the decrease in signal intensity indirectly suggests that the internal milieu of the tendon is altered with aging; however, the physiological and functional consequence of this finding requires further study.
Exposure to cyclic intermittent hypoxia increases expression of functional NMDA receptors in the rat carotid body
Authors: Liu Yuzhen , Ji En-Sheng , Xiang Shuanglin , Tamisier Renaud , Tong Jingli , Huang Jianhua , Weiss J. Woodrow
Published: October 2008

Although large quantities of glutamate are found in the carotid body, to date this excitatory neurotransmitter has not been assigned a role in chemoreception. To examine the possibility that glutamate and its N-methyl-d-aspartate (NMDA) receptors play a role in acclimatization after exposure to cyclic intermittent hypoxia (CIH), we exposed male Sprague-Dawley rats to cyclic hypoxia or to room air sham (Sham) for 8 h/day for 3 wk. Using RT-PCR, Western blot analysis, and immunohistochemistry, we found that ionotropic NMDA receptors, including NMDAR1, NMDAR2A, NMDAR2A/2B, are strongly expressed in the carotid body and colocalize with tyrosine hydroxylase in glomus cells. CIH exposure enhanced the expression of NMDAR1 and NMDAR2A/2B but did not substantially change the level of NMDAR2A. We assessed in vivo carotid sinus nerve activity (CSNA) at baseline, in response to acute hypoxia, in response to infused NMDA, and in response to infused endothelin-1 (ET-1) with and without MK-801, an NMDA receptor blocker. Infusion of NMDA augmented CSNA in CIH rats (124.61 ± 2.64% of baseline) but not in sham-exposed rats. Administration of MK-801 did not alter baseline activity or response to acute hypoxia, in either CIH or sham animals but did reduce the effect of ET-1 infusion on CSNA (CSNA after ET-1 = 160.96 ± 8.05% of baseline; ET-1 after MK-801 = 118.56 ± 9.12%). We conclude that 3-wk CIH exposure increases expression of NMDA functional receptors in rats, suggesting glutamate and its receptors may play a role in hypoxic acclimatization to CIH.
Effect of estrogen on tendon collagen synthesis, tendon structural characteristics, and biomechanical properties in postmenopausal women
Authors: Hansen Mette , Kongsgaard Mads , Holm Lars , Skovgaard Dorthe , Magnusson S. Peter , Qvortrup Klaus , Larsen Jytte O. , Aagaard Per , Dahl Morten , Serup Annette , Frystyk Jan , Flyvbjerg Allan , Langberg Henning , Kjaer Michael
Published: October 2008

The knowledge about the effect of estradiol on tendon connective tissue is limited. Therefore, we studied the influence of estradiol on tendon synthesis, structure, and biomechanical properties in postmenopausal women. Nonusers (control, n = 10) or habitual users of oral estradiol replacement therapy (ERT, n = 10) were studied at rest and in response to one-legged resistance exercise. Synthesis of tendon collagen was determined by stable isotope incorporation [fractional synthesis rate (FSR)] and microdialysis technique (NH2-terminal propeptide of type I collagen synthesis). Tendon area and fibril characteristics were determined by MRI and transmission electron microscopy, whereas tendon biomechanical properties were measured during isometric maximal voluntary contraction by ultrasound recording. Tendon FSR was markedly higher in ERT users ( P < 0.001), whereas no group difference was seen in tendon NH2-terminal propeptide of type I collagen synthesis ( P = 0.32). In ERT users, positive correlations between serum estradiol (s-estradiol) and tendon synthesis were observed, whereas change in tendon synthesis from rest to exercise was negatively correlated to s-estradiol. Tendon area, fibril density, fibril volume fraction, and fibril mean area did not differ between groups. However, the percentage of medium-sized fibrils was higher in ERT users ( P < 0.05), whereas the percentage of large fibrils tended to be greater in control ( P = 0.10). A lower Young's modulus (GPa/%) was found in ERT users ( P < 0.05). In conclusion, estradiol administration was associated with higher tendon FSR and a higher relative number of smaller fibrils. Whereas this indicates stimulated collagen turnover in the resting state, collagen responses to exercise were negatively associated with s-estradiol. These results indicate a pivotal role for estradiol in maintaining homeostasis of female connective tissue.
Long-term progression and therapeutic response of visceral metastatic disease non-invasively monitored in mouse urine using β-human choriogonadotropin secreting tumor cell lines
Authors: Francia Giulio , Emmenegger Urban , Lee Christina R. , Shaked Yuval , Folkins Christopher , Mossoba Miriam , Medin Jeffrey A. , Man Shan , Zhu Zhenping , Witte Larry , Kerbel Robert S.
Published: October 2008

