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At least 1,693 records · Page 94Linked to original sources
PubMed2000

Emergence of a subpopulation in a computational model of tumor growth.

Malignant brain tumors consist of a number of distinct subclonal populations. Each of these subpopulations may be characterized by its own behaviors and properties. These subpopulations arise from the constant genetic and epigenetic alteration of existing cells in the rapidly growing tumor. However, since each single-cell mutation only leads to a small number of offspring initially, very few newly arisen subpopulations survive more than a short time. The present work quantifies "emergence", i.e. the likelihood of an isolated subpopulation surviving for an extended period of time. Only competition between clones is considered; there are no cooperative effects included. The probability that a subpopulation emerges under these conditions is found to be a sigmoidal function of the degree of change in cell division rates. This function has a non-zero value for mutations which confer no advantage in growth rate, which represents the emergence of a distinct subpopulation with an advantage that has yet to be selected for, such as hypoxia tolerance or treatment resistance. A logarithmic dependence on the size of the mutated population is also observed. A significant probability of emergence is observed for subpopulations with any growth advantage that comprise even 0.1% of the proliferative cells in a tumor. The impact of even two clonal populations within a tumor is shown to be sufficient such that a prognosis based on the assumption of a monoclonal tumor can be markedly inaccurate.

Brain Neoplasms↗
PubMed1996

A computational model of cholinergic disruption of septohippocampal activity in classical eyeblink conditioning.

A previous neurocomputational model of corticohippocampal interaction (Gluck & Myers, 1993) can provide a framework for examining the behavioral effects of septohippocampal modulation during classical conditioning. The model assumes that the hippocampal region is necessary for forming new stimulus representations during learning, but not for the formation of simple associations. This paper considers how septohippocampal interaction could affect this function. The septal nuclei provide several modulatory inputs to the hippocampus, including a cholinergic input which Hasselmo (1995) has suggested may function to regulate hippocampal dynamics on a continuum between two states: a storage state in which incoming information is encoded as an intermediate-term memory and a recall state when this information is reactivated. In this theory, anticholinergic drugs such as scopolamine should disrupt learning by selectively reducing the hippocampus's ability to store new information. An approximation of Hasselmo's idea can be implemented in the corticohippocampal model by a simple manipulation of hippocampal learning rate; this manipulation is formally equivalent to adjusting the amount of time the hippocampus spends in learning and recall states. With this manipulation, the model successfully accounts for the effects of scopolamine in retarding classical conditioning in humans (Solomon, Groccia-Ellison, Flynn, Mirak, Edwards, Dunehew, & Stanton, 1993) and animals (Solomon, Soloman, van der Schaaf, & Perry, 1983). The model further predicts that although cholinergic agonists (such as Tacrine) may improve learning in subjects with artificially depressed brain acetylcholine levels, there may be limited memory improvement in normal subjects from such cholinergic therapy. This is consistent with the general finding of a U-shaped dose response curve for cholinergic drugs in normal subjects: low to moderate doses may improve learning, but higher doses are ineffective or even degrade learning (e.g., Ennaceur & Meliani, 1992; Dumery, Derer, & Blozovski, 1988; etc.).

Animals↗
PubMed1991

A computational model of the vertical anatomical organization of primary visual cortex.

A method for modeling anatomical connectivity for a vertically organized slab of cortical tissue in mammalian primary visual cortex has been developed. The modeled slab covers 500 x 500 microns of cortical surface and extends vertically throughout the full depth of the cortex. The model slab was divided into 6 laminae and neuronal somata were distributed in three dimensions through the slab in accordance with experimentally derived cell densities. Axonal and dendritic arborizations were modeled as line segments. A total of 17 morphological types of neurons were included. Connectivity was established based on proximity between axonal and dendritic arbors. There is good general agreement between the vertical distribution of connections generated by the model and the vertical distribution of synapses observed for cat area 17. In all layers, fewer connections were generated in the model than synapses in cat area 17. This is due, at least in part, to the exclusion of long range intracortical projections and sources of afferent input other than the dorsal lateral geniculate nucleus from the model. The connection scheme described here will be used in conjunction with a physiology model to model vertical signal flow, and will be expanded further to model receptive fields of cortical neurons.

Afferent Pathways↗
PubMed1992

Control of rabbit nictitating membrane movements. I. A computer model of the retractor bulbi muscle and the associated orbital mechanics.

Our objective in this study is to synthesize existing experimental data by constructing a realistic neuromechanical control model of rabbit nictitating membrane (NM) movements. We model the retractor bulbi muscle at the motor unit level because this is the level of nervous system control and also facilitates comparison with experimental data. Our motor unit model is derived from an earlier model of muscle activation based on calcium kinetics and includes a post-activation potentiation mechanism. Motor units are combined into a model of whole muscle that includes length-tension and force-velocity effects. Finally, we incorporate the muscle model into a biomechanical model in which the globe and NM are represented as a system of inertial, viscous, and elastic elements. The model takes patterns of neural signals (in the form of impulses) as input and produces movement of the NM as output. Our muscle model quantitatively accounts for data on isometric force development and decay for twitch, double shock, and tetanic stimulation. The complete model may be used for analysis of the relationship of motoneuron activity to behavior or as a realistic response generator in models of NM conditioning. This study also highlights gaps in the experimental data on the rabbit NM effector system.

