bluuebunny/crossref_metadata_2025 huggingface dataset:
Randomised controlled trial of tetanus treatment with antitetanus immunoglobulin by the intrathecal or intramuscular route
Authors: Miranda-Filho Demócrito de Barros , Ximenes Ricardo Arraes de Alencar , Barone Antônio Alci , Vaz Vicente Luiz , Vieira Aderbal Gomes , Albuquerque Valéria Maria Gonçalves
Published: March 2004

Objective To evaluate the effect of intrathecal therapy with human antitetanus immunoglobulin on clinical progression of and mortality from tetanus.

Design Randomised controlled trial.

Setting Intensive care unit of a university hospital, Pernambuco, Brazil.

Participants 120 patients with tetanus allocated to antitetanus immunoglobulin by either the intrathecal and intramuscular route (n = 58) or the intramuscular route (n = 62; control group).

Main outcome measures Clinical progression of disease, duration of hospital stay, duration of occurrence of spasms, complications, respiratory infection, respiratory failure or mechanical ventilation, duration of respiratory assistance, and mortality.

Results Patients in the treatment group showed a better clinical progression than those in the control group (χ2 for trend 7.752, P = 0.005; difference in proportion of patients with improvement 20%, 95% confidence interval 4% to 35%). The duration of occurrence of spasms, hospital stay, and respiratory assistance were all shorter in patients the treatment group: respectively, 14.96, 0.0001 (difference in proportion of patients with spasms lasting ≤ 10 days 36%, 18% to 55%); 4.56, 0.03; and 6.56, 0.01 (proportion of patients who needed assistance for ≤ 10 days 69.2% in the treatment group and 30.8% in the control group (difference 38%, 12% to 65%)).

Conclusion Patients treated with antitetanus immunoglobulin by the intrathecal route show better clinical progression than those treated by the intramuscular route.
QUINTESSENCE AND THE CURVATURE OF THE UNIVERSE AFTER WMAP
Authors: AURICH RALF , STEINER FRANK
Published: March 2004

We study quintessence models with a constant (effective) equation of state. It is investigated whether such quintessence models are consistent with a negative spatial curvature of the Universe with respect to the anisotropy of the cosmic microwave background radiation measured by the WMAP mission. If the reionization is negligibly small, it is found that such models with negative curvature are admissible due to a geometrical degeneracy. However, a very high optical depth τ to the surface of last scattering, as indicated by the polarization measurements of WMAP, would rule out such models.
DETECTION OF NON-STATIONARY VARIATIONS OF METRICS BY INTERFERENCE METHODS
Authors: GOLOVASHKIN A. I. , KULESHOVA G. V. , TZHOVREBOV A. M. , IZMAILOV G. N.
Published: March 2004

The principal features in the detection of non-stationary undulatory metric disturbances based on interference effects are considered. The advantage for these the Aharonov–Bohm effect in superconductors in comparison with conventional optical interference is shown. Schemes of interferometric detectors with SQUID are offered.
REVISED CANONICAL QUANTUM GRAVITY VIA THE FRAME FIXING
Authors: MERCURI SIMONE , MONTANI GIOVANNI
Published: March 2004

We present a new reformulation of the canonical quantum geometrodynamics, which allows one to overcome the fundamental problem of the frozen formalism and, therefore, to construct an appropriate Hilbert space associate to the solution of the restated dynamics. More precisely, to remove the ambiguity contained in the Wheeler–DeWitt approach, with respect to the possibility of a (3+1)-splitting when space–time is in a quantum regime, we fix the reference frame (i.e. the lapse function and the shift vector) by introducing the so-called kinematical action. As a consequence the new super-Hamiltonian constraint becomes a parabolic one and we arrive to a Schrödinger-like approach for the quantum dynamics. In the semiclassical limit our theory provides General Relativity in the presence of an additional energy–momentum density contribution coming from non-zero eigenvalues of the Hamiltonian constraints. The interpretation of these new contributions comes out in natural way that soon as it is recognized that the kinematical action can be recasted in such a way that it describes a pressureless, but, in general, non-geodesic perfect fluid.
INTERMEDIATE-MASS BLACK HOLES
Authors: COLEMAN MILLER M. , COLBERT E. J. M.
Published: March 2004

The mathematical simplicity of black holes, combined with their links to some of the most energetic events in the universe, means that black holes are key objects for fundamental physics and astrophysics. Until recently, it was generally believed that black holes in nature appear in two broad mass ranges: stellar-mass (M~3–20 M⊙), which are produced by the core collapse of massive stars, and supermassive (M~106–1010 M⊙), which are found in the centers of galaxies and are produced by a still uncertain combination of processes. In the last few years, however, evidence has accumulated for an intermediate-mass class of black holes, with M~102–104 M⊙. If such objects exist they have important implications for the dynamics of stellar clusters, the formation of supermassive black holes, and the production and detection of gravitational waves. We review the evidence for intermediate-mass black holes and discuss future observational and theoretical work that will help clarify numerous outstanding questions about these objects.
QUARK STARS ADMITTING A ONE-PARAMETER GROUP OF CONFORMAL MOTIONS
Authors: MAK M. K. , HARKO T.
Published: March 2004

An exact analytical solution describing the interior of a charged strange quark star is found under the assumption of spherical symmetry and the existence of a one-parameter group of conformal motions. The solution describes a unique static charged configuration of quark matter with radius R=9.46 km and total mass M=2.86M⊙.
AUTOPARALLEL ORBITS IN KERR BRANS–DICKE SPACETIMES
Authors: CEBECI H. , DERELI T. , TUCKER R. W.
Published: March 2004

