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At least 1,531 records · Page 85Linked to original sources
PubMed2006

Understanding the evolution dynamics of internet topology.

The internet structure is extremely complex. The positive-feedback preference (PFP) model is a recently introduced internet topology generator. The model uses two generic algorithms to replicate the evolution dynamics observed on the internet historic data. The phenomenological model was originally designed to match only two topology properties of the internet, i.e., the rich-club connectivity and the exact form of degree distribution, whereas numerical evaluation has shown that the PFP model accurately reproduces a large set of other nontrivial characteristics as well. This paper aims to investigate why and how this generative model captures so many diverse properties of the internet. Based on comprehensive simulation results, the paper presents a detailed analysis on the exact origin of each of the topology properties produced by the model. This work reveals how network evolution mechanisms control the obtained topology properties and it also provides insights on correlations between various structural characteristics of complex networks.

Journal Article↗
PubMed1990

Representation of multi-channel evoked potential data using a dipole component model of intracranial generators: application to the auditory P300.

A number of procedures have been employed to decompose recorded scalp potential wave forms into their hypothesized constituent elements. The shortcomings of the various decomposition methods (principal components analysis, topographic components modeling, inverse dipole localization and spatio-temporal dipole modeling) are reviewed and a new dipole components model, which incorporates the strengths of the topographic components model and the spatio-temporal dipole model, is presented. This model decomposes ERPs into subcomponents reflecting the activity of dipole sources with location and orientation fixed across subjects and with the temporal activity of each dipole modeled as a decaying sinusoid. The requirement that the equivalent dipole generators be the same across subjects and experimental conditions permits analysis of inter-group differences and of the effects of experimental variables. An application of the model to data from a 3-tone auditory target detection task is presented, and equivalent dipole sources of the components of the auditory evoked potential are described. Assumptions inherent in the model, as well as practical obstacles to its widespread implementation, are discussed.

Acoustic Stimulation↗
PubMedDate not supplied

Human rhinovirus 3C protease: generation of pharmacophore models for peptidic and nonpeptidic inhibitors and their application in virtual screening.

Three-dimensional pharmacophore models for peptidic and small organic nonpeptidic inhibitors of the human rhinovirus 3C protease were generated in a structure-based as well as in a ligand-based approach, using the software package Catalyst. The inhibitors possess an electrophilic moiety, often a Michael acceptor function, which covalently binds to a cysteine in the active site of the enzyme. Since this process presents the key step for virus inactivation, the creation of a new function in Catalyst was required in order to include this decisive functionality into the pharmacophore models. In the present study we focus on this feature definition process because it presents an innovative strategy to expand the pharmacophore description ability of the Catalyst software to also include covalent bonds between ligand and binding site. The resulting hypotheses were then used for virtual screening of 3D databases in order to verify their quality and to search for structurally diverse, possible new lead substances.

Binding Sites↗
PubMed2004

Modeling action potential generation and propagation in NRK fibroblasts.

Normal rat kidney (NRK) fibroblasts change their excitability properties through the various stages of cell proliferation. The present mathematical model has been developed to explain excitability of quiescent (serum deprived) NRK cells. It includes as cell membrane components, on the basis of patch-clamp experiments, an inwardly rectifying potassium conductance (G(Kir)), an L-type calcium conductance (G(CaL)), a leak conductance (G(leak)), an intracellular calcium-activated chloride conductance [G(Cl(Ca))], and a gap junctional conductance (G(gj)), coupling neighboring cells in a hexagonal pattern. This membrane model has been extended with simple intracellular calcium dynamics resulting from calcium entry via G(CaL) channels, intracellular buffering, and calcium extrusion. It reproduces excitability of single NRK cells and cell clusters and intercellular action potential (AP) propagation in NRK cell monolayers. Excitation can be evoked by electrical stimulation, external potassium-induced depolarization, or hormone-induced intracellular calcium release. Analysis shows the roles of the various ion channels in the ultralong ( approximately 30 s) NRK cell AP and reveals the particular role of intracellular calcium dynamics in this AP. We support our earlier conclusion that AP generation and propagation may act as a rapid mechanism for the propagation of intracellular calcium waves, thus contributing to fast intercellular calcium signaling. The present model serves as a starting point to further analyze excitability changes during contact inhibition and cell transformation.