Historically, the use of mouse models of metastatic disease to evaluate anticancer therapies has been hampered because of difficulties in detection and quantification of such lesions without sacrificing the mice, which in turn may also be dictated by institutional or ethical guidelines. Advancements in imaging technologies have begun to change this situation. A new method to non-invasively measure tumor burden, as yet untested to monitor spontaneous metastases, is the use of transplanted tumors expressing secretable human β-chorionic gonadotropin (β-hCG) that can be measured in urine. We describe examples of β-hCG–transfected tumor cell lines for evaluating the effect of different therapies on metastatic disease, which in some cases involved monitoring tumor growth for >100 days. We used β-hCG–tagged mouse B16 melanoma and erbB-2/Her-2–expressing human breast cancer MDA-MB-231 models, and drug treatments included metronomic low-dose cyclophosphamide chemotherapy with or without a vascular endothelial growth factor receptor 2–targeting antibody (DC101) or trastuzumab, the erbB-2/Her-2–targeting antibody. Both experimental and spontaneous metastasis models were studied; in the latter case, an increase in urine β-hCG always foreshadowed the development of lung, liver, brain, and kidney metastases. Metastatic disease was unresponsive to DC101 or trastuzumab monotherapy treatment, as assessed by β-hCG levels. Our results also suggest that β-hCG levels may be set as an end point for metastasis studies, circumventing guidelines, which have often hampered the use of advanced disease models. Collectively, our data indicates that β-hCG is an effective noninvasive preclinical marker for the long term monitoring of untreated or treated metastatic disease. [Mol Cancer Ther 2008;7(10):3452–9]
Gambogic acid mediates apoptosis as a p53 inducer through down-regulation of mdm2 in wild-type p53-expressing cancer cells
Authors: Gu Hongyan , Wang Xiaotang , Rao Shuyun , Wang Jia , Zhao Jie , Ren Fang Li , Mu Rong , Yang Yong , Qi Qi , Liu Wei , Lu Na , Ling Hua , You Qidong , Guo Qinglong
Published: October 2008

Gambogic acid (GA) is a natural product with potent apoptotic activity. Here, we showed that GA broadly inhibited the growth of cancer cells that expressed wild-type p53 as determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazol-iumbromide assay, 3H-thymidine incorporation analysis, and an in vivo mouse xenograft model. GA induced massive cell apoptosis as judged by Annexin V and propidium iodide dual-staining experiments. Furthermore, we found that GA partially induced cancer cell growth inhibition in a p53-dependent manner because cell survival could be restored after endogenous p53 was attenuated by p53 transcriptional repressor pifithrin-α or p53 small interfering RNA. Interestingly, GA had no influence on p53 mRNA synthesis but dramatically enhanced its protein expression. This unique observation could be accounted for by the down-regulation of mdm2 at both mRNA and protein levels. It is concluded that GA enhances p53 protein level through inhibition of mdm2 expression and thereby hampers p53 harboring tumor growth. [Mol Cancer Ther 2008;7(10):3298–305]
Role of glutathione S-transferase P1-1 in the cellular detoxification of cisplatin
Authors: Peklak-Scott Christina , Smitherman Pamela K. , Townsend Alan J. , Morrow Charles S.
Published: October 2008