The bounded orbital motion of a massive spinless test particle in the background of a Kerr Brans–Dicke geometry is analysed in terms of worldlines that are auto-parallels of different metric compatible spacetime connections. In one case the connection is that of Levi–Civita with zero-torsion. In the second case the connection has torsion determined by the gradient of the Brans–Dicke background scalar field. The calculations permit one in principle to discriminate between these possibilities.
FRACTAL CHARACTERIZATION OF ULTRASONIC SIGNALS FROM POLYCRYSTALLINE MATERIALS
Authors: DUTTA DEBASHREE , GANGULY S.N. , BARAT P. , MUKHERJEE P. , BANDYOPADHYAY S.K. , SEN PINTU
Published: March 2004

For the first time the concept of fractal geometry is introduced to characterize discrete time domain ultrasonic signals scattered from polycrystalline materials aluminium and brass using the pulse echo method. The fractal dimension of these scattered signals was evaluated using the box counting method and power spectral method. These signals possess unique fractal dimension which remains invariant with the change in sampling rate of signal capturing. The fractal dimension evaluated by the above two methods remains constant in case of aluminium but gives remarkably different values for brass. This observation is interpreted on the basis of the variation of scattering mechanism in these two materials.
SEQUENCE GENERATING FUNCTIONS AND THE MULTIFRACTAL FORMALISM: APPLICATIONS TO BIOPOLYMERS
Authors: DEWEY T. GREGORY
Published: March 2004

Helix-coil configurations in biopolymers can be represented as a symbolic sequence of helix and coil units. A given configuration can be generated by progressing down the branches of a binary tree. The probability weighting of the branches in the tree will depend on the specific model under consideration. The multifractal nature of this binary tree can be described by an adaptation of a statistical mechanical formalism that uses sequence generating functions. It is seen that the sequence generating function approach is equivalent to transfer matrix methods for processes involving one-step memory. However, this new approach can have advantages over the transfer matrix for processes involving long term memory. Using this approach, the multifractal character of helix-coil transitions in two biopolymer models is explored. The Bragg-Zimm model of the alpha helix is analyzed and is seen to be equivalent in the transfer matrix approach to a 2×2 P model with one-step memory. The perfect matched double helix model is also explored. This model shows long range effects as a result of the entropy of loop formation. Because of this entropic effect, probabilities of continuous coil sequences decay with length slower than exponentially. This gives the model similar features to those observed in intermittent chaotic systems. These effects are readily handled within the sequence generating function formalism. The double helix model shows a phase transition and this is manifested as a discontinuity in the generalized dimension. For such models with long term memory, the sequence generating function approach provides a convenient formalism for exploring multifractal behavior.
FRACTAL TRACER PATTERNS IN OPEN HYDRODYNAMICAL FLOWS: THE CASE OF LEAPFROGGING VORTEX PAIRS
Authors: PÉNTEK Á. , TÉL T. , TOROCZKAI Z.
Published: March 2004

Patterns obtained by using tracer particles to visualize open hydrodynamical flows are investigated. As an example, the advection problem of passive tracers in the time-periodic velocity field of leapfrogging vortex pairs is considered. We show that the patterns are fractal if the tracer dynamics is chaotic, i.e., there exists a chaotic saddle, and if the initial conditions overlap with the stable manifold of this chaotic set (that is itself a fractal). Dye particles not advected away very quickly then accumulate on the unstable manifold of the chaotic saddle and the fractal dimension of such patterns is thus independent of the initial conditions. The time evolution of the fractal patterns appearing on snaphsots is followed within one period of the velocity field. We investigate which features of the chaotic dynamics determine the fractal properties. They turn out to be independent of when the snapshots are taken. The entropy function of the local Lyapunov exponents is computed based on the scattering motion of the tracer particles, along with the f(α) spectrum of the chaotic saddle.
FINITE CORRELATION DIMENSION AND POSITIVE LYAPUNOV EXPONENTS FOR SURFACE WAVE DATA IN THE ADRIATIC SEA NEAR VENICE
Authors: BERGAMASCO L. , SERIO M. , OSBORNE A.R. , CAVALERI L.
Published: March 2004

We study wind-driven surface wave data taken on an offshore platform in 16 m of water, about 20 km from Venice in the Northern Adriatic Sea. The data are investigated for the effects of chaos and to this end they are subjected to a variety of time series analysis techniques from the field of dynamical systems theory. For certain data sets we find a finite value for the correlation dimension (~7) and a positive value for the largest Lyapunov exponent (~1.5×10−3 bit/sec). In spite of the fact that these results suggest the possibility of chaotic behavior in the data, the correct interpretation is that the data are essentially stochastic, and that the correlation dimensions and Lyapunov exponents result from the anomalous statistical behavior of certain near-Gaussian random processes whose properties we discuss.
CRACK GROWTH IN SOLID WITH MANY INITIAL DEFECTS
Authors: NISHIUMA SABUROU , MIYAZIMA SASUKE
Published: March 2004

Hydrogen-induced fracture of steel is characterized by the formation of internal voids caused by hydrogen precipitation at an inclusion-matrix interface, followed by the formation of microcrack array under the superposed action of internal hydrogen pressure and external forces. The propagation of the hydrogen-induced fracture is considerably random and the fracture develops by stepwise linking of the microcracks.

