bluuebunny/crossref_metadata_2025 huggingface dataset:
A syntactical analysis of non-size-increasing polynomial time computation
Authors: Aehlig Klaus , Schwichtenberg Helmut
Published: July 2002

A syntactical proof is given that all functions definable in a certain affine linear typed λ-calculus with iteration in all types are polynomial time computable. The proof provides explicit polynomial bounds that can easily be calculated.
Resource-bounded continuity and sequentiality for type-two functionals
Authors: Buss Samuel R. , Kapron Bruce M.
Published: July 2002

We define notions of resource-bounded continuity and sequentiality for type-two functionals with total inputs, and prove that in the resource-bounded model there are continuous functionals which cannot be efficiently simulated by sequential functionals. We also show that for some naturally defined classes of continuous functionals an efficient simulation is possible.
Reconfigurable computing
Authors: Compton Katherine , Hauck Scott
Published: July 2002

Due to its potential to greatly accelerate a wide variety of applications, reconfigurable computing has become a subject of a great deal of research. Its key feature is the ability to perform computations in hardware to increase performance, while retaining much of the flexibility of a software solution. In this survey, we explore the hardware aspects of reconfigurable computing machines, from single chip architectures to multi-chip systems, including internal structures and external coupling. We also focus on the software that targets these machines, such as compilation tools that map high-level algorithms directly to the reconfigurable substrate. Finally, we consider the issues involved in run-time reconfigurable systems, which reuse the configurable hardware during program execution.
Topology-reducing surface simplification using a discrete solid representation
Authors: Andújar Carlos , Brunet Pere , Ayala Dolors
Published: July 2002

This paper presents a new approach for generating coarse-level approximations of topologically complex models. Dramatic topology reduction is achieved by converting a 3D model to and from a volumetric representation. Our approach produces valid, error-bounded models and supports the creation of approximations that do not interpenetrate the original model, either being completely contained in the input solid or bounding it. Several simple to implement versions of our approach are presented and discussed. We show that these methods perform significantly better than other surface-based approaches when simplifying topologically-rich models such as scene parts and complex mechanical assemblies.
Cross-entropy and rare events for maximal cut and partition problems
Authors: Rubinstein Reuven Y.
Published: July 2002

We show how to solve the maximal cut and partition problems using a randomized algorithm based on thecross-entropymethod. For the maximal cut problem, the proposed algorithm employs an auxiliary Bernoulli distribution, which transforms the original deterministic network into an associated stochastic one, called theassociated stochastic network(ASN). Each iteration of the randomized algorithm for the ASN involves the following two phases:(1) Generation of random cuts using a multidimensionalBer(p) distribution and calculation of the associated cut lengths (objective functions) and some related quantities, such as rare-event probabilities.(2) Updating the parameter vectorpon the basis of the data collected in the first phase.We show that theBer(p) distribution converges in distribution to a degenerated one,Ber(pd*),pd*= (pd,1,...,pd,n) in the sense that someelements ofpd*, will be unities and the rest zeros. The unity elements ofpd*uniquely define a cut which will be taken as the estimate of the maximal cut. A similar approach is used for the partition problem. Supporting numerical results are given as well. Our numerical studies suggest that for the maximal cut and partition problems the proposed algorithm typically has polynomial complexity in the size of the network.
Algorithm 817: P2MESH
Authors: Bertolazzi Enrico , Manzini Gianmarco
Published: July 2002

The software interface P2MESH is a collection of C++ class templates suitable for developing prototypes of high-performance PDE solvers on unstructured 2-D meshes. P2MESH supports several discretization methods on triangles and quadrilaterals, such as finite volume or finite element. The design philosophy of P2MESH does not consider specific model problems or built-in approximation algorithms. The software package is general purpose and it may also be used as a building block in the implementation of numerical codes both for engineering applications and mathematical problems.
SALT AND DROUGHT STRESS SIGNAL TRANSDUCTION IN PLANTS
Authors: Zhu Jian-Kang
Published: July 2002

▪ Abstract  Salt and drought stress signal transduction consists of ionic and osmotic homeostasis signaling pathways, detoxification (i.e., damage control and repair) response pathways, and pathways for growth regulation. The ionic aspect of salt stress is signaled via the SOS pathway where a calcium-responsive SOS3-SOS2 protein kinase complex controls the expression and activity of ion transporters such as SOS1. Osmotic stress activates several protein kinases including mitogen-activated kinases, which may mediate osmotic homeostasis and/or detoxification responses. A number of phospholipid systems are activated by osmotic stress, generating a diverse array of messenger molecules, some of which may function upstream of the osmotic stress–activated protein kinases. Abscisic acid biosynthesis is regulated by osmotic stress at multiple steps. Both ABA-dependent and -independent osmotic stress signaling first modify constitutively expressed transcription factors, leading to the expression of early response transcriptional activators, which then activate downstream stress tolerance effector genes.
REVEALING THE MOLECULAR SECRETS OF MARINE DIATOMS
Authors: Falciatore Angela , Bowler Chris
Published: July 2002

