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PubMed2003

Molecular dynamics simulations on SDF-1alpha: binding with CXCR4 receptor.

Insights into the interacting mode of CXCR4 with SDF-1alpha are crucial in understanding the structural and functional characteristics of CXCR4 receptor. In this paper a computational pipeline, integrating protein structure prediction, molecular dynamics simulations, automated molecular docking, and Brownian dynamics simulations were employed to investigate the dynamic and energetic aspects of CXCR4 associating with SDF-1alpha. The entire simulation revealed the surface distribution feature of electrostatic potentials and conformational "open-close" process of the receptor. The possible binding conformation of CXCR4 was identified, and the CXCR4-SDF-1alpha binding complex was generated. Arg188-Glu277 salt bridge plays an important role for both the extracellular domain conformational change and SDF-1alpha binding. Two binding sites were mapped at the extracellular domain (Site 1) and inside the transmembrane domain (Site 2), which are composed of conserved residues. Sites 1 and 2 contribute approximately 60% and 40% to the binding affinity with SDF-1alpha, respectively. The binding model is in agreement with most of the experimental data. Transmembrane VI has more significant motion in the harmonious conformational transition of CXCR4 during SDF-1alpha binding, which may be possibly associated with signal transduction. Based on the modeling and simulation, a binding mechanism hypothesis between CXCR4 and SDF-1alpha and its relationship to the signal transduction has been proposed.

Algorithms↗
PubMed2003

Na/K pump current and [Na](i) in rabbit ventricular myocytes: local [Na](i) depletion and Na buffering.

Na/K pump current (I(pump)) and intracellular Na concentration ([Na](i)) were measured simultaneously in voltage-clamped rabbit ventricular myocytes, under conditions where [Na](i) is controlled mainly by membrane transport. Upon abrupt pump reactivation (after 10-12 min blockade), I(pump) decays in two phases. Initially, I(pump) declines with little [Na](i) change, whereas the second phase is accompanied by [Na](i) decline. Initial I(pump) sag was still present at external [K] = 15 mM, but prevented by [Na](i) approximately 100 mM. Initial I(pump) sag might be explained by subsarcolemmal [Na](i) ([Na](SL)) depletion produced by rapid Na extrusion and I(pump). Brief episodes of pump blockade allowed [Na](SL) repletion, since peak postblockade I(pump) exceeded I(pump) at the end of previous activation (without appreciably altered global [Na](i)). The apparent K(m) for [Na](i) was higher for continuous I(pump) activation than peak I(pump) (14.1 +/- 0.2 vs. 11.2 +/- 0.2 mM), whereas that based on d[Na](i)/dt matched peak I(pump) (11.6 +/- 0.3 mM). [Na](SL) depletion (vs. [Na](i)) could be as high as 3 mM for [Na](i) approximately 18-20 mM. A simple diffusion model indicates that such [Na](SL) depletion requires a Na diffusion coefficient 10(3)- to 10(4)-fold below that expected in bulk cytoplasm (although this could be subsarcolemmal only). I(pump) integrals and [Na](i) decline were used to estimate intracellular Na buffering, which is slight (1.39 +/- 0.09).

Adaptation, Physiological↗
PubMed2002

Estimation of the poroelastic parameters of cortical bone.

Cortical bone has two systems of interconnected channels. The largest of these is the vascular porosity consisting of Haversian and Volkmann's canals, with a diameter of about 50 microm, which contains a.o. blood vessels and nerves. The smaller is the system consisting of the canaliculi and lacunae: the canaliculi are at the submicron level and house the protrusions of the osteocytes. When bone is differentially loaded, fluids within the solid matrix sustain a pressure gradient that drives a flow. It is generally assumed that the flow of extracellular fluid around osteocytes plays an important role not only in the nutrition of these cells, but also in the bone's mechanosensory system. The interaction between the deformation of the bone matrix and the flow of fluid can be modelled using Biot's theory of poroelasticity. However, due to the inhomogeneity of the bone matrix and the scale of the porosities, it is not possible to experimentally determine all the parameters that are needed for numerical implementation. The purpose of this paper is to derive these parameters using composite modelling and experimental data from literature. A full set of constants is estimated for a linear isotropic description of cortical bone as a two-level porous medium. Bone, however, has a wide variety of mechanical and structural properties; with the theoretical relationships described in this note, poroelastic parameters can be derived for other bone types using their specific experimental data sets.

