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PubMedDate not supplied

[A study of the change in conductivity of the neuronal membrane caused by a generator potential using a method of computer modeling].

Injection of cAMP induces in snail neurons generator potential, which is related to an increase of sodium and decrease of potassium permeability of the neuron outer membrane. A model is proposed which takes into account cAMP diffusion inside the neuron from the injection place and interaction of these molecules with the intercellular system controlling permeability of the outer membrane. Resulting impulse generation induces calcium ions current through the outer membrane. The model also considers calcium diffusion toward cAMP and its effect on the rate of the enzyme work destroying cAMP. Agreement between the calculations of ionic current I(t) and the experiment permits determination of the model parameters and calculation of the observed change of time distribution of nerve impulses when calcium input is significant.

Animals↗
PubMed1998

Preliminary experience of the DIAS computer model in providing insulin dose advice to patients with insulin dependent diabetes.

The Diabetes Advisory System (DIAS) is a model of human glucose metabolism which predicts hourly blood glucose concentrations and provides advice on insulin dose. Its ability to provide appropriate advice was assessed in 20 well-controlled IDDM patients (mean (SD) age 38 (11), duration 17 (9) years; HbA1 8.8 (0.9)%, reference range 5.4-7.6%). Patients recorded blood glucose measurements, insulin dose and food intake for 4 days. These data were used to generate insulin dose advice by both DIAS and a diabetes specialist nurse. Patients were then allocated to follow either DIAS or nurse advice for a further 4 days. There was no significant difference in mean recorded blood glucose values or frequency of reported hypoglycaemia between the DIAS and nurse groups either before or after insulin dose adjustment. The DIAS model, however, generated significantly lower insulin dose advice than the nurse (median (range)% change in insulin dose: DIAS group -13.3% (-25.0 to +11.6) versus nurse group 0% (-8.7 to +2.5), P < 0.05). We conclude that, in the patients studied, DIAS provided insulin dose advice which maintained good short term control of diabetes, despite significant reductions in dose in some cases.

Adult↗
PubMed2000

Computer modeling of population exposure to a carcinogen: the example of asbestos and mesothelioma mortality in France.

The multistage theory of carcinogenesis allows models to be constructed that provide the individual probability of a diagnosed tumor at a given age as a function of the person's past exposure to carcinogenic agents (exposure level versus age), the time since exposure, and age. When exposure to a carcinogenic agent and its impact in terms of morbidity and mortality are modeled on the scale of the general population, individual exposures must often be estimated. If appropriate data do not already exist, this difficult task necessitates expensive and difficult investigations. We propose here a method that allows this global exposure to be modeled without needing to know the individual exposures. The method is used and illustrated in the context of modeling the asbestos exposure of the French male population and calculating its mortality rate from mesothelioma (a type of cancer for which asbestos is the only carcinogen and for which a risk function based on the multistage theory of carcinogenesis exists). This method assumes that the exposure functions (how exposure levels vary with age) for all individuals are the same, with the exception of one parameter. That is, it utilizes a hypothesis that we called the hypothesis of the Standard Exposure Window (SEW). We used two methods to calculate the probability of death from mesothelioma in a representative sample of the French male population for whom individual histories of asbestos exposure are known: we applied the risk function to all the individuals, and we applied the SEW hypothesis. The number of deaths obtained by the two methods are very close and fit the observed mortality data satisfactorily.

Aged↗
PubMed2003

Chemistry, physics and time: the computer modelling of glassmaking.