We present a new fracture model describing the patterns of crack growth by hydrogen embrittlement to find a generic feature of delayed fracture. Crack growth in solid with many initial defects is studied by Monte Carlo simulation on a square lattice. By analyzing time-dependent cluster size distribution of crack and its dynamic scaling, it is found that the crack growth process has a fractal structure. “Percolation of cracks” which corresponds to macroscopic breakdown of materials is also investigated.
SHADOWS IN A SELF-AFFINE LANDSCAPE
Authors: HANSEN ALEX , PLOURABOUÉ FRANCK , ROUX STÉPHANE
Published: March 2004

We study the distribution of shadows cast in a self-affine landscape. For incidental parallel light forming an angle θ with the basal plane of the landscape, we find that the percentage of the landscape which is illuminated scales as δM=(tan θ)−1/(1−H), where H is the Hurst exponent. The distribution of shadow lengths measured along a cut in the landscape parallel to the incidental light has the form N(δ, θ)=(1/δδM)ϕ(δ/δM), where δ is the length of a shadow, and ϕ is a scaling function whose behavior for small arguments is ϕ(x)∝x−H. We support and illustrate our results with numerical simulations. They form the basis for an efficient method to study self-affine surfaces, and should be of particular interest, for example, in the planetary sciences and fractography.
TREE PATTERNS ON VISCOUS PASTE SURFACES
Authors: TARAFDAR S. , ROY S.
Published: March 2004

A simple method for producing tree-like patterns on a layer of highly viscous paste is reported. The patterns are found to be fractal. A computer simulation reproduces the principal characteristics of the patterns fairly well. Such studies may provide insights into complex processes of viscous fingering and invasion percolation.
STUDIES OF THE CHANGE RATES OF CAPACITY DIMENSION AND INFORMATION DIMENSION AND EARTHQUAKE PREDICTION IN 11 SEISMIC ZONES OF SICHUAN-YUNNAN AREA
Authors: HAN WEIBIN , WANG WEIEN
Published: March 2004

In this paper, temporal curves of capacity dimension D0 and information dimension D1 are calculated with time window of one year and sliding step of half-a-year by using data of 11 seismic zones in the Sichuan-Yunnan area. The possibility of using the change rates of D0 and D1 to predict whether an M≥5 earthquake will occur in the next half-a-year in the seismic zone is discussed. Generally speaking, it is possible to obtain grading values R which are different from those of random prediction. It is demonstrated that the use of the change rates of capacity dimension and information dimension for earthquake prediction has certain prospects.
GEOMETRY OF CONTACT BETWEEN SELF-AFFINE SURFACES
Authors: PLOURABOUÉ FRANCK , ROUX STÉPHANE , SCHMITTBUHL JEAN , VILOTTE JEAN-PIERRE
Published: March 2004

We study the geometry of the contact between two rigid self-affine surfaces. We investigate the mean shape of the surface in the vicinity of the contact point as well as the probability distribution of apertures a as a function of the distance to the contact point. The latter reveals two distinct scaling regimes which are characterized. We show that as the two surfaces are shifted with respect to each other, the contact point on one surface undergoes a “Levy walk”. If u is the relative shift of the surfaces, the distance d between the two contact points (before and after the shift), scales as d ∝ uα where the exponent α is shown to be equal to the roughness exponent of the surfaces.
MINIMUM ENERGY DISSIPATION AND FRACTAL STRUCTURES OF VASCULAR SYSTEMS
Authors: SUN TAO , MEAKIN PAUL , JØSSANG TORSTEIN
Published: March 2004

A two dimensional minimum energy dissipation rate model has been used to study the structure of vascular networks. The geometry of the resulting minimum energy dissipation rate vascular system (MEDVS) has been studied. The structures of MEDVS networks are self-similar and have a fractal dimension of 2 on long length scales with a crossover to a fractal dimension of 1 on short length scales. A power-law distribution of link energy dissipation rates was found. The MEDVS networks have also been studied in terms of their transport properties.
CHAOS AND FRACTALS AROUND BLACK HOLES
Authors: DETTMANN C.P. , FRANKEL N.E. , CORNISH N.J.
Published: March 2004

Fractal basin boundaries provide an important means of characterizing chaotic systems. We apply these ideas to general relativity, where other properties such as Lyapunov exponents are difficult to define in an observer independent manner. Here we discuss the difficulties in describing chaotic systems in general relativity and investigate the motion of particles in two and three black hole spacetimes. We show that the dynamics is chaotic by exhibiting the basins of attraction of the black holes which have fractal boundaries. Overcoming problems of principle as well as numerical difficulties, we evaluate Lyapunov exponents numerically and find that some trajectories have a positive exponent.
ESTIMATION AND SIMULATION OF FRACTAL STOCHASTIC POINT PROCESSES
Authors: LOWEN STEVEN B. , TEICH MALVIN C.
Published: March 2004

We investigate the properties of fractal stochastic point processes (FSPPs). First, we define FSPPs and develop several mathematical formulations for these processes, showing that over a broad range of conditions they converge to a particular form of FSPP. We then provide examples of a wide variety of phenomena for which they serve as suitable models. We proceed to examine the analytical properties of two useful fractal dimension estimators for FSPPs, based on the second-order properties of the points. Finally, we simulate several FSPPs, each with three specified values of the fractal dimension. Analysis and simulation reveal that a variety of factors confound the estimate of the fractal dimension, including the finite length of the simulation, structure or type of FSPP employed, and fluctuations inherent in any FSPP. We conclude that for segments of FSPPs with as many as 106 points, the fractal dimension can be estimated only to within ±0.1.
EXACT SOLUTIONS FOR A CLASS OF FRACTAL TIME RANDOM WALKS
Authors: HILFER R.
Published: March 2004

