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Results for “Coupled model”

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At least 433 records · Page 24Linked to original sources

PubMed1998

Modelling and simulation of motility in actomyosin systems.

We present a model mechanism for simulating the diffusive motion and fluctuations inherent in myofibrillar sarcomere and its subunits at the molecular level. The model couples Langevin dynamics with Huxley kinetics to reproduce the transient patterns of momentum transfer, force generation and resulting motility due to the interactive activities of actin and myosin crossbridges. When myosin is detached from actin, our model predicts Brownian displacements centered at 0 +/- 8 nm (mean +/- SD, n = 265,308) and it is broadly distributed due to the Brownian noise. Attachment events produced displacements with step sizes of approximately 8 +/- 6 nm (mean +/- SD, n = 34,693), which is in agreement with some recent optical-tweezers transducer experimental results. The proposed model could form the basis for a complete qualitative and quantitative description of the evolving complex interactions of the molecular proteins--actin and myosin--in the overall framework of muscular contraction studies.

Actins↗

PubMed1998

Encouraging vaccine results from primate models of HIV type 1 infection.

Challenge studies in primates have established that vaccine-induced protection against immunodeficiency viruses, even against mucosal routes of challenge, is attainable, and that "sterile" immunity is not required for protection. Intelligent use of such studies in primate models, coupled with in vitro measurements of immunity, is the best tool for establishing which vaccine concepts have promise.

AIDS Vaccines↗

PubMed1996

Redox stabilization of the atmosphere and oceans by phosphorus-limited marine productivity

Data from modern and ancient marine sediments demonstrate that burial of the limiting nutrient phosphorus is less efficient when bottom waters are low in oxygen. Mass-balance calculations using a coupled model of the biogeochemical cycles of carbon, phosphorus, oxygen, and iron indicate that the redox dependence of phosphorus burial in the oceans provides a powerful forcing mechanism for balancing production and consumption of atmospheric oxygen over geologic time. The oxygen-phosphorus coupling further guards against runaway ocean anoxia. Phosphorus-mediated redox stabilization of the atmosphere and oceans may have been crucial to the radiation of higher life forms during the Phanerozoic.

Atmosphere↗

PubMed2006

Development and application of hybrid structure based method for efficient screening of ligands binding to G-protein coupled receptors.

G-protein coupled receptors (GPCRs) comprise a large superfamily of proteins that are targets for nearly 50% of drugs in clinical use today. In the past, the use of structure-based drug design strategies to develop better drug candidates has been severely hampered due to the absence of the receptor's three-dimensional structure. However, with recent advances in molecular modeling techniques and better computing power, atomic level details of these receptors can be derived from computationally derived molecular models. Using information from these models coupled with experimental evidence, it has become feasible to build receptor pharmacophores. In this study, we demonstrate the use of the Hybrid Structure Based (HSB) method that can be used effectively to screen and identify prospective ligands that bind to GPCRs. Essentially; this multi-step method combines ligand-based methods for building enriched libraries of small molecules and structure-based methods for screening molecules against the GPCR target. The HSB method was validated to identify retinal and its analogues from a random dataset of approximately 300,000 molecules. The results from this study showed that the 9 top-ranking molecules are indeed analogues of retinal. The method was also tested to identify analogues of dopamine binding to the dopamine D2 receptor. Six of the ten top-ranking molecules are known analogues of dopamine including a prodrug, while the other thirty-four molecules are currently being tested for their activity against all dopamine receptors. The results from both these test cases have proved that the HSB method provides a realistic solution to bridge the gap between the ever-increasing demand for new drugs to treat psychiatric disorders and the lack of efficient screening methods for GPCRs.

Amino Acid Sequence↗

PubMed2005

On the relationship between whole-body vibration exposure and spinal health risk.

