bluuebunny/crossref_metadata_2025 huggingface dataset:
Recognising Tensor Products of Matrix Groups
Authors: Leedham-Green C. R. , O'Brien E. A.
Published: October 2003

As a contribution to the project for recognising matrix groups defined over finite fields, we describe an algorithm for deciding whether or not the natural module for such a matrix group can be decomposed into a non-trivial tensor product. In the affirmative case, a tensor decomposition is returned. As one component, we develop algorithms to compute p-local subgroups of a matrix group.
Relational Sets and Categorical Equivalence of Algebras
Authors: Zádori László
Published: October 2003

We study relation varieties, i.e. classes of relational sets (resets) of the same type that are closed under the formation of products and retracts. The notions of an irreducible reset and a representation of a reset are defined similarly to the ones for partially ordered sets. We give a characterization of finite irreducible resets. We show that every finite reset has a representation by minimal resets which are certain distinguished irreducible retracts. It turns out that a representation by minimal resets is a smallest one in some sense among all representations of a reset. We prove that non-isomorphic finite irreducible resets generate different relation varieties. We characterize categorical equivalence of algebras via product and retract of certain resets associated with the algebras. In the finite case the characterization involves minimal resets. Examples are given to demonstrate how the general theorems work for particular algebras and resets.
Chains and Superchains for ω-Rational Sets, Automata and Semigroups
Authors: Carton Olivier , Perrin Dominique
Published: October 2003

We introduce several equivalent notions that generalize ones introduced by Klaus Wagner for finite Muller automata under the name of chains and superchains. We define such objects in relation to ω-rational sets, Muller automata or also ω-semigroups. We prove their equivalence and derive some basic properties of these objects. In a subsequent paper, we show how these concepts allow us to derive a new presentation of the hierarchy due to K. Wagner and W. Wadge.
A Characterization of Finite Ternary Algebras
Authors: Brzozowski J. A. , Lou J. J. , Negulescu R.
Published: October 2003

A ternary algebra is a De Morgan algebra (that is, a distributive lattice with 0 and 1 and a complement operation that satisfies De Morgan's laws) with an additional constant Φ satisfying [Formula: see text], [Formula: see text], and [Formula: see text]. We provide a characterization of finite ternary algebras in terms of "subset-pair algebras," whose elements are pairs (X, Y) of subsets of a given base set ℰ, which have the property X ∪ Y = ℰ, and whose operations are based on common set operations.
Finite Left Distributive Groupoids with one Generator
Authors: Drápal Aleš
Published: October 2003

Finite monogenerated groupoids G satisfying the left distributive law x · (y · z) = (x · y) · (x · z) are completely described.
Semiclassical Behavior of Uniform-Density Models for Cosmic Strings and Relativistic Stars
Authors: Campanelli Manuela , Lousto Carlos O.
Published: October 2003

In this paper we show how quantum corrections, although perturbatively small, may play an important role in the analysis of the existence of some classical models. This, in fact, appears to be the case of static, uniform-density models of the interior metric of cosmic strings and neutron stars. We consider the fourth-order semiclassical equations and first look for perturbative solutions in the coupling constants α and β of the quadratic curvature terms in the effective gravitational Lagrangian. We find that there is not a consistent solution; neither for strings nor for spherical stars. We then look for nonperturbative solutions and find an explicit approximate metric for the case of straight cosmic strings. We then conclude that nonperturbative solutions are valuable for describing certain physical situations.
Analysis, Synthesis, and Estimation of Fractal-Rate Stochastic Point Processes
Authors: Thurner Stefan , Lowen Steven B. , Feurstein Markus C. , Heneghan Conor , Feichtinger Hans G. , Teich Malvin C.
Published: October 2003

Fractal and fractal-rate stochastic point processes (FSPPs and FRSPPs) provide useful models for describing a broad range of diverse phenomena, including electron transport in amorphous semiconductors, computer-network traffic, and sequences of neuronal action potentials. A particularly useful statistic of these processes is the fractal exponent α, which may be estimated for any FSPP or FRSPP by using a variety of statistical methods. Simulated FSPPs and FRSPPs consistently exhibit bias in this fractal exponent, however, rendering the study and analysis of these processes non-trivial. In this paper, we examine the synthesis and estimation of FRSPPs by carrying out a systematic series of simulations for several different types of FRSPP over a range of design values for α. The discrepancy between the desired and achieved values of α is shown to arise from finite data size and from the character of the point-process generation mechanism. In the context of point-process simulation, reduction of this discrepancy requires generating data sets with either a large number of points, or with low jitter in the generation of the points. In the context of fractal data analysis, the results presented here suggest caution when interpreting fractal exponents estimated from experimental data sets.
Algorithmic Complexity and Thermodynamics of Fractal Growth Processes
Authors: Dewey T. Gregory
Published: October 2003