Fractal time random walks with generalized Mittag-Leffler functions as waiting time densities are studied. This class of fractal time processes is characterized by a dynamical critical exponent 0<ω≤1, and is equivalently described by a fractional master equation with time derivative of noninteger order ω. Exact Greens functions corresponding to fractional diffusion are obtained using Mellin transform techniques. The Greens functions are expressible in terms of general H-functions. For ω<1 they are singular at the origin and exhibit a stretched Gaussian form at infinity. Changing the order ω interpolates smoothly between ordinary diffusion ω=1 and completely localized behavior in the ω→0 limit.
THE RELATIONSHIP BETWEEN FRACTIONAL CALCULUS AND FRACTALS
Authors: TATOM FRANK B.
Published: March 2004

The general relationship between fractional calculus and fractals is explored. Based on prior investigations dealing with random fractal processes, the fractal dimension of the function is shown to be a linear function of the order of fractional integro-differentiation. Emphasis is placed on the proper application of fractional calculus to the function of the random fractal, as opposed to the trail. For fractional Brownian motion, the basic relations between the spectral decay exponent, Hurst exponent, fractal dimension of the function and the trail, and the order of the fractional integro-differentiation are developed.

Based on an understanding of fractional calculus applied to random fractal functions, consideration is given to an analogous application to deterministic or nonrandom fractals. The concept of expressing each coordinate of a deterministic fractal curve as a “pseudo-time” series is investigated. Fractional integro-differentiation of such series is numerically carried out for the case of quadric Koch curves. The resulting time series produces self-similar patterns with fractal dimensions which are linear functions of the order of the fractional integro-differentiation. These curves are assigned the name, fractional Koch curves. The general conclusion is reached that fractional calculus can be used to precisely change or control the fractal dimension of any random or deterministic fractal with coordinates which can be expressed as functions of one independent variable, which is typically time (or pseudo-time).
THE HEART RATE AND HEART RATE VARIABILITY AFTER COMMENCEMENT OF EXERCISE ARE FRACTALS
Authors: KUO CHENG-DENG , TSAI YUH-SHOW , WANG YAR-YI , CHIANG BENJAMIN N.
Published: March 2004

It is already well known that exercise can result in acceleration of heart rate (HR) and progressive withdrawal of vagal activity. However, the ways in which HR and the heart rate variability (HRV) change progressively during the initial stage of exercise have not been fully investigated. The aim of this study is to find a suitable mathematical description for the temporal evolutions of HR and HRV after the initiation of exercise, and to search for possible relation between HR and HRV during exercise in normal subjects. The index of HRV used in this study was the standard deviation (SD) of the heart beat intervals (RRI) measured within sequential steps of predetermined sampling period, and the HR is the inverse of the mean (Mn) of the RRI. We found that both Mn and SD of the RRI decrease progressively with increasing exercise time after the initiation of exercise. The temporal evolutions of both Mn and SD during exercise can be better described by power-law scaling relations. When different sampling periods were used in the calculation of Mn and SD of the RRI, there is self-similarity in time in the distribution of Mn and SD . These findings demonstrated that both HR and HRV after the initiation of exercise are temporal fractals. Fractal dimensions Dm and Ds, defined from the scaling exponents of the power-law scaling relations for HR and HRV, determine the rate of increase in HR and the rate of decrease in HRV after the initiation of exercise, respectively. Because of the fractal nature of HR and HRV during the early phase of exercise, the relation between HR and HRV during exercise can also be described by power-law scaling relation. Consequently, the HRV during exercise is inversely related to HR.
OPTIMAL SPACED SEEDS FOR HOMOLOGOUS CODING REGIONS
Authors: BREJOVÁ BROŇA , BROWN DANIEL G. , VINAŘ TOMÁŠ
Published: March 2004

Optimal spaced seeds were developed as a method to increase sensitivity of local alignment programs similar to BLASTN. Such seeds have been used before in the program PatternHunter, and have given improved sensitivity and running time relative to BLASTN in genome–genome comparison. We study the problem of computing optimal spaced seeds for detecting homologous coding regions in unannotated genomic sequences. By using well-chosen seeds, we are able to improve the sensitivity of coding sequence alignment over that of TBLASTX, while keeping runtime comparable to BLASTN. We identify good seeds by first giving effective hidden Markov models of conservation in alignments of homologous coding regions. We give an efficient algorithm to compute the optimal spaced seed when conservation patterns are generated by these models. Our results offer the hope of improved gene finding due to fewer missed exons in DNA/DNA comparison, and more effective homology search in general, and may have applications outside of bioinformatics.
KERNEL-BASED SELF-ORGANIZED MAPS TRAINED WITH SUPERVISED BIAS FOR GENE EXPRESSION DATA ANALYSIS
Authors: PAPADIMITRIOU STERGIOS , LIKOTHANASSIS SPIRIDON D.
Published: March 2004