A decade or so ago the remains of an early flat glass furnace were discovered in St Helens. Continuous glass production only became feasible after the Siemens Brothers demonstrated their continuous tank furnace at Dresden in 1870. One manufacturer of flat glass enthusiastically adopted the new technology and secretly explored many variations on this theme during the next fifteen years. Study of the surviving furnace remains using today's computer simulation techniques showed how, in 1887, that technology was adapted to the special demands of window glass making. Heterogeneous chemical reactions at high temperatures are required to convert the mixture of granular raw materials into the homogeneous glass needed for windows. Kinetics (and therefore the economics) of glassmaking is dominated by heat transfer and chemical diffusion as refractory grains are converted to highly viscous molten glass. Removal of gas bubbles in a sufficiently short period of time is vital for profitability, but the glassmaker must achieve this in a reaction vessel which is itself being dissolved by the molten glass. Design and operational studies of today's continuous tank furnaces need to take account of these factors, and good use is made of computer simulation techniques to shed light on the way furnaces behave and how improvements may be made. This paper seeks to show how those same techniques can be used to understand how the early Siemens continuous tank furnaces were designed and operated, and how the Victorian entrepreneurs succeeded in managing the thorny problems of what was, in effect, a vulnerable high temperature continuous chemical reactor.

Journal Article↗
PubMed2006

Computational model of the movement of the human muscles of mastication during opening and closing of the jaw.

Muscle fibre bundles comprising the four major muscles of mastication in the human being were studied in cadavers. Markers were placed along each muscle fibre bundle by means of serial dissections. The 3D coordinates of each marker were tabulated and imported to Cinema 4D, a software animation program. Origins and insertions of each fibre bundle were also digitized and imported, as were the coordinates of the surface of the skull, the mandible and temporomandibular joint. It was then possible to visualize the movement of all relevant fibre bundles during the passive motions of the mandible. An animated film depicts the positions of all relevant muscle fibres during passive movement of the mandible. The properties of the masseter muscle were documented as a prototype for the eventual study of all the muscles of mastication. One can now proceed to study the inverse problem, namely the forces within each fibre bundle that actively generate mandibular motion. It is hoped that these studies will aid in the management of conditions affecting the temporomandibular joint.

Aged↗
PubMed2001

Alternating dominance of NMDA and AMPA for learning and recall: a computer model.

Physiological studies reveal a dichotomy in biological Hebbian learning: NMDA receptors are utilized for induction of long term potentiation (LTP) whereas AMPA is used for LTP expression. We propose that this dichotomy would have functional value: preventing previously stored memories from interfering with the storage of new memories. A previous hypothesis reduces this interference by temporarily reducing associative weights during learning. Complementary to this model, we propose a dual transmission algorithm in which one set of synaptic weights are used primarily for learning and another primarily for recall. This algorithm shows good performance in a simple neural network model. Biologically, the model could be mediated by a cholinergic switch from dominance of learning-insensitive NMDA receptors to dominance of learning-modifiable AMPA receptors.

Acetylcholine↗
PubMed1996

Learning stereo disparity using temporal smoothness constraints: a computational model.

An unsupervised learning algorithm is presented for learning stereo disparity. A key assumption is that surface depth varies smoothly over time. This assumption is consistent with a learning rule which maximizes the long-term variance of each unit's outputs, whilst simultaneously minimizing its short-term variance. The learning rule involves a linear combination of anti-Hebbian and Hebbian weight changes, over short and long time scales, respectively. The model is demonstrated on a hyperacuity task: estimating sub-pixel stereo disparity from a temporal sequence of stereograms. The algorithm generalizes, without additional learning, to previously unseen image sequences.

Algorithms↗
PubMed2001

Computer modeling of the biotic cycle formation in a closed ecological system.

The process of biotic turnover in a closed ecological system (CES) with an external energy flow was analyzed by mathematical modeling of the biotic cycle formation. The formation of hierarchical structure in model CESs is governed by energy criteria. Energy flow through the ecosystem increases when a predator is introduced into a "producer-reducer" system at steady state. Analysis of the model shows that under certain conditions the presence of the primary predator with its high mineralization ability accelerates the biotic turnover measured by primary production. We, therefore, conclude that for every system it is possible to find a suitable predator able to provide the system with a higher biotic turnover rate and energy consumption. Grant numbers: 99-04-96017/2000.

Animals↗
PubMed2003

A computer model for reshaping of cells in epithelia due to in-plane deformation and annealing.