A statistical mechanical formalism is developed using the computer information concepts of algorithmic complexity and Kolmogorov universal probability. This formalism provides a thermodynamic description of microstates of a system. For an isolated classical system, the algorithmic complexity is equal to the thermodynamic entropy. This approach does not rely on probabilistic ensemble concepts and can be applied to non-ergodic systems. An H-function is developed from the Kolmogorov universal probability that satisfies the properties of an entropy function. Using this approach, the thermodynamics of irreversible growth processes far from equilibrium can be investigated. Entropy functions for fractal growth processes far from equilibrium are developed from the algorithmic complexity and are seen to be similar to Flory-type equilibrium functions. This development does not require energy minimization procedures associated with equilibrium arguments. Using this approach, constraints can be put on the types of mean field models that will yield fractal structures. The algorithmic complexity of a system can also be used to explore the role of fluctuations and criticality in highly ordered systems.
Adaptive Pole Placement Control Algorithm for Nonlinear Systems
Authors: Wang Jin , Gao Wenzhong
Published: October 2003

A new adaptive control algorithm for unknown nonlinear plants is presented. The paper first describes a modified neural network(MNN) as well as the associated learning algorithm. The learning algorithm converges considerably faster because of the introduction of recursive least squares(RLS) algorithm. And then designs adaptive pole placement controller based on the modified neural network. Simulation results show that the proposed control algorithm can effectively control nonlinear plants.
Bodies of Evidence Versus Simple Interval Probabilities
Authors: Sgarro Andrea
Published: October 2003

We give a convenient criterion which shows that "most" bodies of evidence are not representable through simple interval probabilities, i.e. interval probabilities defined through singleton constraints. Actually, the two theories are largely non-overlapping.
Interval Methods and Fuzzy Optimization
Authors: Lodwick Weldon A. , Jamison K. David
Published: October 2003

In this paper, we describe interval-based methods for solving constrained fuzzy optimization problems. The class of fuzzy functions we consider for the optimization problems is the set of real-valued functions where one or more parameters/coefficients are fuzzy numbers. The focus of this research is to explore some relationships between fuzzy set theory and interval analysis as it relates to optimization problems.
Some Characterizations of the Systems Represented by Choquet and Multi-Linear Functionals through the use of Möbius Inversion
Authors: Fujimoto Katsushige , Murofushi Toshiaki
Published: October 2003

The systems represented by the Choquet or the multi-linear fuzzy integral with respect to fuzzy measure is equivalently decomposable into hierarchically sub-systems through the use of Inclusion-Exclusion Covering (IEC) (Theorem 4.1,4.2). Hence, IEC is one of very useful concepts/indexes for structural analysis of the fuzzy integral systems (short for: the systems represented by the Choquet or the multi-linear fuzzy integral) However, it is quite difficult to identify all IEC's. This paper shows a method for identifying it easily, through the use of Möbius inversion (Theorem 5.1).
Verification and Transformation of Complex and Uncertain Conceptual Schemas
Authors: Yazici Adnan , Merdan Osman
Published: October 2003

In database environment, it is necessary to represent complex and uncertain information at conceptual level and then transform the conceptual schema into the logical one for ultimate implementation. It is also important to verify the conceptual schema with respect to the constraints imposed on the schema definition. In this paper we primarily focus on the verification and transformation of the conceptual schema. For the purpose of verification of the conceptual schema represented by the ExIFO data model (the extension of the IFO data model), we introduce a number of invariants. We also describe the transformation algorithm for mapping the conceptual specification into a logical database schema represented with the extended NF 2 database model. The system that we describe in this paper is implemented and it can test whether the given ExIFO specification is valid and transforms the conceptual specification into the logical schema. The transformation algorithm is computationally efficient and preserves the knowledge represented with verified conceptual schema.
On the Best Scalar Approximation of Cardinality of a Fuzzy Set
Authors: Wygralak Maciej
Published: October 2003

It seems that a suitably constructed fuzzy set of natural numbers does form the most complete and adequate description of cardinality of a finite fuzzy set. Nevertheless, in many applications, one needs a simple scalar approximation (evaluation) of that cardinality. Usually, the well-known, but very imperfect concept of sigma-count of a fuzzy set is then used. The aim of this paper is to find the best approximation of cardinality of a finite fuzzy set by a single natural number.
A Software Testing-Progress Evaluation Model Based on a Digestion Process of Test-Cases
Authors: Kimura Mitsuhiro , Yamada Shigeru
Published: October 2003

It is of great importance for software engineers and managers to evaluate software testing-progress in a large-scale software production process, since tremendous software development resources must be consumed to achieve high quality and reliability of a software product. By focusing on the behavior of the digested test-case data observed in the testing process, we construct a stochastic model and derive several quantitative measures for software testing-progress evaluation. Actual data observed in the testing process are analyzed by the proposed model, and we discuss the applicability of our models.
Propagation of Cylindrically Symmetric Gaussian Beams in a Higher-Order Nonlinear Medium
Authors: Jovanoski Zlatko , Sammut Rowland A.
Published: October 2003

The propagation of a cylindrically symmetric Gaussian beam in a cubic-quintic nonlinear medium is analysed via a variational approach. Explicit conditions for stationary beam propagation are determined and their stability to symmetric perturbation of the spot width is established. Approximate analytical solutions are secured for the spot width modulation with propagation distance. A comparison is made with beams propagating in a medium exhibiting a two-level saturation.
Spatial Solitons and Shock Waves in Photorefractive Crystals with Nonlocal Nonlinearity
Authors: Kutuzov V. , Petnikova V. M. , Shuvalov V. V. , Vysloukh V. A.
Published: October 2003