Self-Organized Maps (SOMs) are a popular approach for analyzing genome-wide expression data. However, most SOM based approaches ignore prior knowledge about functional gene categories. Also, Self Organized Map (SOM) based approaches usually develop topographic maps with disjoint and uniform activation regions that correspond to a hard clustering of the patterns at their nodes. We present a novel Self-Organizing map, the Kernel Supervised Dynamic Grid Self-Organized Map (KSDG-SOM). This model adapts its parameters in a kernel space. Gaussian kernels are used and their mean and variance components are adapted in order to optimize the fitness to the input density. The KSDG-SOM also grows dynamically up to a size defined with statistical criteria. It is capable of incorporating a priori information for the known functional characteristics of genes. This information forms a supervised bias at the cluster formation and the model owns the potentiality of revising incorrect functional labels. The new method overcomes the main drawbacks of most of the existing clustering methods that lack a mechanism for dynamical extension on the basis of a balance between unsupervised and supervised drives.
DEVELOPING OPTIMAL PREDICTION MODELS FOR CANCER CLASSIFICATION USING GENE EXPRESSION DATA
Authors: SOUKUP MAT , LEE JAE K.
Published: March 2004

Microarrays can provide genome-wide expression patterns for various cancers, especially for tumor sub-types that may exhibit substantially different patient prognosis. Using such gene expression data, several approaches have been proposed to classify tumor sub-types accurately. These classification methods are not robust, and often dependent on a particular training sample for modelling, which raises issues in utilizing these methods to administer proper treatment for a future patient. We propose to construct an optimal, robust prediction model for classifying cancer sub-types using gene expression data. Our model is constructed in a step-wise fashion implementing cross-validated quadratic discriminant analysis. At each step, all identified models are validated by an independent sample of patients to develop a robust model for future data. We apply the proposed methods to two microarray data sets of cancer: the acute leukemia data by Golub et al.3and the colon cancer data by Alon et al.12We have found that the dimensionality of our optimal prediction models is relatively small for these cases and that our prediction models with one or two gene factors outperforms or has competing performance, especially for independent samples, to other methods based on 50 or more predictive gene factors. The methodology is implemented and developed by the procedures in R and Splus. The source code can be obtained at .
DEVELOPMENT OF IMAGE PROCESSING PROGRAM FOR YEAST CELL MORPHOLOGY
Authors: OHTANI MIWAKA , SAKA AYAKA , SANO FUMI , OHYA YOSHIKAZU , MORISHITA SHINICHI
Published: March 2004

Every living organism has its own species-specific morphology. Despite the relatively simple ellipsoidal shape of budding yeast cells, the global regulation of yeast morphology remains unclear. In the past, each mutated gene from many mutants with abnormal morphology had to be classified manually. To investigate the morphological characteristics of yeast in detail, we developed a novel image-processing program that extracts quantitative data from microscope images automatically. This program extracts data on cells that are often used by yeast morphology researchers, such as cell size, roundness, bud neck position angle, and bud growth direction, and fits an ellipse to the cell outline. We evaluated the ability of the program to extract quantitative parameters. The results suggest that our image-processing program can play a central objective role in yeast morphology studies.
DYNAMIC INTEGRATION OF GENE ANNOTATION AND ITS APPLICATION TO MICROARRAY ANALYSIS
Authors: DAI HENG , TIAN BIN , ZHAO WEI D. , LEUNG ALBERT , SMITH SIMON R. , WAN JACKSON S. , YAO XIANG
Published: March 2004

Comprehensive and structured annotations for all genes on a microarray chip are essential for the interpretation of its expression data. Currently, most chip gene annotations are one-line free text descriptions that are often partial, outdated and unsuitable for large-scale data analysis. Therefore the interpretation of microarray gene expression clusters is often limited. Although researchers can manually navigate a collection of databases for better annotations, it is only practical for limited number of genes. Existing meta-databases fail to provide comprehensive categorized annotations for hundreds of genes simultaneously. We have developed an automatic system to address this issue.

GeneView system monitors various data sources, extracts gene information from a source whenever it is updated, comprehensively matches genes, and integrates them into a central database by categories, such as pathway, genetic mapping, phenotype, expression profile, domain structure, protein interaction, disease association, and references. The system consists of four major components: (1) relational database; (2) data processing; (3) user curation; (4) data query. We evaluated it by analyzing genes on cDNA and Affymetrix Oligo chips. In both cases, the system provided more accurate and comprehensive information than those provided by the vendors or the chip users, and helped identify new common functions among genes in the same expression clusters.
GENERATION OF A LARGE GENE/PROTEIN LEXICON BY MORPHOLOGICAL PATTERN ANALYSIS
Authors: TANABE LORRAINE , WILBUR W. JOHN
Published: March 2004

The identification of gene/protein names in natural language text is an important problem in named entity recognition. In previous work we have processed MEDLINE© documents to obtain a collection of over two million names of which we estimate that perhaps two thirds are valid gene/protein names. Our problem has been how to purify this set to obtain a high quality subset of gene/protein names. Here we describe an approach which is based on the generation of certain classes of names that are characterized by common morphological features. Within each class inductive logic programming (ILP) is applied to learn the characteristics of those names that are gene/protein names. The criteria learned in this manner are then applied to our large set of names. We generated 193 classes of names and ILP led to criteria defining a select subset of 1,240,462 names. A simple false positive filter was applied to remove 8% of this set leaving 1,145,913 names. Examination of a random sample from this gene/protein name lexicon suggests it is composed of 82% (±3%) complete and accurate gene/protein names, 12% names related to genes/proteins (too generic, a valid name plus additional text, part of a valid name, etc.), and 6% names unrelated to genes/proteins. The lexicon is freely available at .
DISSECTING THE HUMAN SPLICEOSOME THROUGH BIOINFORMATICS AND PROTEOMICS APPROACHES
Authors: PERES LOPES GRAZIELA MIÊ , DE SOUZA SANDRO JOSÉ
Published: March 2004