▪ Abstract  Diatoms are unicellular photosynthetic eukaryotes that contribute close to one quarter of global primary productivity. In spite of their ecological success in the world's oceans, very little information is available at the molecular level about their biology. Their most well-known characteristic is the ability to generate a highly ornamented silica cell wall, which made them very popular study organisms for microscopists in the last century. Recent advances, such as the development of a range of molecular tools, are now allowing the dissection of diatom biology, e.g., for understanding the molecular and cellular basis of bioinorganic pattern formation of their cell walls and for elucidating key aspects of diatom ecophysiology. Making diatoms accessible to genomics technologies will potentiate greatly these efforts and may lead to the use of diatoms to construct submicrometer-scale silica structures for the nanotechnology industry.
MOLECULAR GENETICS OF AUXIN SIGNALING
Authors: Leyser Ottoline
Published: July 2002

▪ Abstract  The plant hormone auxin is a simple molecule similar to tryptophan, yet it elicits a diverse array of responses and is involved in the regulation of growth and development throughout the plant life cycle. The ability of auxin to bring about such diverse responses appears to result partly from the existence of several independent mechanisms for auxin perception. Furthermore, one prominent mechanism for auxin signal transduction involves the targeted degradation of members of a large family of transcriptional regulators that appear to participate in complex and competing dimerization networks to modulate the expression of a wide range of genes. These models for auxin signaling now offer a framework in which to test how each specific response to auxin is brought about.
Eukaryotic DNA Polymerases
Authors: Hübscher Ulrich , Maga Giovanni , Spadari Silvio
Published: July 2002

▪ Abstract  Any living cell is faced with the fundamental task of keeping the genome intact in order to develop in an organized manner, to function in a complex environment, to divide at the right time, and to die when it is appropriate. To achieve this goal, an efficient machinery is required to maintain the genetic information encoded in DNA during cell division, DNA repair, DNA recombination, and the bypassing of damage in DNA. DNA polymerases (pols) α, β, γ, δ, and ϵ are the key enzymes required to maintain the integrity of the genome under all these circumstances. In the last few years the number of known pols, including terminal transferase and telomerase, has increased to at least 19. A particular pol might have more than one functional task in a cell and a particular DNA synthetic event may require more than one pol, which suggests that nature has provided various safety mechanisms. This multi-functional feature is especially valid for the variety of novel pols identified in the last three years. These are the lesion-replicating enzymes pol ζ, pol η, pol ι, pol κ, and Rev1, and a group of pols called pol θ, pol λ, pol μ, pol σ, and pol φ that fulfill a variety of other tasks.
Homogeneous Glycopeptides and Glycoproteins for Biological Investigation
Authors: Grogan Michael J. , Pratt Matthew R. , Marcaurelle Lisa A. , Bertozzi Carolyn R.
Published: July 2002

▪ Abstract  Protein glycosylation is widely recognized as a modulator of protein structure, localization, and cell-cell recognition in multicellular systems. Glycoproteins are typically expressed as mixtures of glycoforms, their oligosaccharides being generated by a template-independent biosynthetic process. Investigation of their function has been greatly assisted by sources of homogeneous material. This review summarizes current efforts to obtain homogeneous glycopeptide and glycoprotein materials by a variety of methods that draw from the techniques of recombinant expression, chemical synthesis, enzymatic transformation, and chemoselective ligation. Some of these techniques remove obstacles to glycoprotein synthesis by installing nonnative linkages and other modifications for facilitated assembly. The end purpose of the described approaches is the production of glycosylated materials for experiments relevant to the biological investigation of glycoproteins, although the strategies presented apply to other posttranslational modifications as well.
Neuronal Ca2+/Calmodulin-Dependent Protein Kinase II: The Role of Structure and Autoregulation in Cellular Function
Authors: Hudmon Andy , Schulman Howard
Published: July 2002

▪ Abstract  Highly enriched in brain tissue and present throughout the body, Ca2+/calmodulin-dependent protein kinase II (CaMKII) is central to the coordination and execution of Ca2+signal transduction. The substrates phosphorylated by CaMKII are implicated in homeostatic regulation of the cell, as well as in activity-dependent changes in neuronal function that appear to underlie complex cognitive and behavioral responses, including learning and memory. The architecture of CaMKII holoenzymes is unique in nature. The kinase functional domains (12 per holoenzyme) are attached by stalklike appendages to a gear-shaped core, grouped into two clusters of six. Each subunit contains a catalytic, an autoregulatory, and an association domain. Ca2+/calmodulin (CaM) binding disinhibits the autoregulatory domain, allowing autophosphorylation and complex changes in the enzyme’s sensitivity to Ca2+/CaM, including the generation of Ca2+/CaM-independent activity, CaM trapping, and CaM capping. These processes confer a type of molecular memory to the autoregulation and activity of CaMKII. Its function is intimately shaped by its multimeric structure, autoregulation, isozymic type, and subcellular localization; these features and processes are discussed as they relate to known and potential cellular functions of this multifunctional protein kinase.
Advances in Proteomic Technologies
Authors: Yarmush Martin L. , Jayaraman Arul
Published: July 2002