An analytical model has been developed to describe both drift and diffusion mechanisms of nonlinear response (local and nonlocal components of nonlinearity) of photorefractive crystals (PRCs) on a microscopic level. Some types of stable self-consistent distributions of light intensity — bright and dark photorefractive spatial solitons — have been considered. Paths of their propagation (self-bending) have been calculated and a possibility of formation of a new type of soliton-like distributions — spatial shock waves — has been shown. Analysis of plane wave modulation instability has been performed and specific spatial scales of light distribution, resulting from self-action processes (fanning), have been calculated. All the analytical results have been confirmed using computer simulation.
Polarization-Squeezed Light Formation in Cubic–Nonlinear Medium with Dissipation
Authors: Chirkin A. S. , Volokhovsky V. V.
Published: October 2003

The influence of losses and thermal noise on the polarization-squeezed light formation in a medium with third order nonlinearity has been analysed. A method of analysis based on the delta-correlation property of noise was developed. Mean values and variances of some Stokes parameter of the light was calculated. It was shown that optimal interaction length for effective fluctuation suppression in the Stokes parameters is determined by damping constants, noise level, and radiation intensity.
Large-Size Monosectorial Crystal Elements for Powerful Laser Systems
Authors: Bespalov V. I.
Published: October 2003

The potentialities of fabricating large-size monosectorial crystals for powerful laser systems are discussed. Two types of technologies used for high-rate growth of profiled crystals and some results attained in crystal growth in the Institute of Applied Physics of the Russian Academy of Science are described briefly. It is concluded that the growth technique developed may be used for producing large-size optical elements (about 400 × 400 mm2) for laser systems intended for nuclear fusion experiments.
Robust Multiscale Deformable Registration of 3D Ultrasound Images
Authors: Pratikakis Ioannis , Barillot Christian , Hellier Pierre , Memin Etienne
Published: October 2003

In this paper, we embed the minimization scheme of an automatic 3D non-rigid registration method in a multiscale framework. The initial model formulation was expressed as a robust multiresolution and multigrid minimization scheme. At the finest level of the multiresolution pyramid, we introduce a focusing strategy from coarse-to-fine scales which leads to an improvement in the accuracy of the registration process. A focusing strategy has been tested for a linear and a non-linear scale-space. Results on real 3D ultrasound images are discussed.
Kidney Glomerulus Observation in Interactive VR Space
Authors: Oshiro Osamu , Kamada Kumi , Imura Masataka , Chihara Kunihiro , Toyota Eiji , Ogasawara Yasuo , Kajiya Fumihiko
Published: October 2003

This paper presents the system designed to observe kidney glomeruli interactively with conventional CCD cameras and immersive virtual reality (VR) space. First, we captured the X-ray transmitted images and converted them to computer tomogram (CT). Second, the three-dimensional (3D) image was reconstructed using various image processing, binarization, dilation, contraction, labeling and surface rendering. Third, we presented the 3D image on the immersive projection system (IPS) and installed the function of on-line counting of the number of glomeruli. This system provides an observer the immersive environment and enables him to count the kidney glomeruli interactively.
Cadherins as Modulators of Cellular Phenotype
Authors: Wheelock Margaret J. , Johnson Keith R.
Published: October 2003

▪ Abstract  Cadherins are transmembrane glycoproteins that mediate calcium-dependent cell-cell adhesion. The cadherin family is large and diverse, and proteins are considered to be members of this family if they have one or more cadherin repeats in their extracellular domain. Cadherin family members are the transmembrane components of a number of cellular junctions, including adherens junctions, desmosomes, cardiac junctions, endothelial junctions, and synaptic junctions. Cadherin function is critical in normal development, and alterations in cadherin function have been implicated in tumorigenesis. The strength of cadherin interactions can be regulated by a number of proteins, including the catenins, which serve to link the cadherin to the cytoskeleton. Cadherins have been implicated in a number of signaling pathways that regulate cellular behavior, and it is becoming increasingly clear that integration of information received from cell-cell signaling, cell-matrix signaling, and growth factor signaling determines ultimate cellular phenotype and behavior.
Branching Morphogenesis of theDrosophilaTracheal System
Authors: Ghabrial Amin , Luschnig Stefan , Metzstein Mark M. , Krasnow Mark A.
Published: October 2003

▪ Abstract  Many organs including the mammalian lung and vascular system consist of branched tubular networks that transport essential gases or fluids, but the genetic programs that control the development of these complex three-dimensional structures are not well understood. The Drosophila melanogaster tracheal (respiratory) system is a network of interconnected epithelial tubes that transports oxygen and other gases in the body and provides a paradigm of branching morphogenesis. It develops by sequential sprouting of primary, secondary, and terminal branches from an epithelial sac of ∼80 cells in each body segment of the embryo. Mapping of the cell movements and shape changes during the sprouting process has revealed that distinct mechanisms of epithelial migration and tube formation are used at each stage of branching. Genetic dissection of the process has identified a general program in which a fibroblast growth factor (FGF) and fibroblast growth factor receptor (FGFR) are used repeatedly to control branch budding and outgrowth. At each stage of branching, the mechanisms controlling FGF expression and the downstream signal transduction pathway change, altering the pattern and structure of the branches that form. During terminal branching, FGF expression is regulated by hypoxia, ensuring that tracheal structure matches cellular oxygen need. A branch diversification program operates in parallel to the general budding program: Regional signals locally modify the general program, conferring specific structural features and other properties on individual branches, such as their substrate outgrowth preferences, differences in tube size and shape, and the ability to fuse to other branches to interconnect the network.
Nodal Signaling in Vertebrate Development
Authors: Schier Alexander F.
Published: October 2003