Although cell reshaping is fundamental to the mechanics of epithelia, technical barriers have prevented the methods of mechanics from being used to investigate it. These barriers have recently been overcome by the cell-based finite element formulation of Chen and Brodland. Here, parameters to describe the fabric of an epithelium in terms of cell shape and orientation and cell edge density are defined. Then, rectangular "patches" of model epithelia having various initial fabric parameters are generated and are either allowed to anneal or are subjected to one of several patterns of in-plane deformation. The simulations show that cell reshaping lags the deformation history, that it is allayed by cell rearrangement and that it causes the epithelium as a whole to exhibit viscoelastic mechanical properties. Equations to describe changes in cell shape due to annealing and in-plane deformation are presented.

Cell Aggregation↗
PubMed1998

Computer model to predict subsurface damage in tibial inserts of total knees.

Two designs of total knee replacements were analysed to determine how the geometry of their bearing surface would affect the susceptibility of their ultra high molecular weight polyethylene tibial inserts to delamination. Orientations of the femoral components on the tibial surfaces were calculated with use of rigid body analysis for discrete intervals during the stance phase of gait. For each successive orientation, finite element analysis was used to compress the components together to determine the stresses in the tibial inserts. A damage function analogous to strain energy density was defined to account for the accumulated amplitudes and frequencies of the maximum shear stress cycles and hence to predict fatigue failure. The damage function was applied to each polyethylene element in the tibial insert, and the highest value calculated for each design was its damage score. One knee had a damage score more than three times less than that of the other because of lower stresses and because the contact points moved in the medial-lateral as well as anterior-posterior directions during internal-external rotation. The femoral and tibial components of this knee had large outer frontal radii and close conformity in the frontal plane. We propose that this method, which accounts for the motions and stresses endured during walking, makes different predictions regarding the likelihood of delamination compared with the predictions made by conventional static compression tests performed when the knee is in a neutral position.

Anterior Cruciate Ligament↗
PubMed2003

A computational model on the modulation of mitogen-activated protein kinase (MAPK) and Akt pathways in heregulin-induced ErbB signalling.

ErbB tyrosine kinase receptors mediate mitogenic signal cascade by binding a variety of ligands and recruiting the different cassettes of adaptor proteins. In the present study, we examined heregulin (HRG)-induced signal transduction of ErbB4 receptor and found that the phosphatidylinositol 3'-kinase (PI3K)-Akt pathway negatively regulated the extracellular signal-regulated kinase (ERK) cascade by phosphorylating Raf-1 on Ser(259). As the time-course kinetics of Akt and ERK activities seemed to be transient and complex, we constructed a mathematical simulation model for HRG-induced ErbB4 receptor signalling to explain the dynamics of the regulation mechanism in this signal transduction cascade. The model reflected well the experimental results observed in HRG-induced ErbB4 cells and in other modes of growth hormone-induced cell signalling that involve Raf-Akt cross-talk. The model suggested that HRG signalling is regulated by protein phosphatase 2A as well as Raf-Akt cross-talk, and protein phosphatase 2A modulates the kinase activity in both the PI3K-Akt and MAPK (mitogen-activated protein kinase) pathways.

Animals↗
PubMed2005

Computational model of electrically coupled, intrinsically distinct pacemaker neurons.

Electrical coupling between neurons with similar properties is often studied. Nonetheless, the role of electrical coupling between neurons with widely different intrinsic properties also occurs, but is less well understood. Inspired by the pacemaker group of the crustacean pyloric network, we developed a multicompartment, conductance-based model of a small network of intrinsically distinct, electrically coupled neurons. In the pyloric network, a small intrinsically bursting neuron, through gap junctions, drives 2 larger, tonically spiking neurons to reliably burst in-phase with it. Each model neuron has 2 compartments, one responsible for spike generation and the other for producing a slow, large-amplitude oscillation. We illustrate how these compartments interact and determine the dynamics of the model neurons. Our model captures the dynamic oscillation range measured from the isolated and coupled biological neurons. At the network level, we explore the range of coupling strengths for which synchronous bursting oscillations are possible. The spatial segregation of ionic currents significantly enhances the ability of the 2 neurons to burst synchronously, and the oscillation range of the model pacemaker network depends not only on the strength of the electrical synapse but also on the identity of the neuron receiving inputs. We also compare the activity of the electrically coupled, distinct neurons with that of a network of coupled identical bursting neurons. For small to moderate coupling strengths, the network of identical elements, when receiving asymmetrical inputs, can have a smaller dynamic range of oscillation than that of its constituent neurons in isolation.