▪ Abstract  Proteomics is a rapidly emerging set of key technologies that are being used to identify proteins and map their interactions in a cellular context. With the sequencing of the human genome, the scope of proteomics has shifted from protein identification and characterization to include protein structure, function and protein-protein interactions. Technologies used in proteomic research include two-dimensional gel electrophoresis, mass spectrometry, yeast two-hybrids screens, and computational prediction programs. While some of these technologies have been in use for a long time, they are currently being applied to study physiology and cellular processes in high-throughput formats. It is the high-throughput approach that defines and characterizes modern proteomics. In this review, we discuss the current status of these experimental and computational technologies relevant to the three major aspects of proteomics—characterization of proteomes, identification of proteins, and determination of protein function. We also briefly discuss the development of new proteomic technologies that are based on recent advances in analytical and biochemical techniques, engineering, microfabrication, and computational prowess. The integration of these advances with established technologies is invaluable for the drive toward a comprehensive understanding of protein structure and function in the cellular milieu.
Three-Dimensional Confocal Microscopy of the Living Human Eye
Authors: Masters Barry R. , Böhnke Matthias
Published: July 2002

▪ Abstract  Three-dimensional confocal microscopy of the living eye is a major development in instrumentation for biomicroscopy of the eye. This noninvasive optical technology has its roots in the application of optics to reflected light imaging of the eye. These instrument developments began with Leeuwenhoek's use of his single lens microscope to investigate the structure of the eye. There followed a series of connected instruments: the ophthalmoscope, the slit lamp, the specular microscope, and the clinical confocal microscope. In vivo confocal microscopy produces high contrast, reflected light images or optical sections through the depth of living ocular tissue. Stacks of registered optical sections can be transformed by computer visualization techniques into three-dimensional volume images of ocular tissues: cornea, ocular lens, retina, and optic nerve. The clinical confocal microscope has resulted in new diagnostic techniques and new cellular descriptions of ocular disorders and pathology.
Mechano-Electrochemical Properties Of Articular Cartilage: Their Inhomogeneities and Anisotropies
Authors: Mow Van C. , Guo X. Edward
Published: July 2002

▪ Abstract  In this chapter, the recent advances in cartilage biomechanics and electromechanics are reviewed and summarized. Our emphasis is on the new experimental techniques in cartilage mechanical testing, new experimental and theoretical findings in cartilage biomechanics and electromechanics, and emerging theories and computational modeling of articular cartilage. The charged nature and depth-dependent inhomogeneity in mechano-electrochemical properties of articular cartilage are examined, and their importance in the normal and/or pathological structure-function relationships with cartilage is discussed, along with their pathophysiological implications. Developments in theoretical and computational models of articular cartilage are summarized, and their application in cartilage biomechanics and biology is reviewed. Future directions in cartilage biomechanics and mechano-biology research are proposed.
Telerehabilitation Research: Emerging Opportunities
Authors: Winters Jack M.
Published: July 2002

▪ Abstract  The field of clinical rehabilitation is rooted in the premise that carefully planned and delivered therapeutic intervention enhances patient outcomes. Underlying this statement is a deeper scientific reality: The field exists because biosystems (e.g., tissues, cells, organs, persons) are inherently adaptive and can dynamically change as a function of a sequence of inputs (e.g., exercise, pharmaceuticals). The tools of telerehabilitation help minimize the barrier of distance, both of patients to rehabilitative services and of researchers to subject populations. This enhanced access opens up new possibilities for discovering and implementing optimized intervention strategies across the continuum of care. Telecommunications technologies are reviewed from the perspective of systems models of the telerehabilitation process, with a focus on human-technology interface design and a special emphasis on emerging home and mobile technologies. Approaches for providing clinical rehabilitation services through telerehabilitation are addressed, including innovative consumer-centered approaches. Finally, telerehabilitation is proposed as a tool for reinvigorating the rehabilitative bioengineering research enterprise.
Single-Particle Imaging of Macromolecules by Cryo-Electron Microscopy
Authors: Frank Joachim
Published: July 2002

▪ Abstract  Cryo-electron microscopy (cryo-EM) of biological molecules in single-particle (i.e., unordered, nonaggregated) form is a new approach to the study of molecular assemblies, which are often too large and flexible to be amenable to X-ray crystallography. New insights into biological function on the molecular level are expected from cryo-EM applied to the study of such complexes “trapped” at different stages of their conformational changes and dynamical interactions. Important molecular machines involved in the fundamental processes of transcription, mRNA splicing, and translation are examples for successful applications of the new technique, combined with structural knowledge gained by conventional techniques of structure determination, such as X-ray crystallography and NMR.
PIP2and Proteins: Interactions, Organization, and Information Flow
Authors: McLaughlin Stuart , Wang Jiyao , Gambhir Alok , Murray Diana
Published: July 2002

▪ Abstract  We review the physical properties of phosphatidylinositol 4,5-bisphosphate (PIP2) that determine both its specific interactions with protein domains of known structure and its nonspecific electrostatic sequestration by unstructured domains. Several investigators have postulated the existence of distinct pools of PIP2within the cell to account for the myriad functions of this lipid. Recent experimental work indicates certain regions of the plasma membrane—membrane ruffles and nascent phagosomes—do indeed concentrate PIP2. We consider two mechanisms that could account for this phenomenon: local synthesis and electrostatic sequestration. We conclude by considering the hypothesis that proteins such as MARCKS bind a significant fraction of the PIP2in a cell, helping to sequester it in lateral membrane domains, then release this lipid in response to local signals such as an increased concentration of Ca++/calmodulin or activation of protein kinase C.
Principles and Biophysical Applications of Lanthanide-Based Probes
Authors: Selvin Paul R.
Published: July 2002