▪ Abstract  TGFß signals belonging to the Nodal family set up the embryonic axes, induce mesoderm and endoderm, pattern the nervous system, and determine left-right asymmetry in vertebrates. Nodal signaling activates a canonical TGFß pathway involving activin receptors, Smad2 transcription factors, and FoxH1 coactivators. In addition, Nodal signaling is dependent on coreceptors of the EGF-CFC family and antagonized by the Lefty and Cerberus families of secreted factors. Additional modulators of Nodal signaling include convertases that regulate the generation of the mature signal, and factors such as Arkadia and DRAP1 that regulate the cellular responses to the signal. Complex regulatory cascades and autoregulatory loops coordinate Nodal signaling during early development. Nodals have concentration-dependent roles and can act both locally and at a distance. These studies demonstrate that Nodal signaling is modulated at almost every level to precisely orchestrate tissue patterning during vertebrate embryogenesis.
Quality Control and Protein Folding in the Secretory Pathway
Authors: Trombetta E. Sergio , Parodi Armando J.
Published: October 2003

▪ Abstract  The biosynthesis of secretory and membrane proteins in the endoplasmic reticulum (ER) yields mostly properly folded and assembled structures with full biological activity. Such fidelity is maintained by quality control (QC) mechanisms that avoid the production of nonnative structures. QC relies on chaperone systems in the ER that monitor and assist in the folding process. When folding promotion is not sufficient, proteins are retained in the ER and eventually retranslocated to the cytosol for degradation by the ubiquitin proteasome pathway. Retention of proteins that fail QC can sometimes occur beyond the ER, and degradation can take place in lysosomes. Several diseases are associated with proteins that do not pass QC, fail to be degraded efficiently, and accumulate as aggregates. In other cases, pathology arises from the downregulation of mutated but potentially functional proteins that are retained and degraded by the QC system.
Regulation of Membrane Protein Transport by Ubiquitin and Ubiquitin-Binding Proteins
Authors: Hicke Linda , Dunn Rebecca
Published: October 2003

▪ Abstract  Ubiquitin regulates protein transport between membrane compartments by serving as a sorting signal on protein cargo and by controlling the activity of trafficking machinery. Monoubiquitin attached to integral plasma membrane proteins or to associated transport modifiers serves as a regulated signal for internalization into the endocytic pathway. Similarly, monoubiquitin attached to biosynthetic and endocytic membrane proteins is a signal for sorting of cargo into vesicles that bud into the late endosome lumen for delivery into the lysosome. Ubiquitination of trans-acting endocytic proteins is also required for transport, and key endocytic proteins are modified by monoubiquitin. Regulatory enzymes of the ubiquitination machinery, ubiquitin ligases, control the timing and specificity of plasma membrane protein downregulation in such diverse biological processes as cell fate specification and neurotransmission. Monoubiquitin signals appended by these ligases are recognized by endocytic proteins carrying ubiquitin-binding motifs, including UBA, UEV, UIM, and CUE domains. The UIM proteins epsins and Hrs are excellent candidates for adaptors that link ubiquitinated cargo to the clathrin-based sorting machinery at appropriate regions of the endosomal or plasma membranes. Other ubiquitin-binding proteins also play crucial roles in cargo transport, although in most cases the role of ubiquitin-binding is not defined. Ubiquitin-binding proteins such as epsins, Hrs, and Vps9 are monoubiquitinated, indicating the general nature of ubiquitin regulation in endocytosis and suggesting new models to explain how recognition of monoubiquitin signals may be regulated.
Cyclic Nucleotide-Gated Ion Channels
Authors: Matulef Kimberly , Zagotta William N.
Published: October 2003

▪ Abstract  Cyclic nucleotide-gated (CNG) ion channels were first discovered in rod photoreceptors, where they are responsible for the primary electrical signal of the photoreceptor in response to light. CNG channels are highly specialized membrane proteins that open an ion-permeable pore across the membrane in response to the direct binding of intracellular cyclic nucleotides. CNG channels have been identified in a number of other tissues, including the brain, where their roles are only beginning to be appreciated. Recently, significant progress has been made in understanding the molecular mechanisms underlying their functional specializations. From these studies, a picture is beginning to emerge for how the binding of cyclic nucleotide is transduced into the opening of the pore and how this allosteric transition is modulated by various physiological effectors.
SNARE Protein Structure and Function
Authors: Ungar Daniel , Hughson Frederick M.
Published: October 2003