A conceptual framework provides the possibility to identify factors determining the effects of whole-body vibration (WBV) on the spine and the internal stress-strain relationships. Epidemiological studies were critically evaluated with respect to their significance for the derivation of quantitative exposure-effect relationships. The approach of deriving such relationships from a comparison with self-generated accelerations during daily activities was considered as unsuited. Trunk muscle activity and control with apparently identical accelerations of body parts during self-generated and forced motions differ widely. Simple biodynamic models coupled with experimental in vivo and in vitro data permitted a preliminary deduction of quantitative relationships between WBV and spinal health with the consideration of individual factors and exposure conditions. Examples of anatomy-based verified finite element models and their application are provided. Such models are considered as a very promising instrument. They can be used to assess quantitatively preventive measures and design. Future research needs concern the examination of (1) the nonlinearity of biodynamics, (2) the effects of WBV in x- and y-axes, (3) the strength of the spine for shear, (4) the contact parameters between the seat and man, (5) the significance of postures and muscle activity, and (6) material properties of spinal structures.

Germany↗

PubMed2005

Impact of distal mutations on the network of coupled motions correlated to hydride transfer in dihydrofolate reductase.

A comprehensive analysis of the network of coupled motions correlated to hydride transfer in dihydrofolate reductase is presented. Hybrid quantum/classical molecular dynamics simulations are combined with a rank correlation analysis method to extract thermally averaged properties that vary along the collective reaction coordinate according to a prescribed target model. Coupled motions correlated to hydride transfer are identified throughout the enzyme. Calculations for wild-type dihydrofolate reductase and a triple mutant, along with the associated single and double mutants, indicate that each enzyme system samples a unique distribution of coupled motions correlated to hydride transfer. These coupled motions provide an explanation for the experimentally measured nonadditivity effects in the hydride transfer rates for these mutants. This analysis illustrates that mutations distal to the active site can introduce nonlocal structural perturbations and significantly impact the catalytic rate by altering the conformational motions of the entire enzyme and the probability of sampling conformations conducive to the catalyzed reaction.

Binding Sites↗

PubMed2000

Nonlinear Markov process amplitude EEG model for nonlinear coupling interaction of spontaneous EEG.

To develop an appropriate model for representing spontaneous electroencephalography (EEG) is an important and necessary work in the field of neuroscience. The Markov process amplitude (MPA) EEG model has been proposed in our previous work for representing the features of the EEG in terms of a few parameters. However, being a linear model, the linear MPA EEG model cannot perfectly describe the spontaneous EEG that displays nonlinear phenomena. In this paper, the nonlinear Markov process amplitude (nonlinear MPA) EEG model that includes nonlinear components is introduced. The consistent consideration of the nonlinear features of the EEG investigated by N. Wiener and P. L. Nunez can be seen from the nonlinear MPA EEG model. The similarity in the time domain and the goodness of fitting in the frequency domain with respect to the ongoing EEG are shown. As a result, the EEG power spectrum can be decomposed into the spontaneous components and the nonlinearly coupled components by use of the nonlinear MPA EEG model, which is useful for a better understanding the mechanism of the EEG generation.

Biomedical Engineering↗

PubMed2004

Influences of synaptic location on the synchronization of rhythmic bursting neurons.

We study how the location of synaptic input influences the stablex firing states in coupled model neurons bursting rhythmically at the gamma frequencies (20-70 Hz). The model neuron consists of two compartments and generates one, two, three or four spikes in each burst depending on the intensity of input current and the maximum conductance of M-type potassium current. If the somata are connected by reciprocal excitatory synapses, we find strong correlations between the changes in the bursting mode and those in the stable phase-locked states of the coupled neurons. The stability of the in-phase phase-locked state (synchronously firing state) tends to change when the individual neurons change their bursting patterns. If, however, the synaptic connections are terminated on the dendritic compartments, no such correlated changes occur. In this case, the coupled bursting neurons do not show the in-phase phase-locked state in any bursting mode. These results indicate that synchronization behaviour of bursting neurons significantly depends on the synaptic location, unlike a coupled system of regular spiking neurons.

Animals↗

PubMed2004

Damage-based finite-element vertebroplasty simulations.