Cells expressing elevated levels of allelic variants of human glutathione S-transferase P1 (GSTP1) and/or efflux transporters, MRP1 or MRP2, were used to evaluate the role of GSTP1-1 in cisplatin resistance. These studies revealed that GSTP1-1 confers low-level resistance (1.4- to 1.7-fold) to cisplatin-induced cytotoxicity in MCF7 cells. However, expression of MRP1 (MCF7 cells) or MRP2 (HepG2 cells) failed to augment or potentiate GSTP1-1-mediated resistance in either cell line. To understand the mechanism by which variants of GSTP1-1 confer resistance to cisplatin, their relative abilities to catalyze conjugation of cisplatin with glutathione were examined. Enzymes encoded by all three alleles tested, GSTP1a (I104A113), GSTP1b (V104A113), and GSTP1c (V104V113), increased the formation rate of the mono-platinum/glutathione derivative of cisplatin with relative catalytic activities of 1.0 (GSTP1a-1a variant) and 1.8 to 1.9 (GSTP1b-1b and GSTP1c-1c variants). Although these data are consistent with the idea that very low level resistance to cisplatin may be conferred by GSTP1-1-mediated cisplatin/glutathione conjugation, two observations indicate that such catalysis plays a minor role in the protection from cisplatin toxicity. First, the rates of GSTP1-1-mediated conjugation are extremely slow (1.7-2.6 h−1 at 25°C). Second, despite an 80% to 90% increase in catalysis of cisplatin conjugation by GSTP1b-1b or GSTP1c-1c over GSTP1a-1a, we observed no discernable differences in relative resistances conferred by these alternative variants when expressed in MCF7 cells. We conclude that high-level cisplatin resistance attributed to GSTP1-1 in other studies is not likely due to catalysis of cisplatin conjugation but rather must be explained by other mechanisms, which may include GSTP1-mediated modulation of signaling pathways. [Mol Cancer Ther 2008;7(10):3247–55]
ABT-263 and rapamycin act cooperatively to kill lymphoma cells in vitro and in vivo
Authors: Ackler Scott , Xiao Yu , Mitten Michael J. , Foster Kelly , Oleksijew Anatol , Refici Marion , Schlessinger Sally , Wang Baole , Chemburkar Sanjay R. , Bauch Joy , Tse Christin , Frost David J. , Fesik Stephen W. , Rosenberg Saul H. , Elmore Steven W. , Shoemaker Alex R.
Published: October 2008

ABT-263 is a potent, orally bioavailable inhibitor of the antiapoptotic Bcl-2 family members Bcl-2, Bcl-xL, and Bcl-w, which is currently in phase I clinical trials. Previous work has shown that this compound has low nanomolar cell-killing activity in a variety of lymphoma and leukemia cell lines, many of which overexpress Bcl-2 through a variety of mechanisms. Rapamycin is a macrolide antibiotic that inhibits the mammalian target of rapamycin complex, leading to cell cycle arrest and inhibition of protein translation. Rapamycin (and its analogues) has shown activity in a variety of tumor cell lines primarily through induction of cell cycle arrest. Activity has also been shown clinically in mantle cell lymphoma and advanced renal cell carcinoma. Here, we show that treatment of the follicular lymphoma lines DoHH-2 and SuDHL-4 with 100 nmol/L rapamycin induces substantial G0-G1 arrest. Addition of as little as 39 nmol/L ABT-263 to the rapamycin regimen induced a 3-fold increase in sub-G0 cells. Combination of these agents also led to a significant increase in Annexin V staining over ABT-263 alone. In xenograft models of these tumors, rapamycin induced a largely cytostatic response in the DoHH-2 and SuDHL-4 models. Coadministration with ABT-263 induced significant tumor regression, with DoHH-2 and SuDHL-4 tumors showing 100% overall response rates. Apoptosis in these tumors was significantly enhanced by combination therapy as measured by staining with an antibody specific for cleaved caspase-3. These data suggest that combination of ABT-263 and rapamycin or its analogues represents a promising therapeutic strategy for the treatment of lymphoma. [Mol Cancer Ther 2008;7(10):3265–74]
Natural polyphenols facilitate elimination of HT-29 colorectal cancer xenografts by chemoradiotherapy: a Bcl-2- and superoxide dismutase 2-dependent mechanism
Authors: Priego Sonia , Feddi Fatima , Ferrer Paula , Mena Salvador , Benlloch María , Ortega Angel , Carretero Julian , Obrador Elena , Asensi Miguel , Estrela José M.
Published: October 2008

Colorectal cancer is one of the most common malignancies worldwide. The treatment of advanced colorectal cancer with chemotherapy and radiation has two major problems: development of tumor resistance to therapy and nonspecific toxicity towards normal tissues. Different plant-derived polyphenols show anticancer properties and are pharmacologically safe. In vitro growth of human HT-29 colorectal cancer cells is inhibited (∼56%) by bioavailable concentrations of trans-pterostilbene (trans-3,5-dimethoxy-4′-hydroxystilbene; t-PTER) and quercetin (3,3′,4′,5,6-pentahydroxyflavone; QUER), two structurally related and naturally occurring small polyphenols. I.v. administration of t-PTER and QUER (20 mg/kg × day) inhibits growth of HT-29 xenografts (∼51%). Combined administration of t-PTER + QUER, FOLFOX6 (oxaliplatin, leucovorin, and 5-fluorouracil; a first-line chemotherapy regimen), and radiotherapy (X-rays) eliminates HT-29 cells growing in vivo leading to long-term survival (>120 days). Gene expression analysis of a Bcl-2 family of genes and antioxidant enzymes revealed that t-PTER + QUER treatment preferentially promotes, in HT-29 cells growing in vivo, (a) superoxide dismutase 2 overexpression (∼5.7-fold, via specificity protein 1-dependent transcription regulation) and (b) down-regulation of bcl-2 expression (∼3.3-fold, via inhibition of nuclear factor-κB activation). Antisense oligodeoxynucleotides to human superoxide dismutase 2 and/or ectopic bcl-2 overexpression avoided polyphenols and chemoradiotherapy-induced colorectal cancer elimination and showed that the mangano-type superoxide dismutase and Bcl-2 are key targets in the molecular mechanism activated by the combined application of t-PTER and QUER. [Mol Cancer Ther 2008;7(10):3330–42]
Oncogene AF1q enhances doxorubicin-induced apoptosis through BAD-mediated mitochondrial apoptotic pathway
Authors: Co Ngai Na , Tsang Wing Pui , Wong Timothy W.L. , Cheung Hoi Hung , Tsang Tsun Yee , Kong Siu Kai , Kwok Tim Tak
Published: October 2008