▪ Abstract  The SNARE superfamily has become, since its discovery approximately a decade ago, the most intensively studied element of the protein machinery involved in intracellular trafficking. Intracellular membrane fusion in eukaryotes requires SNARE (soluble N-ethylmaleimide-sensitive-factor attachment protein receptor) proteins that form complexes bridging the two membranes. Although common themes have emerged from structural and functional studies of SNAREs and other components of the eukaryotic membrane fusion machinery, there is still much to learn about how the assembly and activity of this machinery is choreographed in living cells.
Modulation of Notch Signaling During Somitogenesis
Authors: Weinmaster Gerry , Kintner Chris
Published: October 2003

▪ Abstract  The Notch signaling pathway is known to govern various aspects of tissue differentiation during embryonic development by mediating local cell-cell interactions that often control cell fate. The conserved components that underlie Notch signaling have been isolated in vertebrates, leading to a biochemical delineation of a core Notch signaling pathway and functional studies of this pathway during embryogenesis. Herein we highlight recent progress in determining how Notch signaling contributes to the development of the vertebrate embryo. We first discuss the role of Notch in the process of segmentation where rapid changes have been shown to occur in both the spatial and temporal aspects of Notch signaling, which are critical for segmental patterning. Indeed, the role of Notch in segmentation re-emphasizes a recurring question in Notch biology: How are the components involved in Notch signaling regulated to ensure their dynamic properties? Second, we address this question by discussing recent work on the biochemical mechanisms that potentially regulate Notch signaling during segmentation, including those that act on the receptors, ligands, and signal transduction apparatus.
Plasma Membrane Disruption: Repair, Prevention, Adaptation
Authors: McNeil Paul L. , Steinhardt Richard A.
Published: October 2003

▪ Abstract  Many metazoan cells inhabit mechanically stressful environments and, consequently, their plasma membranes are frequently disrupted. Survival requires that the cell rapidly repair or reseal the disruption. Rapid resealing is an active and complex structural modification that employs endomembrane as its primary building block, and cytoskeletal and membrane fusion proteins as its catalysts. Endomembrane is delivered to the damaged plasma membrane through exocytosis, a ubiquitous Ca2+-triggered response to disruption. Tissue and cell level architecture prevent disruptions from occurring, either by shielding cells from damaging levels of force, or, when this is not possible, by promoting safe force transmission through the plasma membrane via protein-based cables and linkages. Prevention of disruption also can be a dynamic cell or tissue level adaptation triggered when a damaging level of mechanical stress is imposed. Disease results from failure of either the preventive or resealing mechanisms.
Anthrax Toxin
Authors: Collier R. John , Young John A.T.
Published: October 2003

▪ Abstract  Anthrax toxin consists of three nontoxic proteins that associate in binary or ternary combinations to form toxic complexes at the surface of mammalian cells. One of these proteins, protective antigen (PA), transports the other two, edema factor (EF) and lethal factor (LF), to the cytosol. LF is a Zn2+-protease that cleaves certain MAP kinase kinases, leading to death of the host via a poorly defined sequence of events. EF, a calmodulin- and Ca2+-dependent adenylate cyclase, is responsible for the edema seen in the disease. Both enzymes are believed to benefit the bacteria by inhibiting cells of the host's innate immune system. Assembly of toxic complexes begins after PA binds to cellular receptors and is cleaved into two fragments by furin proteases. The smaller fragment dissociates, allowing the receptor-bound fragment, PA63 (63 kDa), to self-associate and form a ring-shaped, heptameric pore precursor (prepore). The prepore binds up to three molecules of EF and/or LF, and the resulting complexes are endocytosed and trafficked to an acidic compartment. There, the prepore converts to a transmembrane pore, mediating translocation of EF and LF to the cytosol. Recent studies have revealed (a) the identity of receptors; (b) crystallographic structures of the three toxin proteins and the heptameric PA63 prepore; and (c) information about toxin assembly, entry, and action within the cytosol. Knowledge of the structure and mode of action of the toxin has unveiled potential applications in medicine, including approaches to treating anthrax infections.
Genes, Signals, and Lineages in Pancreas Development
Authors: Murtaugh L. Charles , Melton Douglas A.
Published: October 2003

▪ Abstract  Type I diabetes results from the autoimmune-mediated destruction of pancreatic beta (β) cells, which regulate blood sugar levels by secretion of insulin. Recent clinical data suggest that the disease could be cured if an adequate supply of new β-cells were available, and one goal of pancreatic developmental biology is to understand how endogenous β-cells are made, with the hope of making them exogenously. Much is now known about the transcriptional regulation of pancreatic organ specification, growth, and lineage allocation; less is known about intercellular signals that regulate this process, but candidates continue to emerge. Additional insights, often contradicting older models, have come from the application of new lineage-tracing techniques. Altogether, these studies also shed light on the still-elusive pancreatic stem cell, which may participate in normal organ maintenance as well as recovery from injury. A rigorous proof of the existence of such a cell, whether in vivo or in vitro, would offer real hope for the prospect of controlled β-cell generation in a clinical setting.
Adhesion-Dependent Cell Mechanosensitivity
Authors: Bershadsky Alexander D. , Balaban Nathalie Q. , Geiger Benjamin
Published: October 2003