▪ Abstract  Using luminescent lanthanides, instead of conventional fluorophores, as donor molecules in resonance energy transfer measurements offers many technical advantages and opens up a wide range of new applications. Advantages include farther measurable distances (∼100 Å) with greater accuracy, insensitivity to incomplete labeling, and the ability to use generic relatively large labels, when necessary. Applications highlighted include the study of ion channels in living cells, protein-protein interaction in cells, DNA-protein complexes, and high-throughput screening assays to measure peptide dimerization associated with DNA transcription factors and ligand-receptor interactions.
Kinetic Monte Carlo Simulation of Chemical Vapor Deposition
Authors: Battaile Corbett C. , Srolovitz David J.
Published: July 2002

▪ Abstract  The kinetic Monte Carlo method is a powerful tool for exploring the evolution and properties of a wide range of problems and systems. Kinetic Monte Carlo is ideally suited for modeling the process of chemical vapor deposition, which involves the adsorption, desorption, evolution, and incorporation of vapor species at the surface of a growing film. Deposition occurs on a time scale that is generally not accessible to fully atomistic approaches such as molecular dynamics, whereas an atomically resolved Monte Carlo method parameterized by accurate chemical kinetic data is capable of exploring deposition over long times (min) on large surfaces (mm2). There are many kinetic Monte Carlo approaches that can simulate chemical vapor deposition, ranging from coarse-grained model systems with hypothetical input parameters to physically realistic atomic simulations with accurate chemical kinetic input. This article introduces the kinetic Monte Carlo technique, reviews some of the major approaches, details the construction and implementation of the method, and provides an example of its application to a technologically relevant deposition system.
Transcriptional Codes and the Control of Neuronal Identity
Authors: Shirasaki Ryuichi , Pfaff Samuel L.
Published: July 2002

▪ Abstract  The topographic assembly of neural circuits is dependent upon the generation of specific neuronal subtypes, each subtype displaying unique properties that direct the formation of selective connections with appropriate target cells. Studies of motor neuron development in the spinal cord have begun to elucidate the molecular mechanisms involved in controlling motor projections. In this review, we first describe the actions of transcription factors within motor neuron progenitors, which initiate a cascade of transcriptional interactions that lead to motor neuron specification. We next highlight the contribution of the LIM homeodomain (LIM-HD) transcription factors in establishing motor neuron subtype identity. Importantly, it has recently been shown that the combinatorial expression of LIM-HD transcription factors, the LIM code, confers motor neuron subtypes with the ability to select specific axon pathways to reach their distinct muscle targets. Finally, the downstream targets of the LIM code are discussed, especially in the context of subtype-specific motor axon pathfinding.
Molecular Control of Cortical Dendrite Development
Authors: Whitford Kristin L. , Dijkhuizen Paul , Polleux Franck , Ghosh Anirvan
Published: July 2002

▪ Abstract  Dendritic morphology has a profound impact on neuronal information processing. The overall extent and orientation of dendrites determines the kinds of input a neuron receives. Fine dendritic appendages called spines act as subcellular compartments devoted to processing synaptic information, and the dendritic branching pattern determines the efficacy with which synaptic information is transmitted to the soma. The acquisition of a mature dendritic morphology depends on the coordinated action of a number of different extracellular factors. Here we discuss this evidence in the context of dendritic development in the cerebral cortex. Soon after migrating to the cortical plate, neurons extend an apical dendrite directed toward the pial surface. The oriented growth of the apical dendrite is regulated by Sema3A, which acts as a dendritic chemoattractant. Subsequent dendritic development involves signaling by neurotrophic factors and Notch, which regulate dendritic growth and branching. During postnatal development the formation and stabilization of dendritic spines are regulated in part by patterns of synaptic activity. These observations suggest that extracellular signals play an important role in regulating every aspect of dendritic development and thereby exert a critical influence on cortical connectivity.
SCATTERING RESONANCES IN THE SIMPLEST CHEMICAL REACTION
Authors: Fernández-Alonso Félix , Zare Richard N.
Published: July 2002

▪ Abstract  Recent studies of state-resolved angular distributions show the participation of reactive scattering resonances in the simplest chemical reaction. This review is intended for those who wish to learn about the state-of-the-art in the study of the H + H2 reaction family that has made this breakthrough possible. This review is also intended for those who wish to gain insight into the nature of reactive scattering resonances. Following a tour across several fields of physics and chemistry where the concept of resonance has been crucial for the understanding of new phenomena, we offer an operational definition and taxonomy of reactive scattering resonances. We introduce simple intuitive models to illustrate each resonance type. We focus next on the last decade of H + H2 reaction dynamics. Emphasis is placed on the various experimental approaches that have been applied to the search for resonance behavior in the H + H2 reaction family. We conclude by sketching the road ahead in the study of H + H2 reactive scattering resonances.
Homocysteine Upregulates Vascular Cell Adhesion Molecule-1 Expression in Cultured Human Aortic Endothelial Cells and Enhances Monocyte Adhesion
Authors: Silverman Matthew D. , Tumuluri Ramagopal J. , Davis Mishel , Lopez Gladys , Rosenbaum James T. , Lelkes Peter I.
Published: July 2002