The objectives of this study were to quantify the efficacy of vertebroplasty according to: (1) damage and (2) cement quantity (fill) and modulus. Vertebral body damage was numerically simulated using a previously validated two-dimensional finite-element model coupled with an elasto-plastic modulus reduction (EPMR) scheme. The effects of cement fill (% marrow replaced by cement, % MRC) and cement modulus on vertebral apparent modulus and trabecular bone tissue stress concentrations were parametrically assessed for four EPMR damage models (19%, 33%, 60%, and 91% modulus reduction). For this analysis, the elastic modulus of the trabecular bone tissue and marrow elements were assumed to be 10 GPa and 10 kPa, respectively. The effect of cement modulus (varied in the range 1 GPa to 9 GPa) on vertebral apparent modulus was also examined for partial fill (39% MRC) and complete fill (100% MRC) using the 33% modulus reduction damage model. In the case of polymethylmethacrylate (PMMA cement modulus = 2.16 GPa), restoration of the thoracic vertebral body (T10) apparent modulus to undamaged levels required 71% and 100% cement fill for the 19-33% and 60-91% modulus reduction damage models, respectively. Variations in cement modulus had no appreciable effect on the recovery of vertebral apparent modulus to undamaged levels for simulations of partial cement fill (39% MRC). For complete cement fill, however, a PMMA cement modulus produced approximately a 2-fold increase (82%) in vertebral apparent modulus relative to the undamaged vertebral body. Increasing the cement modulus to 9 GPa increased the vertebral apparent modulus over 2.5-fold (158%) relative to the undamaged state. The EPMR damage scheme and repair simulations performed in this study will help clinicians and cement manufacturers to improve vertebroplasty procedures.

Aged↗

PubMed2006

Kinetics of microbial reduction of Solid phase U(VI).

Sodium boltwoodite (NaUO2SiO3OH x 1.5 H2O) was used to assess the kinetics of microbial reduction of solid-phase U(VI) by a dissimilatory metal-reducing bacterium (DMRB), Shewanella oneidensis strain MR-1. The bioreduction kinetics was studied with Na-boltwoodite in suspension or within alginate beads in a nongrowth medium with lactate as electron donor at pH 6.8 buffered with PIPES. Concentrations of U(VI)tot and cell number were varied to evaluate the coupling of U(VI) dissolution, diffusion, and microbial activity. Microscopic and spectroscopic analyses with transmission electron microscopy (TEM), energy dispersive spectroscopy (EDS), and laser-induced fluorescence spectroscopy (LIFS) collectively indicated that solid-phase U(VI) was first dissolved and diffused out of grain interiors before it was reduced on bacterial surfaces and/or within the periplasm. The kinetics of solid-phase U(VI) bioreduction was well described by a coupled model of bicarbonate-promoted dissolution of Na-boltwoodite, intragrain uranyl diffusion, and Monod type bioreduction kinetics with respect to dissolved U(VI) concentration. The results demonstrated that microbial reduction of solid-phase U(VI) is controlled by coupled biological, chemical, and physical processes.

Hydrogen-Ion Concentration↗

PubMedDate not supplied

Trials, tribulations, and trends in tumor modeling in mice.

Selection of mouse models of cancer is often based simply on availability of a mouse strain and a known compatible tumor. Frequently this results in use of tumor models long on history but short on homology and quality control. Other factors including genetics, sex, immunological status, method and site of tumor implantation, technical competence, biological activity of the tumor, protocol sequence and timing, and selection of endpoints interact to produce outcomes in tumor models. Common reliance on survival and tumor burden data in a single mouse model often skews expectations towards high remission and cure rates; a finding seldom duplicated in clinical trials. Inherent limitations of tumor models coupled with the advent of new therapeutic targets reinforce need for careful attention to design, conduct, and stringent selection of in vivo and ex vivo endpoints. Preclinical efficacy testing for anti-tumor therapies should progress through a series of models of increasing sophistication that includes incorporation of genetically engineered animals, and orthotopic and combination therapy models. Pharmacology and safety testing in tumor-bearing animals may also help to improve predictive value of these models for clinical efficacy. Trends in bioinformatics, genetic refinements, and specialized imaging techniques are helping to maintain mice as the most scientifically and economically powerful model of malignant neoplasms.

Animals↗

PubMedDate not supplied

Enhancing specificity and sensitivity of pharmacophore-based virtual screening by incorporating chemical and shape features--a case study of HIV protease inhibitors.