▪ Abstract  The conversion of physical signals, such as contractile forces or external mechanical perturbations, into chemical signaling events is a fundamental cellular process that occurs at cell–extracellular matrix contacts, known as focal adhesions. At these sites, transmembrane integrin receptors are associated via their cytoplasmic domains with the actin cytoskeleton. This interaction with actin is mediated by a submembrane plaque, consisting of numerous cytoskeletal and signaling molecules. Application of intrinsic or external forces to these structures dramatically affects their assembly and triggers adhesion-mediated signaling. In this review, we discuss the structure-function relationships of focal adhesions and the possible mode of action of the putative mechanosensor associated with them. We also discuss the general phenomenon of mechanosensitivity, and the approaches used to measure local forces at adhesion sites, the cytoskeleton-mediated regulation of local contractility, and the nature of the signaling networks that both affect contractility and are affected by it.
Structure, Function, and Regulation of Budding Yeast Kinetochores
Authors: McAinsh Andrew D. , Tytell Jessica D. , Sorger Peter K.
Published: October 2003

…S. cerevisiae centromeres represent the ultimate stage of centromere optimization… ( Malik & Henikoff 2002 )

Kinetochores are multiprotein complexes that assemble on centromeric DNA and mediate the attachment and movement of chromosomes along the microtubules (MTs) of the mitotic spindle. This review focuses on the simplest eukaryotic centromeres and kinetochores, those found in the budding yeast Saccharomyces cerevisiae. Research on kinetochore function and chromosome segregation is focused on four questions of general significance: What specifies the location of centromeres? What are the protein components of kinetochores, and how do they assemble a MT attachment site? How do MT attachments generate force? How do cells sense the state of attachment via the spindle assembly checkpoint?
Intraflagellar Transport
Authors: Scholey Jonathan M.
Published: October 2003

▪ Abstract  It has been a decade since a novel form of microtubule (MT)-based motility, i.e., intraflagellar transport (IFT), was discovered in Chlamydomonas flagella. Subsequent research has supported the hypothesis that IFT is required for the assembly and maintenance of all cilia and flagella and that its underlying mechanism involves the transport of nonmembrane-bound macromolecular protein complexes (IFT particles) along axonemal MTs beneath the ciliary membrane. IFT requires the action of the anterograde kinesin-II motors and the retrograde IFT-dynein motors to transport IFT particles in opposite directions along the MT polymer lattice from the basal body to the tip of the axoneme and back again. A rich diversity of biological processes has been shown to depend upon IFT, including flagellar length control, cell swimming, mating and feeding, photoreception, animal development, sensory perception, chemosensory behavior, and lifespan control. These processes reflect the varied roles of cilia and flagella in motility and sensory signaling.
The Dynamic and Motile Properties of Intermediate Filaments
Authors: Helfand Brian T. , Chang Lynne , Goldman Robert D.
Published: October 2003

▪ Abstract  For many years, cytoplasmic intermediate filaments (IFs) were considered to be stable cytoskeletal elements contributing primarily to the maintenance of the structural and mechanical integrity of cells. However, recent studies of living cells have revealed that IFs and their precursors possess a remarkably wide array of dynamic and motile properties. These properties are in large part due to interactions with molecular motors such as conventional kinesin, cytoplasmic dynein, and myosin. The association between IFs and motors appears to account for much of the well-documented molecular cross talk between IFs and the other major cytoskeletal elements, microtubules, and actin-containing microfilaments. Furthermore, the associations with molecular motors are also responsible for the high-speed, targeted delivery of nonfilamentous IF protein cargo to specific regions of the cytoplasm where they polymerize into IFs. This review considers the functional implications of the motile properties of IFs and discusses the potential relationships between malfunctions in these motile activities and human diseases.
Pigment Cells: A Model for the Study of Organelle Transport
Authors: Nascimento Alexandra A. , Roland Joseph T. , Gelfand Vladimir I.
Published: October 2003

▪ Abstract  Eukaryotic organisms rely on intracellular transport to position organelles and other components within their cells. Pigment cells provide an excellent model to study organelle transport as they specialize in the translocation of pigment granules in response to defined chemical signals. Pigment cells of lower vertebrates have traditionally been used as a model for these studies because these cells transport pigment organelles in a highly coordinated fashion, are easily cultured and transfected, are ideal for microsurgery, and are good for biochemical experiments, including in vitro analysis of organelle motility. Many important properties of organelle transport, for example, the requirement of two cytoskeletal filaments (actin and microtubules), the motor proteins involved, and the mechanisms of their regulation and interactions, have been studied using pigment cells of lower vertebrates. Genetic studies of mouse melanocytes allowed the discovery of essential elements involved in organelle transport including the myosin-Va motor and its receptor and adaptor molecules on the organelle surface. Future studies of pigment cells will contribute to our understanding of issues such as the cooperation among multiple motor proteins and the mechanisms of regulation of microtubule motors.
Actin Assembly and Endocytosis: From Yeast to Mammals
Authors: Engqvist-Goldstein Åsa E.Y. , Drubin David G.
Published: October 2003