Action Potentials↗
PubMed2002

An experimental clot model in sheep; generation of a heterologous clot and its detection in vivo using venography and (125)I labelled fibrinogen.

An experimental venous clot model using the lateral saphenous vein of sheep is described. Eight experimental Suffolk crossbred sheep were used. A mixture of human fibrinogen, in some cases labelled with (125)I, bovine thrombin and homologous whole blood was placed via a catheter into a surgically isolated segment of the lateral saphenous vein. The resulting heterologous clot was imaged daily for 6 days using venography, or monitored using an external gamma ray detector. Clots were radiographically detectable for the 6 days of the study. They were totally occlusive for a mean of 4.2 days (SD 2.2) and were occlusive in the immediate 24 hour period after surgery. The fibrin component of the clot was persistent (85 per cent of the initial fibrin[ogen] present after 6 days). Radiographically the clots were seen as filling defects within partially filled vessels, or their presence was inferred from the absence of filling. A collateral blood supply was apparent immediately on vessel occlusion. No adverse effects, evidence of infection or limb oedema were seen. The model provided a reproducible blood clot within the lateral saphenous vein of the sheep. Clot imaging using venography was effective and readily achieved. It is suggested that the model is useful when a stable, intravenous deposit of heterologous (e.g. human) fibrin is required in vivo at a site suitable for venography and radionucleid monitoring.

Animals↗
PubMed2004

Successful virtual screening for a submicromolar antagonist of the neurokinin-1 receptor based on a ligand-supported homology model.

The neurokinin-1 (NK1) receptor belongs to the family of G-protein-coupled receptors (GPCRs), which represents one of the most relevant target families in small-molecule drug design. In this paper, we describe a homology modeling of the NK1 receptor based on the high-resolution X-ray structure of rhodopsin and the successful virtual screening based on this protein model. The NK1 receptor model has been generated using our new MOBILE (modeling binding sites including ligand information explicitly) approach. Starting with preliminary homology models, it generates improved models of the protein binding pocket together with bound ligands. Ligand information is used as an integral part in the homology modeling process. For the construction of the NK1 receptor, antagonist CP-96345 was used to restrain the modeling. The quality of the obtained model was validated by probing its ability to accommodate additional known NK1 antagonists from structurally diverse classes. On the basis of the generated model and on the analysis of known NK1 antagonists, a pharmacophore model was deduced, which subsequently guided the 2D and 3D database search with UNITY. As a following step, the remaining hits were docked into the modeled binding pocket of the NK1 receptor. Finally, seven compounds were selected for biochemical testing, from which one showed affinity in the submicromolar range. Our results suggest that ligand-supported homology models of GPCRs may be used as effective platforms for structure-based drug design.

Amino Acid Sequence↗
PubMedDate not supplied

A computational model for heat generation in a radially layered tissue inside a 'coaxial TEM' applicator.

The electromagnetic heat dissipation in a radially layered biological tissue inside a circular cylinder has been investigated theoretically. The theory is based on a three-dimensional model and the electromagnetic field is assumed to be generated by a prescribed electric field along a ring-shaped aperture. The method of computation employs the spatial Fourier transform of all field quantities with respect to the axial coordinate, after which the field equations are solved in the spectral domain. Subsequently, an inverse Fourier transform is carried out to compute the quantities that are of interest to the clinical deep-body hyperthermia system at hand. For a number of representative configurations numerical results at 70 MHz are given.

Body Temperature↗
PubMed1987

Model for 82Sr/82Rb generator elution profiles: a secondary approach to radioassay/dosimetry.

Static (dose calibrator) assays of 82Rb bolus yield erroneous estimates of administered activity by ignoring the asymmetric output of 82Sr/82Rb generators. Though on-line monitoring of elution profile improves accuracy for quantitative purposes, it requires an elaborately shielded detector and associated electronics at patient-study site. Our alternative approach based on mathematical description of the dynamic characteristics of the generator accurately predicts elution profiles over a broad range of flow rates.