Animals↗
PubMed2006

Evaluation of HI 6 treatment after percutaneous VR exposure by use of a kinetic-based dynamic computer model.

The availability of highly toxic OP-type chemical warfare agents (nerve agents) and the exertion of organophosphorus compounds during military conflicts and terrorist attacks against civilians in the past underlines the necessity of an effective treatment regimen of OP-poisoning. Presently, standard treatment includes administration of an antimuscarinic agent (e.g. atropine) and a reactivator of inhibited AChE (oxime), but is considered to be rather ineffective with certain nerve agents due to low oxime effectiveness of the currently available oximes, obidoxime and pralidoxime. The evaluation of new oximes as antidotes relies on the implementation of animal experiments for ethical reasons and is complicated by a limited extrapolation of animal data to humans. The development of a reliable animal model might accelerate the evaluation of new substances and their approval as antidotes, whereas, the pig as higher mammalian species seems to be promising as model animal. A dynamic in vitro model, which allows the calculation of AChE activities at different scenarios was developed to facilitate the definition of effective oxime concentrations and the optimization of oxime treatment of OP poisoning of humans and may furthermore be helpful by designing animal experiments. The model is based on a combination of enzyme kinetics (inhibition, reactivation, aging) of AChE with OP, toxicokinetics and oxime pharmacokinetics. By considering species-specific kinetic data this dynamic model was used for the calculation of AChE activities in humans and pigs after percutaneous exposure with 5x LD(50) VR (Russian VX) and treatment with HI 6, a promising new reactivator of OP-inhibited AChE. Due to a low affinity of HI 6 with VR-inhibited pig AChE the oxime dose that causes maximal reactivation of VR-inhibited pig AChE is conspicuously higher compared to humans. Therefore, the design of animal experiments in consideration of calculated data based on species-specific kinetic values may lead to a more reliable extrapolation of animal data to humans and may reduce the number of necessary animal experiments.

Administration, Cutaneous↗
PubMed2000

The role of the crista terminalis in atrial flutter and fibrillation: a computer modeling study.

Although atrial fibrillation is a common arrhythmia, the underlying mechanisms are incompletely understood. Recent studies have determined the role of the crista terminalis in the mechanisms of a simpler arrhythmia, atrial flutter. We hypothesize that as transverse coupling across the crista terminalis increases, the activation pattern that results is less like typical atrial flutter and more like atrial fibrillation. 6480 Van Capelle elements were coupled in an icosahedron, simulating the right atrium. Atrial simulations were created which incorporated no heterogeneity, heterogeneous coupling, heterogeneous effective refractory periods, and both heterogeneous coupling and effective refractory periods. When the entire crista terminalis was uncoupled, typical atrial flutter occurred. When transverse coupling allowed activation to propagate across the crista terminalis, the flutter cycle length decreased (p<0.0001). In addition, when heterogeneity was present, both the coefficient of variation of cycle length and the number of activation wavelets increased (p<0.0001). Thus, a more rapid reentrant circuit in the superior right atrium drove fibrillatory activity in the remainder of the atrium, as predicted by the "mother wavelet hypothesis." While awaiting in vivo validation, our study indicates that transverse coupling along the crista terminalis may play an important role in the development of atrial fibrillation from atrial flutter.

Atrial Fibrillation↗
PubMed2003

Automated docking of ligands to an artificial active site: augmenting crystallographic analysis with computer modeling.