Elevated plasma homocysteine is an independent risk factor for atherosclerosis. We hypothesized that homocysteine enhances monocyte/human aortic endothelial cell (HAEC) interactions, a pivotal early event in atherogenesis, by upregulating endothelial adhesion molecules. After incubation of cultured HAECs with reduceddl-homocysteine for up to 24 hours, adhesion of human monocytes to homocysteine-stimulated HAECs was significantly upregulated in a time- and dose-dependent fashion. Pretreatment of HAECs with 100 μmol/L homocysteine caused a 4.5-fold increase in the adhesion of normal human monocytes (P<0.001). Similarly, adhesion of monocytic U937 cells was maximally elevated by 3.5-fold at 100 μmol/L homocysteine (P<0.001). In support of our hypothesis, vascular cell adhesion molecule (VCAM)-1 mRNA expression increased 5-fold in HAECs after 3 hours of treatment with 100 μ mol/L homocysteine, as assessed by quantitative reverse transcription– polymerase chain reaction. Neutralizing antibody studies confirmed the involvement of VCAM-1 in mediating monocyte adhesion to homocysteine-stimulated HAECs. Coincubation of HAECs with homocysteine and tumor necrosis factor-α synergistically elevated monocyte adhesion as well as VCAM-1 protein expression, with the latter evaluated by flow cytometry. Preincubation of HAECs with cyclooxygenase inhibitors completely abrogated homocysteine-induced monocyte adhesion, whereas scavenging reactive oxygen species and the elevation of NO caused partial inhibition only. These data support the notion that the proinflammatory effects of homocysteine may have important implications in atherogenesis.
Inflammatory Mediators and Cell Adhesion Molecules as Indicators of Severity of Atherosclerosis
Authors: van der Meer Irene M. , de Maat Moniek P.M. , Bots Michiel L. , Breteler Monique M.B. , Meijer John , Kiliaan Amanda J. , Hofman Albert , Witteman Jacqueline C.M.
Published: July 2002

Inflammatory mediators and soluble cell adhesion molecules predict cardiovascular events. It is not clear whether they reflect the severity of underlying atherosclerotic disease. Within the Rotterdam Study, we investigated the associations of C-reactive protein (CRP), interleukin-6 (IL-6), soluble intercellular adhesion molecule-1, and soluble vascular cell adhesion molecule-1 with noninvasive measures of atherosclerosis. Levels of CRP were assessed in a random sample of 1317 participants, and levels of IL-6 and soluble cell adhesion molecules were assessed in a subsample of 714 participants. In multivariate analyses, logarithmically transformed CRP (regression coefficient [β]=−0.023, 95% CI −0.033 to −0.012) and IL-6 (β=−0.025, 95% CI −0.049 to −0.001) were inversely associated with the ankle-arm index. Only CRP was associated with carotid intima-media thickness (β=0.018, 95% CI 0.010 to 0.027). Compared with the lowest tertile, the odds ratio for moderate to severe carotid plaques associated with levels of CRP in the highest tertile was 2.0 (95% CI 1.3 to 3.0). Soluble intercellular adhesion molecule-1 levels were strongly associated with carotid plaques (odds ratio 2.5, 95% CI 1.5 to 4.4 [highest versus lowest tertile]). Soluble vascular cell adhesion molecule-1 was not significantly associated with any of the measures of atherosclerosis. This study indicates that CRP is associated with the severity of atherosclerosis measured at various sites. Associations of the other markers with atherosclerosis were less consistent.
Rho-GTPase–Dependent Platelet-Neutrophil Interaction Affected by HMG-CoA Reductase Inhibition With Altered Adenosine Nucleotide Release and Function
Authors: Kaneider Nicole C. , Egger Petra , Dunzendorfer Stefan , Wiedermann Christian J.
Published: July 2002

Platelet activation and aggregation is considered a crucial step in the initiation and aggravation of arterial thrombosis. ADP from activated platelets is recognized as major factor in thrombus formation and is a potent stimulator of oxygen-free radical release from neutrophils. The aim of the present investigation was to determine in vitro the direct effects of statins on ATP and ADP secretion by platelets and its impact on subsequent oxidative burst activity in neutrophils. Human neutrophils and platelets were isolated from peripheral blood. Levels of platelet-derived ATP and ADP were measured by high-performance liquid chromatography, oxygen-free radical release of neutrophils was measured fluorometrically, and chemotaxis experiments were performed. Rho-GTPases were studied by Western blot analysis. Thrombin-activated platelets primed neutrophils for enhanced oxygen-free radical release on triggering with formyl-Met-Leu-Phe, reduced by cerivastatin and simvastatin treatment of platelets. The two statins decreased the amount of adenosine-derivative release in these cells. Rho-GTPases, required for the thrombin signaling in platelets and neutrophils, were decreased after coincubation with statins. Data demonstrate that inhibition of Rho-GTPases by statins inhibit platelet ADP and ATP release and the consecutive augmentation of neutrophil oxygen-free radical release. Statins affect platelet-neutrophil interactions by altering Rho-GTPase–dependent adenosine nucleotide function.
Curcuma longa
Extract Supplementation Reduces Oxidative Stress and Attenuates Aortic Fatty Streak Development in Rabbits
Authors: Quiles José L. , Mesa M. Dolores , Ramírez-Tortosa César L. , Aguilera Concepción M. , Battino Maurizio , Gil Ángel , Ramírez-Tortosa M. Carmen
Published: July 2002

Objective

—

This study evaluates the effect of a
Curcuma longa
extract on the development of experimental atherosclerosis (fatty streak) in rabbits and its interaction with other plasmatic antioxidants.