The precise excision of introns from mRNAs is executed by the spliceosome, a cellular machinery composed by five small nuclear RNAs and hundreds of proteins. In the last few years, several groups have used proteomics and computational biology tools to characterize the components of the human spliceosome. These reports have identified basically all known splicing factors and several new proteins. The composition of the human spliceosome confirms the link between splicing and other steps in gene expression. Here we comment on these reports and discuss the perspectives for the coming years.
DISCOVERING PROTEIN–PROTEIN INTERACTIONS
Authors: NG SEE-KIONG , TAN SOON-HENG
Published: March 2004

The ongoing genomics and proteomics efforts have helped identify many new genes and proteins in living organisms. However, simply knowing the existence of genes and proteins does not tell us much about the biological processes in which they participate. Many major biological processes are controlled by protein interaction networks. A comprehensive description of protein–protein interactions is therefore necessary to understand the genetic program of life. In this tutorial, we provide an overview of the various current high-throughput methods for discovering protein–protein interactions, covering both the conventional experimental methods and new computational approaches.
Mechanism and regulation of folate uptake by human pancreatic epithelial MIA PaCa-2 cells
Authors: Nabokina Svetlana M. , Ma Thomas Y. , Said Hamid M.
Published: March 2004

After the liver, the pancreas contains the second highest level of folate among human tissues, and folate deficiency adversely affects its physiological function. Despite that, nothing is currently known about the cellular mechanisms involved in folate uptake by cells of this important exocrine organ or about folate uptake regulation. We have begun to address these issues, and in this report we present the results of our findings on the mechanism of folate uptake by the human-derived pancreatic MIA PaCa-2 cells. Our results show folic acid uptake to be 1) temperature and energy dependent; 2) pH dependent, with a markedly higher uptake at acidic pH compared with neutral or alkaline pH; 3) Na+ independent; 4) saturable as a function of substrate concentration (apparent Km = 0.762 ± 0.10 μM); 5) inhibited (with similar affinity) by reduced, substituted, and oxidized folate derivatives; and 6) sensitive to the inhibitory effect of anion transport inhibitors. RT-PCR and Western blot analysis showed expression of the human reduced folate carrier (hRFC) at the RNA and protein levels, respectively. The functional contribution of hRFC in carrier-mediated folate uptake was confirmed by gene silencing using gene-specific small interfering RNA. Evidence also was found suggesting that the folate uptake process by MIA PaCa-2 cells is regulated by cAMP- and protein tyrosine kinase (PTK)-mediated pathways. These studies demonstrate for the first time the involvement of a specialized, acidic pH-dependent, carrier-mediated mechanism for folate uptake by human pancreatic MIA PaCa-2 cells. The results also show the involvement of hRFC in the uptake process and suggest the possible involvement of intracellular cAMP- and PTK-mediated pathways in the regulation of folate uptake.
Permeabilities of teleost and elasmobranch gill apical membranes: evidence that lipid bilayers alone do not account for barrier function
Authors: Hill Warren G. , Mathai John C. , Gensure Rebekah H. , Zeidel Joshua D. , Apodaca Gerard , Saenz James P. , Kinne-Saffran Evamaria , Kinne Rolf , Zeidel Mark L.
Published: March 2004

Teleosts and elasmobranchs faced with considerable osmotic challenges living in sea water, use compensatory mechanisms to survive the loss of water (teleosts) and urea (elasmobranchs) across epithelial surfaces. We hypothesized that the gill, with a high surface area for gas exchange must have an apical membrane of exceptionally low permeability to prevent equilibration between seawater and plasma. We isolated apical membrane vesicles from the gills of Pleuronectes americanus (winter flounder) and Squalus acanthias (dogfish shark) and demonstrated approximately sixfold enrichment of the apical marker, ADPase compared to homogenate. We also isolated basolateral membranes from shark gill (enriched 2.3-fold for Na-K-ATPase) and using stopped-flow fluorometry measured membrane permeabilities to water, urea, and NH3. Apical membrane water permeabilities were similar between species and quite low (7.4 ± 0.7 × 10−4 and 6.6 ± 0.8 × 10−4 cm/s for shark and flounder, respectively), whereas shark basolateral membranes showed twofold higher water permeability (14 ± 2 × 10−4 cm/s). Permeabilities to urea and NH3 were also low in apical membranes. Because of the much lower apical to basolateral surface area we conclude that the apical membrane represents an effective barrier. However, the values we obtained were not low enough to account for low water loss (teleosts) and urea loss (elasmobranchs) measured in vivo by others. We conclude that there are other mechanisms which permit gill epithelia to serve as effective barriers. This conclusion has implications for the function of other barrier epithelia, such as the gastric mucosa, mammalian bladder, and renal thick ascending limb.
Effects of intracellular acidification and varied temperature on force, stiffness, and speed of shortening in frog muscle fibers
Authors: Radzyukevich T. , Edman K. A. P.
Published: March 2004