▪ Abstract  Internalization of receptors, lipids, pathogens, and other cargo at the plasma membrane involves several different pathways and requires coordinated interactions between a variety of protein and lipid molecules. The actin cytoskeleton is an integral part of the cell cortex, and there is growing evidence that F-actin plays a direct role in these endocytic events. Genetic studies in yeast have firmly established a functional connection between actin and endocytosis. Identification of several proteins that may function at the interface between actin and the endocytic machinery has provided further evidence for this association in both yeast and mammalian cells. Several of these proteins are directly involved in regulating actin assembly and could thus harness forces produced during actin polymerization to facilitate specific steps in the endocytic process. Recent microscopy studies in mammalian cells provide powerful evidence that localized recruitment and polymerization of actin occurs at endocytic sites. In this review, we focus on progress made in elucidating the functions of the actin cytoskeleton in endocytosis.
Genetic Ablation of Caveolin-1 Confers Protection Against Atherosclerosis
Authors: Frank Philippe G. , Lee Hyangkyu , Park David S. , Tandon Narendra N. , Scherer Phillip E. , Lisanti Michael P.
Published: October 2003

Objective—

The development of atherosclerosis is a process characterized by the accumulation of lipids in the form of modified lipoproteins in the subendothelial space. This initiating step is followed by the subsequent recruitment and proliferation of other cell types, including monocytes/macrophages and smooth muscle cells. Here, we evaluate the potential role of caveolae membrane domains in the pathogenesis of atherosclerosis by using apolipoprotein E-deficient (ApoE−/−) mice as a model system.

Methods and Results—

Caveolin-1 (Cav-1) is a principal structural protein component of caveolae membrane domains. To directly assess the in vivo role of caveolae and Cav-1 in atherosclerosis, we interbred Cav-1−/− mice with ApoE−/− mice. Interestingly, loss of Cav-1 resulted in a dramatic >2-fold increase in non-HDL plasma cholesterol levels in the ApoE−/− background. However, despite this hypercholesterolemia, we found that loss of Cav-1 gene expression was clearly protective against the development of aortic atheromas, with up to an ≈70% reduction in atherosclerotic lesion area. Mechanistically, we demonstrated that loss of Cav-1 resulted in the dramatic downregulation of certain proatherogenic molecules, namely, CD36 and vascular cell adhesion molecule-1.

Conclusions—

Taken together, our results indicate that loss of Cav-1 can counteract the detrimental effects of atherogenic lipoproteins. Thus, Cav-1 is a novel target for drug development in the pharmacologic prevention of atheroma formation. Our current data also provide the first molecular genetic evidence to support the hypothesis that caveolar transcytosis of modified lipoproteins (from the blood to the sub-endothelial space) is a critical initiating step in atherosclerosis.
Time-Dependent and Tissue-Specific Accumulation of mtDNA and Respiratory Chain Defects in Chronic Doxorubicin Cardiomyopathy
Authors: Lebrecht Dirk , Setzer Bernhard , Ketelsen Uwe-Peter , Haberstroh Jörg , Walker Ulrich A.
Published: October 2003

Background—

Doxorubicin causes a chronic cardiomyopathy of unknown pathogenesis. We investigated whether acquired defects in mitochondrial DNA (mtDNA) and interconnected respiratory chain dysfunction may represent a molecular mechanism for its late onset.

Methods and Results—

Rats were treated weekly with intravenous doxorubicin (1 mg/kg) for 7 weeks, starting at 11 weeks of age (group B). Controls received saline. Group C received doxorubicin identically to group B, but the course was started at 41 weeks of age. All rats were killed at week 48. Doxorubicin was also injected once, either 6 days (group D) or 2 hours (group E) before euthanasia. Heart and skeletal muscle were examined. Only group B rats developed a significant clinical, macroscopic, histological, and ultrastructural cardiomyopathy. Group B hearts had the lowest cytochrome
c
oxidase (COX) activity (24% of controls;
P
=0.003), the highest citrate synthase activity (135% of controls;
P
=0.005), and the highest production of superoxide. In group B, the respiratory subunit COXI, which is encoded by mtDNA, was reduced (
P
<0.001), as was mtDNA (49% of controls,
P
<0.001). Group C hearts differed from group B in their lower cardiomyopathy score (
P
=0.006), higher COX activity (
P
=0.02), and higher mtDNA content (
P
=0.04). Group B and to a lesser extent group C hearts contained deleted mtDNA. There was no detectable mitochondrial toxicity in group D and E hearts or in skeletal muscle.

Conclusions—

In doxorubicin cardiomyopathy, mtDNA alterations, superoxide, and respiratory chain dysfunction accumulate long-term in the absence of the drug and are associated with a late onset.
Cariporide (HOE642), a Selective Na
+
-H
+
Exchange Inhibitor, Inhibits the Mitochondrial Death Pathway
Authors: Teshima Yasushi , Akao Masaharu , Jones Steven P. , Marbán Eduardo
Published: October 2003

Background—

The Na
+
-H
+
exchanger figures prominently in cardiac ischemia-reperfusion injury. Several experimental and clinical studies have demonstrated a cardioprotective effect of Na
+
-H
+
exchanger inhibition; however, the precise mechanisms have not been established.