Methods and Results

—

Two experimental groups of male New Zealand White rabbits, a control group and a curcuma-extract (CU) group, were fed an atherogenic diet. Additionally, the CU group received an oral curcuma hydroalcoholic extract. Six animals from each experimental group were killed after 10, 20, and 30 days. Compared with the CU group, the control group showed significantly higher plasma lipid peroxide at all experimental times (10, 20, and 30 days) and significantly lower α-tocopherol and coenzyme Q levels at 20 and 30 days. Histological results for the fatty streak lesions revealed damage in the thoracic and abdominal aorta that was significantly lower in the CU group than in the control group at 30 days.

Conclusions

—

Supplementation with
Curcuma longa
reduces oxidative stress and attenuates the development of fatty streaks in rabbits fed a high cholesterol diet.
Genetic and Environmental Influences on Lipids, Lipoproteins, and Apolipoproteins
Authors: Middelberg Rita P.S. , Spector Tim D. , Swaminathan Ramasamyiyer , Snieder Harold
Published: July 2002

Objective

—

Levels of lipids and (apo)lipoproteins are known to increase after menopause, but it is unknown whether the genetic and environmental variability alters or whether lipids and (apo)lipoproteins are influenced by different genes before and after menopause.

Methods and Results

—

We studied 453 monozygotic and 1280 dizygotic pairs of female white twins recruited from the St. Thomas’ UK Adult Twin Registry and measured total cholesterol, low density lipoprotein (LDL), high density lipoprotein (HDL), triglycerides, lipoprotein(a) [Lp(a)], apolipoprotein A1 (apoA1), and apolipoprotein B (apoB). Variance components software was used to estimate genetic and environmental influences on serum lipid levels in premenopausal and postmenopausal women. Total variance was higher for triglycerides, HDL, and apoB after menopause. Postmenopausal women showed larger genetic variance for most lipids, apart from apoB and Lp(a). In premenopausal females, total cholesterol, LDL, HDL, apoA1, and apoB all showed an influence of the shared environment (22% to 34%), which, after menopause, decreased in HDL and completely disappeared in total cholesterol, LDL, and apoA1. Only for Lp(a), with a high heritability of 87%, did the same model fit premenopausal and postmenopausal women. Generally, there was no indication that different genes influence lipids before and after menopause.

Conclusions

—

These findings imply that genetic studies of lipids can pool results from premenopausal and postmenopausal women and that family-based interventions, such as changes in diet, are more likely to succeed in younger women, in whom the environmental influences are greater.
Opposing Functions of the Ets Factors NERF and ELF-1 During Chicken Blood Vessel Development
Authors: Gaspar John , Thai Shelley , Voland Carole , Dube Antoinise , Libermann Towia A. , Iruela-Arispe M.Luisa , Oettgen Peter
Published: July 2002

Objective

—

The purpose of this study was to evaluate the role of the Ets factor NERF in the regulation of the Tie1 and Tie2 genes during chicken blood vessel development.

Methods and Results

—

We have isolated the full-length cDNA for the chicken homologue of the human Ets factor NERF2 (cNERF2). Northern blot analysis and in situ hybridization demonstrate that cNERF2 is enriched in the developing blood vessels of the chicken chorioallantoic membrane. Interestingly, cNERF2 functions as a competitive inhibitor of a highly related Ets factor cELF-1, which we have previously shown to be enriched in chicken blood vessel development. Although in vitro–translated cELF-1 and cNERF2 can bind equally well to conserved Ets binding sites in the promoters of the Tie1 and Tie2 genes, cELF-1 preferentially binds to the Ets sites in these promoters during early stages of chicken blood vessel development, suggesting that cNERF may bind during later stages of blood vessel development and vascular remodeling.

Conclusions

—

cNERF2 is enriched during embryonic and extraembryonic blood vessel development in the chicken and facilitates tight control of Tie1 and Tie2 gene regulation.
Pulmonary Hypertension and Risk of Death in Cardiomyopathy
Authors: Cappola Thomas P. , Felker G. Michael , Kao W.H. Linda , Hare Joshua M. , Baughman Kenneth L. , Kasper Edward K.
Published: July 2002

Background

—

Pulmonary hypertension is a clinically useful predictor of death in patients with heart failure. Whether pulmonary hypertension has the same prognostic value among specific underlying causes of cardiomyopathy is unknown. Using a diverse cohort of cardiomyopathy patients, we tested the hypotheses that (1) elevated mean pulmonary arterial pressure is the most important hemodynamic predictor of death and (2) the prognostic value of mean pulmonary pressure varies among different cardiomyopathies.