Animals↗
PubMedDate not supplied

Computational model of touch sensory cells (T Cells) of the leech: role of the afterhyperpolarization (AHP) in activity-dependent conduction failure.

Bursts of spikes in T cells produce an AHP, which results from activation of a Na+/K+ pump and a Ca2+-dependent K+ current. Activity-dependent increases in the AHP are believed to induce conduction block of spikes in several regions of the neuron, which in turn, may decrease presynaptic invasion of spikes and thereby decrease transmitter release. To explore this possibility, we used the neurosimulator SNNAP to develop a multi-compartmental model of the T cell. The model incorporated empirical data that describe the geometry of the cell and activity-dependent changes of the AHP. Simulations indicated that at some branching points, activity-dependent increases of the AHP reduced the number of spikes transmitted from the minor receptive fields to the soma and beyond. More importantly, simulations also suggest that the AHP could modulate, under some circumstances, transmission from the soma to the synaptic terminals, suggesting that the AHP can regulate spike conduction within the presynaptic arborizations of the cell and could in principle contribute to the synaptic depression that is correlated with increases in the AHP.

Action Potentials↗
PubMed1985

The degree to which myocardial infarct site and size determine the electrocardiographic axis. Analysis of correlative data by computational modeling.

The spatial electrical QRS axis was determined for 428 twelve-lead electrocardiograms from patients subsequently shown by postmortem dissection to have ventricular myocardial fibrosis or necrosis. Four 16-segment ventricular models of the heart were used to "predict" the spatial electrical QRS axis from known ventricular mass and deficit. The raw model I in ideal anatomic position and vectors perpendicularly outward for each muscle segment showed a mean correlation value of -0.494; model II was rotated in the chest to produce best fit with a correlation of 0.638, but the anatomic orientation was not reasonable; model III maintained original position and orientation but the vectors were scaled (correlation 0.780); and model IV, with nonperpendicular vectors, yielded a mean correlation of 0.793. The exceptions to good predictability formed a distinct subset largely composed of electrocardiograms with some form of variant intraventricular conduction (slight QRS widening, fascicular block patterns and "indeterminate frontal-plane axis").

Electrocardiography↗
PubMed1995

Testing a computational model of light-adaptation dynamics.

Experiments from the periodic and aperiodic traditions were used to guide the development of a quantitatively valid model of light adaptation dynamics. Temporal contrast sensitivity data were collected over a range of 3 log units of mean luminance for sinusoids of 2 to 50 Hz. Probe thresholds on flashed backgrounds were collected over a range of stimulus-onset asynchronies and background intensities from 0.1 to 1000 td. All experiments were performed foveally in the photopic range and used a consistent stimulus paradigm and psychophysical method. The resulting model represents a merging of elements from both traditions, and consists of a frequency-dependent front-end followed by a subtractive process and static nonlinearity.

Adaptation, Ocular↗
PubMed1987

Computational model of the motor program generator for pursuit.

A parallel processing neural network model of a motor program generator (MPG) for pursuit eye movements (PEM) was developed. The MPG model consists of two neural networks (velocity maps), which represent velocity values theta R and theta L respectively, as eccentric locations on the map with zero in the center. Neurons are arranged in a circular layer and connected only to their immediate neighbors. The potential field P of all neurons is analogous to a flat circular membrane whose center can be pushed up or down. During PEM one of the two maps, which are connected in a push-pull fashion, always features an activity peak (AP) which travels with constant velocity vT from one neuron to the next. The shape of P defines whether AP travels in a circle (theta = constant), towards the periphery (theta increase) or towards the center (theta decrease). Such a model provides a novel approach for understanding neural generators of non-periodical motor programs.

Animals↗
PubMed1996

Biarticulating two-dimensional computer model of the human patellofemoral joint.

A biarticulating two-dimensional model of the patellofemoral joint has been developed using geometric and force equilibrium constraints to calculate the orientation of the patella about its mediolateral axis. The equations developed from these constraints were solved using an iterative numerical procedure. The model predicts and explains the proximal rolling of the patella on the femur during flexion; it predicts transfer of contact from the trochlea to the femoral condyles at high knee flexion angles. Variation with flexion angle of the patellar mechanism angle and the patellofemoral joint reaction force magnitude agree well with published experimental results.

Journal Article↗
PubMed1993

Coupling of computer modeling with in vitro methodologies to reduce animal usage in toxicity testing.

The use of in vitro data to support the development of physiologically based pharmacokinetic (PBPK) models and to reduce the requirement for in vivo testing is demonstrated by three examples. In the first example, polychlorotrifluoroethylene, in vitro studies comparing metabolism and tissue response in rodents and primates made it possible to obtain definitive data for a human risk assessment without resorting to additional in vivo studies with primates. In the second example, a PBPK model for organophosphate esters was developed in which the parameters defining metabolism, tissue partitioning, and enzyme inhibition were all characterized by in vitro studies, and the rest of the model parameters were established from the literature. The resulting model was able to provide a coherent description of enzyme inhibition following both acute and chronic exposures in mice, rats, and humans. In the final example, the carcinogenic risk assessment for methylene chloride was refined by the incorporation of in vitro data on human metabolism into a PBPK model.

Animal Testing Alternatives↗