This study aimed to establish whether the temperature-dependent effect of acidification on maximum force observed in mammalian muscles also applies to frog muscle. Measurements of force, stiffness, and unloaded velocity of shortening in intact single muscle fibers from the anterior tibialis muscle of Rana temporaria were performed between 0 and 22°C during fused tetani in H2CO3-CO2-buffered Ringer solution with pH adjusted to 7.0 and 6.3, respectively. The force-to-stiffness ratio increased as a rectilinear function of temperature between 0 and 20°C at pH 7.0. Lowering the pH to 6.3 reduced the tetanic force by 13.5 ± 1.2 and 11.5 ± 1.4% at 2.8 and 20.5°C, respectively, with only a minor reduction in fiber stiffness. The maximum speed of shortening was decreased by lowered pH by 12.9 ± 1.5 and 7.8 ± 1.1% at low and high temperature, respectively. Acidification increased the time to reach 70% of maximum force by 18.0% at ∼2°C; the same pH change performed at ∼20°C in the same fibers reduced the rise time by 24.1%. The same increase in the rate of rise of force at high temperature was also found at normal pH after the fibers were fatigued by frequent stimulation. It is concluded that, in frog muscle, the force-depressant effect of acidification does not vary significantly with temperature. By contrast, acidification affects the onset of activation in a manner that is critically dependent on temperature.
Potassium depletion improves myocardial potassium uptake in vivo
Authors: Bundgaard Henning
Published: March 2004

Potassium depletion (KD) is a very common clinical entity often associated with adverse cardiac effects. KD is generally considered to reduce muscular Na-K-ATPase density and secondarily reduce K uptake capacity. In KD rats we evaluated myocardial Na-K-ATPase density, ion content, and myocardial K reuptake. KD for 2 wk reduced plasma K to 1.8 ± 0.1 vs. 3.5 ± 0.2 mM in controls ( P < 0.01, n = 7), myocardial K to 80 ± 1 vs. 86 ± 1 μmol/g wet wt ( P < 0.05, n = 7), increased Mg, and induced a tendency to increased Na. Myocardial Na-K-ATPase α2-subunit abundance was reduced by ∼30%, whereas increases in α1- and K-dependent pNPPase activity of 24% ( n = 6) and 13% ( n = 6), respectively, were seen. This indicates an overall upregulation of the myocardial Na-K pump pool. KD rats tolerated a higher intravenous KCl dose. KCl infusion until animals died increased myocardial K by 34% in KD rats and 18% in controls ( P < 0.05, n = 6 for both) but did not induce different net K uptake rates between groups. However, clamping plasma K at ∼5.5 mM by KCl infusion caused a higher net K uptake rate in KD rats (0.22 ± 0.04 vs. 0.10 ± 0.03 μmol·g wet wt−1·min−1; P < 0.05, n = 8). In conclusion, a minor KD-induced decrease in myocardial K increased Na-K pump density and in vivo increased K tolerance and net myocardial K uptake rate during K repletion. Thus the heart is protected from major K losses and accumulates considerable amounts of K during exposure to high plasma K. This is of clinical interest, because a therapeutically induced rise in myocardial K may affect contractility and impulse generation-propagation and may attenuate increased myocardial Na, the hallmark of heart failure.
Potentiating role of IGFBP-2 on IGF-II-stimulated alkaline phosphatase activity in differentiating osteoblasts
Authors: Palermo Claudia , Manduca Paola , Gazzerro Elisabetta , Foppiani Luca , Segat Daniela , Barreca Antonina
Published: March 2004

The insulin-like growth factor (IGF) system plays an important role in the autocrine and paracrine regulation of bone formation and remodeling. The aim of this study was to evaluate the role of the autocrine IGF system during osteogenic differentiation in rat tibial osteoblasts (ROB) in culture. In this in vitro model, the stages of osteogenesis studied were S1, corresponding to the onset of alkaline phosphatase (AP) expression ( days 0-3); S2, coincident with the peak of AP expression in differentiation culture conditions ( days 4-6), and S3, corresponding to the onset of mineral deposition in the extracellular matrix ( days 7-9). The results showed that conditioned medium of ROB contains greater amounts of IGF-II than IGF-I at all differentiation stages. Both peptides showed the highest concentrations on day 3 of differentiation (end of S1). All IGF-binding proteins (IGFBPs), except IGFBP-1 and -6, were detected, and IGFBP-2 was the most abundant IGFBP present in the conditioned media, and its degradation increased from S1 to S3. By semiquantitative RT-PCR, IGF-I and IGF-II were highly expressed on days 3 and 6, whereas IGFBP-2 was constantly expressed. We focused our study on the role of IGF-II and IGFBP-2 on the synthesis of AP, an early marker of osteoblast maturation. The results showed that a significant increase in AP expression was induced by IGF-II added to the differentiating osteoblasts continuously or in S1 but not in S2 or S3. IGFBP-2 was able to potentiate endogenous and exogenous IGF-II-dependent stimulation of AP activity, and its proteolytic degradation in late stages of osteogenesis (S2 and S3) was highly correlated with the increase of active matrix metalloproteinase-2 in the CM and with the decreased efficacy of IGF-II action. These data suggest that IGFBP-2, at nearly equimolar concentration with IGF-II, plays a potentiating role in IGF-II action on ROB differentiation in vitro.
Cortisol rapidly suppresses intracellular calcium and voltage-gated calcium channel activity in prolactin cells of the tilapia (Oreochromis mossambicus)
Authors: Hyde Gregory N. , Seale Andre P. , Grau E. Gordon , Borski Russell J.
Published: March 2004