The W191G cavity of cytochrome c peroxidase is useful as a model system for introducing small molecule oxidation in an artificially created cavity. A set of small, cyclic, organic cations was previously shown to bind in the buried, solvent-filled pocket created by the W191G mutation. We docked these ligands and a set of non-binders in the W191G cavity using AutoDock 3.0. For the ligands, we compared docking predictions with experimentally determined binding energies and X-ray crystal structure complexes. For the ligands, predicted binding energies differed from measured values by +/- 0.8 kcal/mol. For most ligands, the docking simulation clearly predicted a single binding mode that matched the crystallographic binding mode within 1.0 A RMSD. For 2 ligands, where the docking procedure yielded an ambiguous result, solutions matching the crystallographic result could be obtained by including an additional crystallographically observed water molecule in the protein model. For the remaining 2 ligands, docking indicated multiple binding modes, consistent with the original electron density, suggesting disordered binding of these ligands. Visual inspection of the atomic affinity grid maps used in docking calculations revealed two patches of high affinity for hydrogen bond donating groups. Multiple solutions are predicted as these two sites compete for polar hydrogens in the ligand during the docking simulation. Ligands could be distinguished, to some extent, from non-binders using a combination of two trends: predicted binding energy and level of clustering. In summary, AutoDock 3.0 appears to be useful in predicting key structural and energetic features of ligand binding in the W191G cavity.

Automation↗
PubMed2005

Computational model for the estimation of the extracranial doses received during Leksell gamma knife model C treatment.

OBJECT: Extracranial doses received by patients undergoing Leksell gamma knife surgery (GKS) can be of clinical concern. Therefore, the ability to preestimate peripheral doses received outside the treatment field during the GKS would be beneficial and could be used for the optimization of treatment planning by providing a reference for practitioners to calculate the extracranial dose burden to the body before the start of treatment. METHODS: A dose of 40 Gy was delivered to the Rando phantom in a single fraction to a midline hypothetical target close to the center of the skull. Treatment planning was performed for multiple isocenters with a prescription to the 50% isodose of each collimator. Treatment plans were produced for 1, 5, 10, 15, and 20 shots, keeping the same dose and dose distribution at different target volumes. An automatic positioning system was used for positioning the phantom during the treatment. The doses to different organs were measured during GKS using a thermoluminescent dosimeter. In vivo measurements were also made in 200 patients who underwent GKS with the model C unit for different diagnoses at Na Homolce Hospital. CONCLUSIONS: The peripheral dose depended on the collimator size with a logarithmic dependence on collimator size and a linear dependence on the number of shots. This model can be used for the estimation of peripheral doses with a total error less than 20%. This information can help clinicians with treatment planning optimization, especially in patients with long survival expectancy.

Breast↗
PubMed2000

[Computer modeling and experimental research of interactions between two anti-hTNF alpha monoclonal antibody variable regions and hTNF alpha].

On SGI workstation, we constructed two anti-hTNF alpha McAbs by means of homologous protein-structure-prediction method. And then, on the basis of relative experimental results and the surface properties of hTNF alpha and two McAbs, we performed the docking of hTNF alpha into two anti-hTNF alpha McAbs. In order to confirm the models, we prepared two hTNF alpha mutants designed according to the binding models, analysed and predicted the possible changes in complexes resulted from hTNF alpha mutations. The experimental analysis results proved these complex models. This will make the base of our next antibody humanization and/or reshape work.

Antibodies, Monoclonal↗
PubMedDate not supplied

[Computer model for prognosis of incidence of aseptic meningitis].

A possibility of construction of a mathematical model for current prognosing of aseptic meningitis incidence both for 2-4 months in advance and for the whole year has been demonstrated. The initial information consisted of the data on prevalence of enteroviruses in water objects as from May. Comparison of the actual and estimated incidence indicates that with the proposed model, up to 90.4% of the incidence of aseptic meningitis may be explained.

Computer Simulation↗