Bone Matrix↗
PubMed2003

Thermodynamical interpretation of an adaptive walk on a Mt. Fuji-type fitness landscape: Einstein relation-like formula holds in a stochastic evolution.

We have theoretically studied the statistical properties of adaptive walks (or hill-climbing) on a Mt. Fuji-type fitness landscape in the multi-dimensional sequence space through mathematical analysis and computer simulation. The adaptive walk is characterized by the "mutation distance" d as the step-width of the walker and the "population size" N as the number of randomly generated d-fold point mutants to be screened. In addition to the fitness W, we introduced the following quantities analogous to thermodynamical concepts: "free fitness" G(W) is identical with W+T x S(W), where T is the "evolutionary temperature" T infinity square root of d/lnN and S(W) is the entropy as a function of W, and the "evolutionary force" X is identical with d(G(W)/T)/dW, that is caused by the mutation and selection pressure. It is known that a single adaptive walker rapidly climbs on the fitness landscape up to the stationary state where a "mutation-selection-random drift balance" is kept. In our interpretation, the walker tends to the maximal free fitness state, driven by the evolutionary force X. Our major findings are as follows: First, near the stationary point W*, the "climbing rate" J as the expected fitness change per generation is described by J approximately L x X with L approximately V/2, where V is the variance of fitness distribution on a local landscape. This simple relationship is analogous to the well-known Einstein relation in Brownian motion. Second, the "biological information gain" (DeltaG/T) through adaptive walk can be described by combining the Shannon's information gain (DeltaS) and the "fitness information gain" (DeltaW/T).

Animals↗
PubMed2001

Numerical and graphical description of the information matrix in calibration experiments for state-space models.

This paper describes a mathematical tool for local identifiability analysis that can easily be applied to high-order state-space nonlinear systems and implemented in simulators with a discrete-time approach. The methodology is based on the recursive numerical evaluation of a reduced information matrix during the simulation of a calibration experiment and in the setting-up of a group of information parameters based on geometric interpretations of this matrix. As an example of application, the proposed methodology has been used in the study of an OUR batch test from the point of view of ASM No. 1 calibration.

Biodegradation, Environmental↗
PubMed1996

Crosstalk between cellular morphology and calcium oscillation patterns. Insights from a stochastic computer model.

Agonist-induced oscillations in the concentration of intracellular free calcium ([Ca2+]i) display a wide variety of temporal and spatial patterns. In non-excitable cells, typical oscillatory patterns are somewhat cell-type specific and range from frequency-encoded, repetitive Ca2+ spikes to oscillations that are more sinusoidal in shape. Although the response of a cell population, even to the same stimulus, is often extremely heterogeneous, the response of the same cell to successive exposures can be remarkably similar. We propose that such "Ca2+ fingerprints' can be a consequence of cell-specific morphological properties. The hypothesis is tested by means of a stochastic computer simulation of a two-dimensional model for oscillatory Ca2+ waves which encompasses the basic elements of the two-pool oscillator introduced by Goldbeter et al. (Goldbeter A., Dupont G., Berridge M.J. Minimal model for signal-induced Ca(2+)-oscillations and for their frequency encoding through protein phosphorylation. Proc Natl Acad Sci USA 1990; 87: 1461-1465). In the framework of our extended spatiotemporal model, single cells can display various oscillation patterns which depend on the agonist dose, Ca2+ diffusibility, and several morphological parameters. These are, for example, size and shape of the cell and the cell nucleus, the amount and distribution of Ca2+ stores, and the subcellular location of the inositol(1,4,5)-trisphosphate-generating apparatus.

Biological Clocks↗
PubMed2003

A simple measure of correlation across time, frequency and space between continuous brain signals.