AF1q is an oncogenic factor involved in leukemia development, thyroid tumorigenesis, and breast cancer metastasis. In the present study, AF1q was found to be down-regulated in a doxorubicin-resistant subline of human squamous carcinoma A431 cells. Knockdown of AF1q decreased the apoptosis induced by doxorubicin, Taxol, γ-radiation, IFN-α, and IFN-γ in A431 cells. On the other hand, overexpression of AF1q increased the doxorubicin-induced apoptosis in A431 cells as well as in HepG2 and HL60 cells. Both exogenous and ectopic expression of AF1q in A431 cells increased the mRNA and protein levels of BAD, a proapoptotic BCL-2 family protein. Gene silencing of BAD by small interfering RNA suppressed the AF1q enhancement of apoptosis, suggesting that BAD is downstream of AF1q in regulation of apoptosis. Furthermore, AF1q enhanced the mitochondrial membrane depolarization, mitochondrial cytochrome c release, and activation of caspase-9 and caspase-3 on doxorubicin treatment. Collectively, AF1q increases doxorubicin-induced apoptosis in cells through activation of BAD-mediated apoptotic pathway. The study provides the first evidence that AF1q plays a critical role in the regulation of apoptosis and drug resistance. [Mol Cancer Ther 2008;7(10):3160–8]
Coronarin D, a labdane diterpene, inhibits both constitutive and inducible nuclear factor-κB pathway activation, leading to potentiation of apoptosis, inhibition of invasion, and suppression of osteoclastogenesis
Authors: Kunnumakkara Ajaikumar B. , Ichikawa Haruyo , Anand Preetha , Mohankumar Chiramel J. , Hema Padmanabhan S. , Nair Mangalam S. , Aggarwal Bharat B.
Published: October 2008

Compounds isolated from members of the Zingiberaceae family are traditionally used as a medicine against inflammatory diseases, but little is known about the mechanism. Here, we report the isolation and structural identification of coronarin D [E-labda-8(17),12-diene-15-ol], a labdane-type diterpene, from Hedychium coronarium and delineate its mechanism of action. Because the transcription factor nuclear factor-κB (NF-κB) is a key mediator of inflammation, apoptosis, invasion, and osteoclastogenesis, we investigated the effect of coronarin D on NF-κB activation pathway, NF-κB-regulated gene products, and NF-κB-regulated cellular responses. The coronarin D inhibited NF-κB activation induced by different inflammatory stimuli and carcinogens. This labdane also suppressed constitutive NF-κB activity in different cell lines and inhibited IκBα kinase activation, thus leading to the suppression of IκBα phosphorylation, degradation, p65 nuclear translocation, and reporter gene transcription. Coronarin D also inhibited the NF-κB-regulated gene products involved in cell survival (inhibitor of apoptosis protein 1, Bcl-2, survivin, and tumor necrosis factor receptor-associated factor-2), proliferation (c-myc, cyclin D1, and cyclooxygenase-2), invasion (matrix metalloproteinase-9), and angiogenesis (vascular endothelial growth factor). Suppression of these gene products by the diterpene enhanced apoptosis induced by TNF and chemotherapeutic agents, suppressed TNF-induced cellular invasion, and abrogated receptor activator of NF-κB ligand-induced osteoclastogenesis. Coronarin D was found to be more potent than its analogue coronarin D acid. Overall, our results show that coronarin D inhibited NF-κB activation pathway, which leads to inhibition of inflammation, invasion, and osteoclastogenesis, as well as potentiation of apoptosis. [Mol Cancer Ther 2008;7(10):3306–17]