Cortisol was previously shown to rapidly (10-20 min) reduce the release of prolactin (PRL) from pituitary glands of tilapia ( Oreochromis mossambicus). This inhibition of PRL release by cortisol is accompanied by rapid reductions in45Ca2+and cAMP accumulation. Cortisol's early actions occur through a protein synthesis-independent pathway and are mimicked by a membrane-impermeable analog. The signaling pathway that mediates rapid, nongenomic membrane effects of glucocorticoids is poorly understood. Using the advantageous characteristics of the teleost pituitary gland from which a nearly pure population of PRL cells can be isolated and incubated in defined medium, we examined whether cortisol rapidly reduces intracellular free calcium ([Formula: see text]) and suppresses L-type voltage-gated ion channel activity in events that lead to reduced PRL release. Microspectrofluorometry, used in combination with the Ca2+-sensitive dye fura 2 revealed that cortisol reversibly reduces basal and hyposmotically induced [Formula: see text] within seconds ( P < 0.001) in dispersed pituitary cells. Somatostatin, a peptide known to inhibit PRL release through a membrane receptor-coupled mechanism, similarly reduces [Formula: see text]. Under depolarizing [K+], the L-type calcium channel agonist BAY K 8644, a factor known to delay the closing of L-type Ca2+channels, stimulates PRL release in a concentration-dependent fashion ( P < 0.01). Cortisol (and somatostatin) blocks BAY K 8644-induced PRL release ( P < 0.01; 30 min), well within the time course over which its actions occur, independent of protein synthesis and at the level of the plasma membrane. Results indicate that cortisol inhibits tilapia PRL release through rapid reductions in [Formula: see text] that likely involve an attenuation of Ca2+entry through L-type voltage-gated Ca2+channels. These results provide further evidence that glucocorticoids rapidly modulate hormone secretion via a membrane-associated mechanism similar to that observed with the fast effects of peptides and neurotransmitters.
Adipose tissue triglyceride turnover, de novo lipogenesis, and cell proliferation in humans measured with2H2O
Authors: Strawford A. , Antelo F. , Christiansen M. , Hellerstein M. K.
Published: March 2004

The turnover of adipose tissue components (lipids and cells) and the pathways of adipose lipid deposition have been difficult to measure in humans. We apply here a2H2O long-term labeling technique for concurrent measurement of adipose-triglyceride (TG) turnover, cell (DNA) proliferation, and de novo lipogenesis (DNL). Healthy subjects drank2H2O (70 ml/day) for 5-9 wk. Subcutaneous adipose tissue aspirates were taken (gluteal, thigh, and flank depots). Deuterium incorporation into TG glycerol (representing all-source TG synthesis), TG palmitate (representing DNL, by mass isotopomer distribution analysis), and DNA (representing cell proliferation) was measured by gas chromatography-mass spectrometry. Subjects tolerated the protocol well, and body2H2O enrichments were stable. Mean TG-glycerol fractional synthesis was 0.12 (i.e., 12%) with a range of 0.03-0.32 after 5 wk and 0.20 (range 0.08-0.49) after 9 wk (TG half-life 200-270 days). Label decay measurements 5-8 mo after discontinuing2H2O gave similar turnover estimates. Net lipolysis (TG turnover) was 50-60 g/day. DNL contribution to adipose-TG was 0.04 after 9 wk, representing ∼20% of newly deposited TG. Cell proliferation was 0.10-0.17 after 9 wk (half-life 240-425 days). In summary, long-term2H2O administration to human subjects allows measurement of the dynamics of adipose tissue components. Turnover of all elements is slow, and DNL contributes ∼20% of new TG.
Orexin A (hypocretin 1) injected into hypothalamic paraventricular nucleus and spontaneous physical activity in rats
Authors: Kiwaki Kohji , Kotz Catherine M. , Wang Chuanfeng , Lanningham-Foster Lorraine , Levine James A.
Published: March 2004

In humans, nonexercise activity thermogenesis (NEAT) increases with positive energy balance. The mediator of the interaction between positive energy balance and physical activity is unknown. In this study, we address the hypothesis that orexin A acts in the hypothalamic paraventricular nucleus (PVN) to increase nonfeeding-associated physical activity. PVN-cannulated rats were injected with either orexin A or vehicle during the light and dark cycle. Spontaneous physical activity (SPA) was measured using arrays of infrared activity sensors and night vision videotaped recording (VTR). O2 consumption and CO2 production were measured by indirect calorimetry. Feeding behavior was assessed by VTR. Regardless of the time point of injection, orexin A (1 nmol) was associated with dramatic increases in SPA for 2 h after injection (orexin A: 6.27 ± 1.95 × 103 beam break count, n = 24; vehicle: 1.85 ± 1.13 × 103, n = 38). This increase in SPA was accompanied by compatible increase in O2 consumption. Duration of feeding was increased only when orexin A was injected in the early light phase and accounted for only 3.5 ± 2.5% of the increased physical activity. In a dose-response experiment, increases in SPA were correlated with dose of orexin A linearly up to 2 nmol. PVN injections of orexin receptor antagonist SB-334867 were associated with decreases in SPA and attenuated the effects of PVN-injected orexin A. Thus orexin A can act in PVN to increase nonfeeding-associated physical activity, suggesting that this neuropeptide might be a mediator of NEAT.