This paper introduces a simple but systematic method to estimate correlations between the spectral energy of two continuous electrophysiological signals in such a way that it can detect relationships between different frequencies and different latencies. From two series of signals (e.g. electroencephalogram, magnetoencephalogram or local field potentials) recorded from two sites in response to repeated sensory stimulations, the method computes the time-frequency energy of each signal. Then, it computes the Spearman rank order correlation coefficient across all the trials between the energy of the first signal series in one time-frequency region and the energy of the second signal series in a second time-frequency region. The method was designed to analyze interactions between frequency bands, in an effort to describe how the main brain rhythms interact with each other across time and space. It was applied to two simulations and to intracranial electro-encephalogram (EEG) recordings obtained from an epileptic patient performing two verbal discrimination tests (a phonological and a semantic task). It led to the identification of different correlations patterns in the gamma band depending on the level of semantic analysis performed by the patient.

Brain↗
PubMed1996

Sebaceous epithelioma: a review of twenty-one cases.

BACKGROUND: Sebaceous epithelioma is a benign tumor that must be differentiated from basal cell carcinoma and other appendageal tumors. OBJECTIVE: Histologic and clinical findings were reviewed in 21 patients with sebaceous epitheliomas. METHODS: Twenty-one cases of sebaceous epithelioma collected during a 5-year period were reviewed. RESULTS: The tumors appeared as yellow to flesh-colored papules, most often on the face and neck. They consisted of basaloid cells with foci of sebaceous differentiation. Cystic spaces formed by holocrine degeneration or simulating sebaceous duct lining were common findings. Patients with sebaceous epitheliomas were more likely than the general population to have an internal malignancy. CONCLUSION: Patients with sebaceous epithelioma should be examined for an underlying malignancy.

Adult↗
PubMed2006

Quantifying the genomic decay paradox due to Muller's ratchet in human mitochondrial DNA.

The observation of high mitochondrial mutation rates in human pedigrees has led to the question of how such an asexual genetic system can survive the accumulation of slightly deleterious mutations caused by Muller's ratchet. I define a null model to quantify in unprecedented detail the threat from extinction caused by Muller's ratchet. This model is general enough to explore the biological significance of Muller's ratchet in various species where its operation has been suspected. For increased precision over a wide range of parameter space I employ individual-based simulations run by evolution@home, the first global computing system for evolutionary biology. After compiling realistic values for the key parameters in human mitochondrial DNA (mtDNA) I find that a surprisingly large range of biologically realistic parameter combinations would lead to the extinction of the human line over a period of 20 million years - if accepted wisdom about mtDNA and Muller's ratchet is correct. The resulting genomic decay paradox complements a similar threat from extinction due to mutation accumulation in nuclear DNA and suggests evaluation of unconventional explanations for long-term persistence. A substantial list of potential solutions is given, including compensatory back mutations, mutation rate heterogeneity and occasional recombination in mtDNA. Future work will have to explore which of these actually solves the paradox. Nonetheless, the results presented here provide yet another reason to minimize anthropogenic increase of mutation rates.

Computer Simulation↗
PubMed2004

Conformational and molecular modeling studies of beta-cyclodextrin-heptagastrin and the third extracellular loop of the cholecystokinin 2 receptor.

The conformational features of a conjugate of the C-terminus of human gastrin (HG[11-17]), the shortest gastrin sequence retaining biological function, with beta-cyclodextrin ([Nle(15)]-HG[11-17]-betaCD) were determined by NMR spectroscopy in an aqueous solution of dodecylphosphocholine (DPC) micelles. The peptide-betaCD conjugate displays a binding affinity and activation profile comparable to those of HG[11-17] at the cholecysokinin 2 (CCK(2)) receptor, the G protein-coupled receptor responsible for the gastrointestinal function of gastrin. The structure of the peptide consisted of a well-defined beta-turn between Gly(13) and Asp(16) of gastrin. The structural preferences of [Nle(15)]-HG[11-17]-betaCD in DPC micelles and the 5-doxylstearate-induced relaxation of the (1)H NMR resonances support a membrane-associated receptor recognition mechanism. Addition of [Nle(15)]-HG[11-17]-betaCD to the third extracellular loop domain of the CCK(2) receptor, CCK(2)-R(352-379), generated a number of intermolecular nuclear Overhauser enhancements (NOEs) and chemical shift perturbations. NOE-restrained MD simulations of the [Nle(15)]-HG[11-17]-betaCD-CCK(2)-R complex produced a topological orientation in which the C-terminus was located in a shallow hydrophobic pocket near the confluence of TM2 and -3. Despite the steric bulk and physicochemical properties of betaCD, the [Nle(15)]-HG[11-17]-betaCD-CCK(2)-R complex is similar to the CCK-8-CCK(2)-R complex determined previously, providing insight into the mode of ligand binding and the role of electrostatic interactions.