Humans↗
PubMed1989

Haemoglobin and myoglobin as inhibitors of hydroxyl radical generation in a model system of "iron redox" cycle.

Methionine was oxidized to ethylene by an "Iron Redox" system containing H2O2, Fe-EDTA and ascorbate, generating hydroxyl radicals or another species of similar reactivity. Oxy or met forms of haemoglobin and myoglobin were found to inhibit methionine oxidation. Methionine oxidation was elevated in the "Iron Redox" system by increasing ascorbic acid concentration. However, in the presence of metmyoglobin or methaemoglobin, the increases in ascorbic acid did not lower the haemproteins' inhibitory effects but rather increased them. The pro-oxidative or anti-oxidative activities of haemproteins in biological oxidative reactions seem to be dependent on compartmentalization and on the presence and concentrations of reducing compounds and H2O2.

Animals↗
PubMed2002

Analysis of mitochondrial free radical generation in animal models of neuronal disease.

Mitochondria, the power plant of all eukaryotic cells, produce cellular energy in the form of ATP via electron transport and oxidative phosphorylation. However, the mitochondria leak electrons that can act as major sources of oxidative stress, and their dysfunction, have been proposed as causative events underlying neurodegeneration in stroke and neurodegenerative diseases. We examined whether MitoTracker Red CM-H(2)XRos, a rosamine derivative used to detect mitochondrial free radicals in vitro, would be applied to analyze the mitochondrial free radicals in various models of neurological diseases in vivo. The injections of MitoTracker Red CM-H(2)XRos revealed generation of mitochondrial free radicals primarily in vulnerable neurons following focal cerebral ischemia as well as administration of Fe(2+) or 3-nitropropionic acid. MitoTracker Red CM-H(2)XRos was retained after fixation, compatible with immunocytochemistry or nuclear staining, and can be applied to study roles of mitochondrial free radicals in the process of neurodegeneration in vivo.

Adenosine Triphosphate↗
PubMed1994

Superior colliculus cell types and models of saccade generation.

Recent experiments on the cat and monkey have revealed several different cell types within the superior colliculus, including fixation, burst, and build up cells. During primate saccades, activity remains fixed at one location in burst cells, but spreads across the colliculus in build up cells. New models based on the activity of these cell types suggest their functional roles in saccade generation.

Animals↗
PubMed1999

Structural basis for the guanosine requirement of the hairpin ribozyme.

To form a catalytically active complex, the essential nucleotides of the hairpin ribozyme, embedded within the internal loops of the two domains, must interact with one another. Little is known about the nature of these essential interdomain interactions. In the work presented here, we have used recent topographical constraints and other biochemical data in conjunction with molecular modeling (constraint-satisfaction program MC-SYM) to generate testable models of interdomain interactions. Visual analysis of the generated models has revealed a potential interdomain base pair between the conserved guanosine immediately downstream of the reactive phosphodiester (G(+1)) and C(25) within the large domain. We have tested this former model through activity assays, using all 16 combinations of bases at positions +1 and 25. When the standard ribozyme was used, catalytic activity was severely suppressed with substrates containing U(+1), C(+1), or A(+1). Similarly, mutations of the putative pairing partner (C(25) to A(25) or G(25)) reduce activity by several orders of magnitude. The U(25) substitution retains a significant level of activity, consistent with the possible formation of a G.U wobble pair. Strikingly, when combinations of Watson-Crick (or wobble) base pairs were introduced in these positions, catalytic activity was restored, strongly suggesting the existence of the proposed interaction. These results provide a structural basis for the guanosine requirement of this ribozyme and indicate that the hairpin ribozyme can now be engineered to cleave a wider range of RNA sequences.

Base Pairing↗
PubMed2001

Models of respiratory rhythm generation in the pre-Bötzinger complex. III. Experimental tests of model predictions.