Virtual screening (VS), if applied appropriately, could significantly shorten the hit identification and hit-to-lead processes in drug discovery. Recently, the version of VS that is based upon similarity to a pharmacophore has received increased attention. This is due to two major factors: first, the public availability of the ZINC1 conformational database has provided a large selection pool with high-quality and purchasable small molecules; second, new technology has enabled a more accurate and flexible definition of pharmacophore models coupled with an efficient search speed. The major goal of this study was to achieve improved specificity and sensitivity of pharmacophore-based VS by optimizing the variables used to generate conformations of small molecules and those used to construct pharmacophore models from known inhibitors or from inhibitor-protein complex structures. By using human immunodeficiency virus protease and its inhibitors (PIs) as a case study, the impact of the key variables, including the selection of chemical features, involvement of excluded volumes (EV), the tolerance radius of excluded volumes, energy windows, and the maximum number of conformers in conformation generation, was explored. Protein flexibility was simulated by adjusting the sizes of EV. Our best pharmacophore model, combining both chemical features and excluded volumes, was able to correctly identify 60 out of 75 structurally diverse known PIs, while misclassifying only 5 out of 75 similar compounds that are not inhibitors. To evaluate the specificity of the model, 1193 oral drugs on the market were screened, and 25 original hits were identified, including 5 out of 6 known PI drugs.

Drug Design↗

PubMed2003

Syntheses, structural analyses, and magneto-structural correlations of three polymeric Fe(II) complexes with azide ligand.

Three new metal-organic polymeric complexes, [Fe(N(3))(2)(bpp)(2)] (1), [Fe(N(3))(2)(bpe)] (2), and [Fe(N(3))(2)(phen)] (3) [bpp = (1,3-bis(4-pyridyl)-propane), bpe = (1,2-bis(4-pyridyl)-ethane), phen = 1,10-phenanthroline], have been synthesized and characterized by single-crystal X-ray diffraction studies and low-temperature magnetic measurements in the range 300-2 K. Complexes 1 and 2 crystallize in the monoclinic system, space group C2/c, with the following cell parameters: a = 19.355(4) A, b = 7.076(2) A, c = 22.549(4) A, beta = 119.50(3) degrees, Z = 4, and a = 10.007(14) A, b = 13.789(18) A, c = 10.377(14) A, beta = 103.50(1) degrees, Z = 4, respectively. Complex 3 crystallizes in the triclinic system, space group P(-)1, with a = 7.155(12) A, b = 10.066(14) A, c = 10.508(14) A, alpha = 109.57(1) degrees, beta = 104.57(1) degrees, gamma = 105.10(1) degrees, and Z = 2. All coordination polymers exhibit octahedral Fe(II) nodes. The structural determination of 1 reveals a parallel interpenetrated structure of 2D layers of (4,4) topology, formed by Fe(II) nodes linked through bpp ligands, while mono-coordinated azide anions are pendant from the corrugated sheet. Complex 2 has a 2D arrangement constructed through 1D double end-to-end azide bridged iron(II) chains interconnected through bpe ligands. Complex 3 shows a polymeric arrangement where the metal ions are interlinked through pairs of end-on and end-to-end azide ligands exhibiting a zigzag arrangement of metals (Fe-Fe-Fe angle of 111.18 degrees) and an intermetallic separation of 3.347 A (through the EO azide) and of 5.229 A (EE azide). Variable-temperature magnetic susceptibility data suggest that there is no magnetic interaction between the metal centers in 1, whereas in 2 there is an antiferromagnetic interaction through the end-to-end azide bridge. Complex 3 shows ferro- as well as anti-ferromagnetic interactions between the metal centers generated through the alternating end-on and end-to-end azide bridges. Complex 1 has been modeled using the D parameter (considering distorted octahedral Fe(II) geometry and with any possible J value equal to zero) and complex 2 has been modeled as a one-dimensional system with classical and/or quantum spin where we have used two possible full diagonalization processes: without and with the D parameter, considering the important distortions of the Fe(II) ions. For complex 3, the alternating coupling model impedes a mathematical solution for the modeling as classical spins. With quantum spin, the modeling has been made as in 2.

Journal Article↗

PubMed2004

A challenge for green chemistry: designing molecules that readily dissolve in carbon dioxide.

Carbon dioxide is a green yet feeble solvent whose full potential won't be realized until we develop a more thorough understanding of its solvent behavior at the molecular level. Fortunately, advances in molecular modeling coupled with experiments are rapidly improving our understanding of CO(2)'s behavior, permitting design of new, more sustainable "CO(2)-philes".