Amino Acid Sequence↗
PubMedDate not supplied

Accelerated K-means clustering in metric spaces.

The K-means method is a popular technique for clustering data into k-partitions. In the adaptive form of the algorithm, Lloyds method, an iterative procedure alternately assigns cluster membership based on a set of centroids and then redefines the centroids based on the computed cluster membership. The most time-consuming part of this algorithm is the determination of which points being clustered belong to which cluster center. This paper discusses the use of the vantage-point tree as a method of more quickly assigning cluster membership when the points being clustered belong to intrinsically low- and medium-dimensional metric spaces. Results will be discussed from simulated data sets and real-world data in the clustering of molecular databases based upon physicochemical properties. Comparisons will be made to a highly optimized brute-force implementation of Lloyd's method and to other pruning strategies.

Journal Article↗
PubMed2004

Multiphoton microscopy guides neurotrophin modification with poly(ethylene glycol) to enhance interstitial diffusion.

Brain-derived neurotrophic factor (BDNF) is a promising therapeutic agent for the treatment of neurodegenerative diseases. However, the limited distribution of this molecule after administration into the brain tissue considerably hampers its efficacy. Here, we show how multiphoton microscopy of fluorescently tagged BDNF in brain-tissue slices provides a useful and rapid screening method for examining the diffusion of large molecules in tissues, and for studying the effects of chemical modifications-for example, conjugating with polyethylene glycol (PEG)-on the diffusion constant. This single variable, obtained by monitoring short-term diffusion in real time, can be effectively used for rational drug design. In this study on fluorescently tagged BDNF and BDNF-PEG, we identify slow diffusion as a major contributing factor to the limited penetration of BDNF, and demonstrate how chemical modification can be used to overcome this barrier.

Animals↗
PubMed2003

Lymphocyte reduction induced by hindlimb unloading: distinct mechanisms in the spleen and thymus.

Hindlimb unloading (HU) in rodent is a well-accepted ground-based model used to simulate some of the conditions of space flight and reproduce its deleterious effects on the musculoskeletal, cardiovascular and immune systems. In this study, the effects of HU on lymphocyte homeostasis in the spleen and thymus of mice were examined. HU was found to drastically deplete various cell populations in the spleen and thymus. These changes are likely to be mediated by apoptosis, since DNA strand breaks indicative of apoptosis were detected by terminal deoxynucleotidyl transferase-mediated nick end-labeling in both splenocytes and thymocytes. Surprisingly, administration of opioid antagonists or interference with the Fas-FasL interaction was able to block HU-induced reductions of splenocytes, but not thymocytes. On the other hand, steroid receptor antagonists blocked the reduction of lymphocyte numbers in both spleen and thymus. Therefore, the effects of HU on the homeostasis of splenocytes and thymocytes must be exerted through distinct mechanisms.

Animals↗
PubMed2003

Study of unipolar electrogram morphology in a computer model of atrial fibrillation.

INTRODUCTION: Electrograms exhibit a wide variety of morphologies during atrial fibrillation (AF). The basis of these time courses, however, is not completely understood. In this study, data from computer models were studied to relate features of the signals to the underlying dynamics and tissue substrate. METHODS AND RESULTS: A computer model of entire human atria with a gross fiber architecture based on histology and membrane kinetics based on the Courtemanche et al. atrial model was developed to simulate paced activation and simulated AF. Unipolar electrograms were computed using a current source approximation at 256 sites in right atrium, to simulate a mapping array. The results show the following: (1) In a homogeneous and isotropic tissue, the presence of highly asymmetric electrograms is rare (<2%), although there is a marked variability in amplitude and symmetry. (2) The introduction of anisotropy increases this variability in symmetry and amplitude of the, electrograms especially for propagation across fibers. The percentage of highly asymmetric electrograms increases to 12% to 15% for anisotropy ratios greater than 3:1. (3) Multiphasic and fractionated electrograms are rarely seen in the model with uniform properties but are more common (15%-17%) in a model including regions with abrupt changes in conductivity. Beat-to-beat variations in the occurrence of multiphasic signals are possible with fixed anatomic heterogeneity, due to beat-to-beat variations in the direction of the wavefront relative to the heterogeneity. CONCLUSION: Analysis of the amplitude and symmetry of unipolar atrial electrograms can provide information about the electrophysiologic substrate maintaining AF.