Methods and Results—

We examined the effects of cariporide (HOE642, 10 μmol/L) on cell death induced by oxidative stress (H
2
O
2
, 100 μmol/L) in cultured neonatal rat cardiomyocytes. Cariporide significantly suppressed markers of cell death, such as TUNEL positivity and caspase-3 cleavage, at 8 or 16 hours after H
2
O
2
. The early phase of cell death, reported by increases in phosphatidylserine exposure and propidium iodide uptake, was also inhibited by cariporide. To explore the mechanisms of cell protection, we examined the effects of cariporide on increases in intracellular Na
+
and Ca
2+
induced by oxidative stress. Cariporide remarkably suppressed cytosolic Na
+
and Ca
2+
accumulation. Next, we investigated the effects of cariporide on mitochondria-associated death process. Mitochondrial Ca
2+
overload induced by H
2
O
2
was remarkably suppressed by cariporide. Loss of mitochondrial membrane potential is a critical step of the death pathway; cariporide prevented mitochondrial membrane potential loss induced by H
2
O
2
.

Conclusions—

Cariporide protects cardiomyocytes against oxidant-induced cell death by preserving intracellular ion homeostasis and mitochondrial integrity.
Inflammatory Markers and Onset of Cardiovascular Events
Authors: Cesari Matteo , Penninx Brenda W.J.H. , Newman Anne B. , Kritchevsky Stephen B. , Nicklas Barbara J. , Sutton-Tyrrell Kim , Rubin Susan M. , Ding Jingzhong , Simonsick Eleanor M. , Harris Tamara B. , Pahor Marco
Published: October 2003

Background—

Inflammation plays an important role in cardiovascular disease. The aim of this study is to investigate the predictive value of several inflammatory markers on the incidence of cardiovascular events in well-functioning older persons.

Methods and Results—

The subjects were 2225 participants 70 to 79 years old, without baseline cardiovascular disease, who were enrolled in the Health, Aging, and Body Composition study. Incident coronary heart disease (CHD), stroke, and congestive heart failure (CHF) events were detected during an average follow-up of 3.6 years. Blood levels of interleukin-6 (IL-6), C-reactive protein (CRP), and tumor necrosis factor-α (TNF-α) were assessed. After adjustment for potential confounders, IL-6 was significantly associated with all outcomes (CHD events, per IL-6 SD increase: RR, 1.27; 95% CI, 1.10 to 1.48; stroke events, per IL-6 SD increase: RR, 1.45; 95% CI, 1.12 to 1.86; CHF events, per IL-6 SD increase: RR, 1.72; 95% CI, 1.40 to 2.12). TNF-α showed significant associations with CHD (per TNF-α SD increase: RR, 1.22; 95% CI, 1.04 to 1.43) and CHF (per TNF-α SD increase: RR, 1.59; 95% CI, 1.30 to 1.95) events. CRP was significantly associated with CHF events (per CRP SD increase: RR, 1.48; 95% CI, 1.23 to 1.78). A composite summary indicator of inflammation showed a strong association with incident cardiovascular events, with an especially high risk if all 3 inflammatory markers were in the highest tertile.

Conclusions—

Findings suggest that inflammatory markers are independent predictors of cardiovascular events in older persons.
Long-Term Treatment With Oral Sildenafil Is Safe and Improves Functional Capacity and Hemodynamics in Patients With Pulmonary Arterial Hypertension
Authors: Michelakis Evangelos D. , Tymchak Wayne , Noga Michelle , Webster Linda , Wu Xi-Chen , Lien Dale , Wang Shao-Hua , Modry Dennis , Archer Stephen L.
Published: October 2003

Background—

The prognosis and functional capacity of patients with pulmonary arterial hypertension (PAH) is poor, and there is a need for safe, effective, inexpensive oral treatments. A single dose of sildenafil, an oral phosphodiesterase type-5 (PD-5) inhibitor, is an effective and selective pulmonary vasodilator in PAH. However, the long-term effects of PD-5 inhibition and its mechanism of action in human pulmonary arteries (PAs) are unknown.

Methods and Results—

We hypothesized that 3 months of sildenafil (50 mg orally every 8 hours) added to standard treatment would be safe and improve functional capacity and hemodynamics in PAH patients. We studied 5 consecutive patients (4 with primary pulmonary hypertension, 1 with Eisenmenger’s syndrome; New York Heart Association class II to III). Functional class improved by ≥1 class in all patients. Pretreatment versus posttreatment values (mean±SEM) were as follows: 6-minute walk, 376±30 versus 504±27 m,
P
<0.0001; mean PA pressure, 70±3 versus 52±3 mm Hg,
P
<0.007; pulmonary vascular resistance index 1702±151 versus 996±92 dyne · s · cm
−5
· m
−2
,
P
<0.006. The systemic arterial pressure was unchanged, and no adverse effects occurred. Sildenafil also reduced right ventricular mass measured by MRI. In 7 human PAs (6 cardiac transplant donors and 1 patient with PAH on autopsy), we showed that PD-5 is present in PA smooth muscle cells and that sildenafil causes relaxation by activating large-conductance, calcium-activated potassium channels.

Conclusion—

This small pilot study suggests that long-term sildenafil therapy might be a safe and effective treatment for PAH. At a monthly cost of $492 Canadian, sildenafil is more affordable than most approved PAH therapies. A large multicenter trial is indicated to directly compare sildenafil with existing PAH treatments.