Methods and Results

—

Patients (n=1134) with new cardiomyopathy were prospectively assigned a specific diagnosis on the basis of clinical evaluation and endomyocardial biopsy. All patients underwent right heart catheterization at baseline and were followed for an average of 4.4 years. In multivariate Cox models that allowed for nonlinear relations between hemodynamics and death, mean systemic pressure (mSP) and mean pulmonary arterial pressure (mPA) emerged as the most important hemodynamic predictors of death. Moreover, there was a statistically significant positive interaction between mPA and the diagnosis of myocarditis. For each 5–mm Hg increase in baseline mSP, mortality rates decreased with relative hazard (RH) of 0.89 (0.86 to 0.92). For a 5–mm Hg increase in baseline mPA, mortality rates increased in patients who did not carry the diagnosis of myocarditis with RH 1.23 (1.17 to 1.29); among patients with myocarditis, mortality rates increased substantially with RH of 1.85 (1.50 to 2.29;
P
<0.001 for interaction).

Conclusions

—

Baseline mPA is particularly important for stratifying risk in myocarditis. These findings suggest that secondary pulmonary hypertension may have different biological features in myocarditis and that patients with pulmonary hypertension and myocarditis should be targeted for aggressive medical therapy.
Imaging of Oxygen Transfer Among Microvessels of Rat Cremaster Muscle
Authors: Kobayashi Hirosuke , Takizawa Naosada
Published: July 2002

Background—

The proximity of capillaries, arterioles, and venules provides complex spatial relationships that lead to oxygen transfer among microvessels. Although a conceptual image of complex oxygen transfer among microvessels has been hypothesized, in vivo mapping of oxygen saturation (S
o
2
) levels in microvessels had never been performed.

Methods and Results—

The oxygen profile of the arterioles and venules of the rat cremaster muscle during normoxia and hypoxia was visualized by preparing pseudo-color images of S
o
2
levels based on microspectrophotometry data obtained by using 3 different optical filters and a cooled CCD camera. The S
o
2
images showed lower S
o
2
levels in arterioles close to their walls, and the S
o
2
levels in the paired venules showed higher S
o
2
levels close to the arterioles. There were capillaries that crossed the microvessels whose S
o
2
levels changed as they crossed the microvessels. The S
o
2
levels were lower close to the vessel wall than in the centerline level of the microvessels, and the highest S
o
2
levels in venules paralleling arterioles were skewed toward the arterial side. The S
o
2
images showed that the S
o
2
level in arterioles decreased after crossing venules, whereas the S
o
2
level in venules increased after crossing arterioles.

Conclusions—

Visualization of intravascular S
o
2
levels suggested that oxygen is transferred between paired microvessels and between crossing microvessels in rat cremaster muscle. The possibility that oxygen is transported from some arterioles to venules and tissue through adjacent capillaries is proposed.
Artifact-Free In-Stent Lumen Visualization by Standard Magnetic Resonance Angiography Using a New Metallic Magnetic Resonance Imaging Stent
Authors: Buecker Arno , Spuentrup Elmar , Ruebben Alexander , Günther Rolf W.
Published: July 2002

Background
—

Metallic stents cause susceptibility and radiofrequency artifacts on MR images, which, up to now, have not allowed for complete visualization of the stent lumen by MR angiography. The aim of this study was to investigate the potential of a new dedicated renal MRI stent for artifact-free in-stent lumen visualization in vitro and in a swine model.

Methods and Results
—

In vitro investigations were performed with prototypes of balloon-expandable Aachen Resonance Renal MRI Stents dilated to diameters of 3 to 6 mm and placed in an aqueous gadolinium solution (1:25). Phase-contrast and contrast-enhanced T
1
-weighted gradient echo images were acquired. Renal MRI stents (n=12) were deployed in the renal arteries of 6 pigs. Renal arteries were examined with phase-contrast angiography and with flow measurements before and after stent placement in the stented area, respectively. Additionally, a contrast-enhanced, T
1
-weighted, spoiled-gradient echo sequence after administration of 0.2 mmol gadolinium-DTPA/kg body weight was performed after stent placement. The visibility of artifacts was analyzed on in vitro and in vivo images by two investigators who knew the stent positions. Stent positions were determined visually (in vitro) or by x-ray angiography (animal experiments). No artifacts were detected independent of the applied imaging sequence and the stent orientation to the main magnetic field.

Conclusion
—

The examined prototypes of fully MR-compatible MRI stents allow artifact-free visualization of the stent lumen with phase-contrast and contrast-enhanced T
1
-weighted angiography, as well as phase-contrast flow measurements in the stented area.
First Clinical Experience With a Paclitaxel Derivate–Eluting Polymer Stent System Implantation for In-Stent Restenosis
Authors: Liistro Francesco , Stankovic Goran , Di Mario Carlo , Takagi Takuro , Chieffo Alaide , Moshiri Shahram , Montorfano Matteo , Carlino Mauro , Briguori Carlo , Pagnotta Paolo , Albiero Remo , Corvaja Nicola , Colombo Antonio
Published: July 2002

Background

—

It has been shown that antiproliferative drugs such as paclitaxel lower the amount of intimal hyperplasia after stent implantation. We report the first clinical experience of 7-hexanoyltaxol (QP2)–eluting polymer stent system (QuaDS) implantation for in-stent restenosis.