Algorithms↗
PubMed2003

On the estimate of the stochastic layer width for a model of tracer dynamics.

An analytical estimate of the width of the generated chaotic layer in a time-periodically driven stream function model for the motion of passive tracers is discussed. It is based essentially on the method of the separatrix map and the use of the Melnikov theory. Energy-time variables are used to derive lower bounds for the half width of the layer. In order to perform a comparison with numerical simulations, the results are transformed into space variables. The analytic results of the layer thickness in both parallel and perpendicular directions to the shear flow are compared with numerical computations and some systematic deviations are discussed.

Journal Article↗
PubMed2004

Transitory response of confined polymer films subjected to oscillatory shear.

Molecular-dynamics simulations were used to study the response of a nanometer thin polymer film to oscillatory shear. Several types of response occur, depending on the amplitude of the shear. At low amplitude, the film deforms elastically. At intermediate ones it deforms plastically. Short-range stress-induced structured crystalline domains occur. This flexible elastic state is very dynamic. The crystalline domains oscillate with the applied stress. In the course of repeated cycling, they slowly increase in size. These mesoscopic domains may account for experimentally observed memory behavior. Ultra-thin polymer films typically possess relaxation times that are orders of magnitudes larger than those of the individual polymers. When oscillated at even higher amplitude, stick-slip is observed. In our constant pressure simulations, the film yields when wall spacing is increased to a value at which the polymer segments can smoothly rearrange and hence relax the internal stress.

Journal Article↗
PubMed2006

Feedback loops for Shil'nikov chaos: The peroxidase-oxidase reaction.

Special structures in a chemical reaction network can give rise to bistability, oscillations, and chaos. It has been shown recently [A. Sensse and M. Eiswirth, J. Chem. Phys. 122, 044516 (2005)] that the introduction of an additional species in a supplementary feedback loop to a minimal autocatalytic oscillator gives rise to chaotic dynamics in a certain range of parameters, independent of the particular realization of the additional loop. This provides a possibility to decide if chaos may occur just by analyzing the network structure of an existing model. Here, we apply this concept to analyze the complex dynamics in several essential subsystems of the peroxidase-oxidase reaction system. The aim of the present paper is to determine the nature of the occurring chaos and its location in the parameter space by numerical bifurcation analysis and simulations.

Algorithms↗
PubMed2006

Analyzing solution-phase time-resolved x-ray diffraction data by isolated-solute models.

Extracting transient structural information of a solute from time-resolved x-ray diffraction (TRXD) data is not trivial because the signal from a solution contains not only the solute-only term as in the gas phase, but also solvent-related terms. To obtain structural insights, the diffraction signal in q space is often Fourier sine transformed (FT) into r space, and molecular dynamics (MD) simulation-aided signal decomposition into the solute, cage, and solvent terms has so far been indispensable for a clear-cut assignment of structural features. Here we present a convenient method of comparative structural analysis without involving MD simulations by incorporating only isolated-species models for the solute. FT is applied to both the experimental data and candidate isolated-solute models, and comparison of the correlation factors between the experimental FT and the model FTs can distinguish the best candidate among isolated-solute models for the reaction intermediates. The low q region whose influence by solvent-related terms is relatively high can be further excluded, and this mode of truncated Fourier transform (TFT) improves the correlation factors and facilitates the comparison. TFT analysis has been applied to TRXD data on the photodissociation of C(2)H(4)I(2) in two different solvents (methanol and cyclohexane), HgI(2) in methanol, and I(3) (-) in methanol excited at 267 nm. The results are consistent with previous conclusions for C(2)H(4)I(2) in methanol and HgI(2) in methanol, and the new TRXD data reveal that the C(2)H(4)I transient radical has a bridged structure in cyclohexane and I(3) (-) in methanol decomposes into I+I(2) (-) upon irradiation at 267 nm. This TFT method should greatly simplify the analysis because it bypasses MD simulations.

Journal Article↗