We used the testable predictions of mathematical models proposed by Butera et al. to evaluate cellular, synaptic, and population-level components of the hypothesis that respiratory rhythm in mammals is generated in vitro in the pre-Bötzinger complex (pre-BötC) by a heterogeneous population of pacemaker neurons coupled by fast excitatory synapses. We prepared thin brain stem slices from neonatal rats that capture the pre-BötC and maintain inspiratory-related motor activity in vitro. We recorded pacemaker neurons extracellularly and found: intrinsic bursting behavior that did not depend on Ca(2+) currents and persisted after blocking synaptic transmission; multistate behavior with transitions from quiescence to bursting and tonic spiking states as cellular excitability was increased via extracellular K(+) concentration ([K(+)](o)); a monotonic increase in burst frequency and decrease in burst duration with increasing [K(+)](o); heterogeneity among different cells sampled; and an increase in inspiratory burst duration and decrease in burst frequency by excitatory synaptic coupling in the respiratory network. These data affirm the basis for the network model, which is composed of heterogeneous pacemaker cells having a voltage-dependent burst-generating mechanism dominated by persistent Na(+) current (I(NaP)) and excitatory synaptic coupling that synchronizes cell activity. We investigated population-level activity in the pre-BötC using local "macropatch" recordings and confirmed these model predictions: pre-BötC activity preceded respiratory-related motor output by 100-400 ms, consistent with a heterogeneous pacemaker-cell population generating inspiratory rhythm in the pre-BötC; pre-BötC population burst amplitude decreased monotonically with increasing [K(+)](o) (while frequency increased), which can be attributed to pacemaker cell properties; and burst amplitude fluctuated from cycle to cycle after decreasing bilateral synaptic coupling surgically as predicted from stability analyses of the model. We conclude that the pacemaker cell and network models explain features of inspiratory rhythm generation in vitro.

Animals↗
PubMed2006

Generation of variable anatomical models for surgical training simulators.

The generation of variable surgical scenes is a key element for effective training with surgery simulators. Our current research aims at a high fidelity hysteroscopy simulator which challenges the trainee with a new surgical scene in every training session. We previously reported on methods able to generate a broad range of pathologies within an existing healthy organ model. This paper presents the methods necessary to produce variable models of the healthy organ. In order to build a database of uteri, a volunteer study was conducted. The segmentation was carried out interactively, also covering the establishment of an anatomically meaningful correspondence between the individual organs. The variability of the shape parameters has been characterized by principal component analysis. A new method has been developed and tested, allowing the derivation of realistic new instances based on the stochastic model and complying with non-linear shape constraints which are defined and interactively controlled by medical experts.

Computer Graphics↗
PubMed1979

[Possibilities of the clinical comparison of diseases with a hereditary burden in the descendant generation using the model of "parents-children" ill with schizophrenia].

A special statistic method of confrontation of diseases with aggravation hereditary in the group "parents - children" is proposed. This method can be used under clinical formalization of the diseases. It is shown on a model group parents - children (118 pairs) suffering with schizophrenia, that statistical confrontation makes possible to work out group and individual prognoses in the descending generation. It is found that invariability in the descending generation is provided by a small number of stable indices, other symptoms being variable. Statistic description of the disease symptoms in the descending generation is of interest for planning genetic interpretation.

Adult↗
PubMed2006

Homology modeling using parametric alignment ensemble generation with consensus and energy-based model selection.

The accuracy of a homology model based on the structure of a distant relative or other topologically equivalent protein is primarily limited by the quality of the alignment. Here we describe a systematic approach for sequence-to-structure alignment, called 'K*Sync', in which alignments are generated by dynamic programming using a scoring function that combines information on many protein features, including a novel measure of how obligate a sequence region is to the protein fold. By systematically varying the weights on the different features that contribute to the alignment score, we generate very large ensembles of diverse alignments, each optimal under a particular constellation of weights. We investigate a variety of approaches to select the best models from the ensemble, including consensus of the alignments, a hydrophobic burial measure, low- and high-resolution energy functions, and combinations of these evaluation methods. The effect on model quality and selection resulting from loop modeling and backbone optimization is also studied. The performance of the method on a benchmark set is reported and shows the approach to be effective at both generating and selecting accurate alignments. The method serves as the foundation of the homology modeling module in the Robetta server.

Amino Acid Sequence↗