Carbon Dioxide↗

PubMed2001

Intra-operative image updating.

Intraoperative brain shift and deformation pose challenges for image-guided surgery. One strategy to address these problems utilizes computational modeling coupled with intraoperatively acquired information from efficient and economical sources such as ultrasound and the optics of the operating microscope. Calibration algorithms for the accurate integration of these sparse data sources have been implemented. Assessment has been performed in both phantom and pig brain models, and accuracy better than 2 mm has been achieved. Methods of incorporating these data into the computational model are being developed.

Animals↗

PubMed2005

Pathogenesis of psoriatic arthritis.

PURPOSE OF REVIEW: Heterogeneity in clinical presentation and disease course has hindered understanding of disease mechanisms in psoriatic arthritis, but recent studies have provided insights into pathogenesis. This review examines relevant animal models and genetic factors implicated in disease susceptibility. Also, recent reports on mechanisms related to synovial and entheseal inflammation are discussed. RECENT FINDINGS: Two transgenic mouse models (amphiregulin, STAT-3) were reported that have features of psoriatic arthritis and psoriasis respectively. Genetic studies did not find associations between psoriatic arthritis and several class I major histocompatibility complex alleles, the caspase-activating recruitment domain 15 domain, or the major histocompatibility complex class I chain-related gene A9 allele, in sharp contrast to previous reports. The striking association of psoriatic arthritis with mutations in the killer immunoglobulin receptors on natural killer cells is particularly exciting but needs further study. Psoriatic arthritis has histopathologic features that are more characteristic of other forms of spondyloarthritis than rheumatoid arthritis. Moreover, several of these features correlate with clinical disease activity. Matrix metalloproteinases are strongly expressed in psoriatic arthritis synovium, and serum matrix metalloproteinases-3 may be a reliable biomarker for monitoring disease response. Finally, the concept of an 'enthesis organ' may explain the magnetic resonance imaging findings and clinical signs of psoriatic enthesitis and dactylitis. SUMMARY: Recent findings highlight the importance of innate immune mechanisms in disease pathogenesis. Moreover, psoriatic arthritis and rheumatoid arthritis synovium have divergent histopathologic features that indicate distinct disease mechanisms. The generation of appropriate animal models coupled with reliable biomarkers will result in a deeper understanding of disease pathogenesis and will facilitate the identification of new therapeutic targets.

Animals↗

PubMed1993

On the solutions of Huxley-type models in cardiac muscle fiber contractions.

Huxley's sliding filament crossbridge muscle model coupled with parallel and series elastic components was simulated to examine the effect of various solution techniques in cardiac contractions. Solutions of both isometric and isotonic contraction cases showed that the force versus time curves were not significantly altered by solving the three-element Hill model with Huxley's Equation written as either an ordinary or partial differential equation (ODE or PDE), but this makes a difference in the solution time required. Various theoretical studies have used either the ODE or PDE representation. The crossbridge cycles at the end of a contraction showed approximately 25% and 15% difference in the isometric and isotonic cases when Huxley's Equation was written as either an ODE or PDE. Examination of the crossbridge distribution (distribution among states of reach) showed that assuming that the crossbridge distribution is a Gaussian function is a poor approximation since the shape changes considerably between the cardiac contracting and expanding phases, and using a technique such as a distribution moment approximation is questionable. Recent experimental studies have demonstrated that solving Huxley-type relations as ordinary differential equations gives good agreement with cardiac data, implying that as a first approximation, this can be successfully used.

Animals↗

PubMed2003

Hepatic tumor enhancement in computed tomography: combined models of liver perfusion and dynamic imaging.

The objective of this study is to show how computational modeling can be used to increase our understanding of liver enhancement in dynamic computer tomography. It relies on two models: (1). a vascular model, based on physiological rules, is used to generate the 3D hepatic vascular network; (2). the physical process of CT acquisition allows to synthesize timed-stamped series of images, aimed at tracking the propagation of a contrast material through the vessel network and the parenchyma. The coupled models are used to simulate the enhancement of a hyper-vascular tumor at different acquisition times, showing a maximum conspicuity during the arterial phase.

Algorithms↗