Methods and Results

—

Fifteen consecutive patients with elective indication to percutaneous coronary intervention for in-stent restenosis were treated with the QuaDS-QP2 stent implantation. The QuaDS-QP2 stent was successfully implanted in all but 2 target lesions. In one lesion, the restenotic segment could not be completely covered by the stent, and in another lesion, a bare metal stent was implanted distally to the QuaDS-QP2 stent. One patient suffered from postprocedural non–Q-wave myocardial infarction (NQWMI). No other adverse events were observed during hospital stay. Six- and 12-month angiographic and clinical follow-up was scheduled for all patients. At 6 months, 3 patients had target lesion revascularization (20%). Two patients had restenosis (13.3%); one experienced restenosis in a gap between 2 drug-eluting stents, and the other had stent occlusion leading to NQWMI. Minimal intimal hyperplasia was observed in all the segments covered by drug-eluting stents (late loss=0.47±1.01 mm with a loss index=0.17±0.39). At 12 months, 1 patient suffered from NQWMI, and 8 of 13 patients (61.5%) had angiographic restenosis (late loss=1.36±0.94 mm with a loss index=0.62±0.44).

Conclusion

—

This first experience with QuaDS-QP2 stent implantation for in-stent restenosis revealed minimal intimal hyperplasia at the 6-month follow-up. However, the antiproliferative effect was not maintained at the 12-month follow-up, resulting in delayed occurrence of angiographic restenosis.
Identification of a Novel Redox-Sensitive Gene, Id3, Which Mediates Angiotensin II–Induced Cell Growth
Authors: Mueller Cornelius , Baudler Stephanie , Welzel Hilke , Böhm Michael , Nickenig Georg
Published: July 2002

Background

—

Reactive oxygen species, such as superoxide (O
2
−
), are involved in the abnormal growth of various cell types. Angiotensin II (Ang II) is one of the most potent inducers of oxidative stress in the vasculature. The molecular events involved in Ang II–induced proliferation of vascular smooth muscle cells (VSMCs) are only partially understood.

Methods and Results

—

Ang II as well as xanthine/xanthine oxidase (X/XO) led to enhanced DNA synthesis and proliferation of VSMCs. The effect of Ang II was abolished by diphenylene iodonium. Consequently, VSMCs were incubated with X/XO, and modulation of gene expression was monitored by differential display, leading to the identification of a novel redox-sensitive gene, the dominant-negative helix-loop-helix protein Id3, which was upregulated within 30 minutes by X/XO and Ang II. Superoxide dismutase but not catalase inhibited this effect. Overexpression of antisense Id3 via transfection in VSMCs completely abolished Ang II– and X/XO-induced cell proliferation. Ang II, X/XO, and overexpression of sense Id3 downregulated protein expression of p21
WAF1/Cip1
, p27
Kip1
, and p53. Overexpression of antisense Id3 abrogated the effect of Ang II on the expression of p21
WAF1/Cip1
, p27
Kip1
, and p53. Ang II and overexpression of sense Id3 caused hyperphosphorylation of the retinoblastoma protein. Ang II–induced phosphorylation of the retinoblastoma protein was decreased by overexpression of antisense Id3.

Conclusions

—

Ang II induces proliferation of VSMCs via production of superoxide, which enhances the expression of Id3. Id3 governs the downstream mitogenic processing via depression of p21
WAF1/Cip1
, p27
Kip1
, and p53. These findings reveal a novel redox-sensitive pathway involved in growth control.
Red Wine Polyphenols Inhibit Vascular Smooth Muscle Cell Migration Through Two Distinct Signaling Pathways
Authors: Iijima Katsuya , Yoshizumi Masao , Hashimoto Masayoshi , Akishita Masahiro , Kozaki Koichi , Ako Junya , Watanabe Tokumitsu , Ohike Yumiko , Son Bokyung , Yu Jing , Nakahara Koichi , Ouchi Yasuyoshi
Published: July 2002

Background
—

Red wine polyphenols (RWPs) have been shown to have an antiatherogenic activity mainly through antioxidative effects on LDL oxidation. Although vascular smooth muscle cell (SMC) migration is critical to atherosclerosis formation, the effect of RWPs on SMC migration has not been elucidated. In this study, we investigated whether RWPs could affect the migration of cultured SMCs stimulated by growth factors.

Methods and Results
—

RWP concentration dependently inhibited platelet-derived growth factor (PDGF)-BB–induced and serum-induced SMC migration in wounding assay and Boyden chamber assay. However, these inhibitory effects of RWPs were not seen in serum-stimulated vascular endothelial cell migration in either assay. Moreover, specific inhibitors of phosphatidylinositol-3′ kinase (PI3K) and p38 mitogen-activated protein kinase (p38
MAPK
), but not of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), reduced PDGF-BB–induced SMC migration. To elucidate the signaling mechanism underlying the RWP effects, we investigated the effects of RWPs on the activity of PI3K and the phosphorylation of MAPK pathways in PDGF-BB–stimulated SMCs. RWPs inhibited the PI3K activity and p38
MAPK
phosphorylation, but not ERK1/2 phosphorylation, in a concentration-dependent manner. Moreover, the phosphorylation of MKK3/6, an upstream kinase of p38
MAPK
, was also inhibited by RWP treatment in a concentration-dependent manner, suggesting that the inhibitory effect of RWPs on the p38
MAPK
pathway works upstream of MKK3/6. The concentration-effect relationship of RWPs necessary for the inhibition of PI3K and p38
MAPK
pathways was similar to that of cell migration assays.

Conclusions
—

RWPs inhibit the SMC migration through the inhibition of 2 distinct signaling pathways and thus exert antiatherogenic actions.