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PubMed1995

Computer modelling of sulfated carbohydrates: applications to carrageenans.

In this study, X-ray crystallographic data of sulfated monosaccharides have been used to derive appropriate parameters for sulfate groups in the Tripos force field, previously parameterized for carbohydrates. A database of nine sulfated monosaccharides occurring as building blocks of sulfated polysaccharides such as carrageenans and sulfated glycosaminoglycans has been built. These tools have then been used to evaluate the conformational energies of the repeating units of the kappa-, iota- and lambda-carrageenan polymers, taking into account the rotation around the sulfate groups. In a third step, helical conformations of carrageenans have been explored and the results compared with the experimental data obtained by X-ray fibre diffraction. Stable, single, right-handed helices, with geometric and helical parameters in close correspondence with the best models derived from X-ray diffraction data, have been generated. Finally, the configurational statistics of random-coil carrageenan chains have been investigated and compared with experimental data currently available on these polymers. A highly flexible character is predicted for kappa- and iota-carrageenans, with lambda-carrageenan showing slightly more extension.

Carbohydrate Conformation↗

PubMed1999

A computational model of electrical stimulation of the retinal ganglion cell.

Localized retinal electrical stimulation in blind volunteers results in discrete round visual percepts corresponding to the location of the stimulating electrode. The success of such an approach to provide useful vision depends on elucidating the neuronal target of surface electrical stimulation. To determine if electrodes preferentially stimulate ganglion cells directly below them or passing fibers from distant ganglion cells, we developed a compartmental model for electric field stimulation of the retinal ganglion cell (RGC). In this model a RGC is stimulated by extracellular electrical fields with active channels and realistic cell morphology derived directly from a neuronal tracing. Three membrane models were applied: a linear passive model, a Hodgkin-Huxley model with passive dendrites (HH), and a model composed of all active compartments (FCM) with five nonlinear ion channels. Idealized monopolar point and disk stimulating electrodes were positioned above the cell. For the HH and FCM models, the position of lowest cathodal threshold to propagate an action potential was over the soma. Brief (100 microseconds) cathodic stimuli were 20% (HH with disk electrode) to 73% (FCM with point-source) more effective over the soma than over the axon. In the passive model, the axon is preferentially stimulated versus the soma. Although it may be possible to electrically stimulate RGC's near their cell body at lower thresholds than at their axon, these differences are relatively small. Alternative explanations should be sought to explain the focal perceptions observed in previously reported patient trials.

Action Potentials↗

PubMed1991

Does tortuosity in cerebral arterioles impair down-autoregulation in hypertensives and elderly normotensives? A hypothesis and computer model.

A mathematical model of pressure/flow relationships in straight and tortuous intracerebral arterioles is presented. Using this model, it is predicted that patients with severe tortuosity would never be able to tolerate an appreciable decrease in MAP. This morphological alteration may explain the inability of a few hypertensive and normotensive elderly patients to tolerate periods of mild reductions in blood pressure. The alkaline phosphatase histochemical staining technique is potentially an excellent method of establishing the identity of deep white matter signal alterations seen on MRI because of its ability to trace the vascular supply from the brain surface to the lesion.

Aging↗

PubMed2006

[Computer modeling the concentration characteristics of the membrane potential for polymeric membrane, separated non-homogeneous electrolyte solutions].

The influence of the concentration boundary layers on membrane potential (deltapsis) in a single-membrane system on basis of the Kedem-Katchalsky equations was described in cases of horizontally mounted neutral polymeric membrane separates non-homogeneous (mechanically unstirred) binary electrolytic solutions at different concentrations. Results of calculations of deltapsis as a function of ratio solution concentrations (Ch/Cl) at constant values of: concentration Rayleigh number (Rc), concentration polarization coefficient (zetas) and hydrostatic pressure (deltaP) were presented. Calculations were made for the case where on a one side of the membrane aqueous solution of NaCl at steady concentration 10(-3) mol x l(-1) (Cl) was placed and on the other aqueous solutions of NaCl at concentrations from 10(-3) mol x l(-1) to 2 x 10(-2) mol x l(-1) (Ch). Their densities were greater than NaCl solution's at 10(-3) mol x l(-1). It was shown that membrane potential depends on hydrodynamic state of a complex concentration boundary layer-membrane-concentration boundary layer, what is controlled by deltaP, Ch/Cl, Rc and zetas.

Biological Transport↗

PubMed2005

Computational modeling reveals molecular details of epidermal growth factor binding.

BACKGROUND: The ErbB family of receptors are dysregulated in a number of cancers, and the signaling pathway of this receptor family is a critical target for several anti-cancer drugs. Therefore a detailed understanding of the mechanisms of receptor activation is critical. However, despite a plethora of biochemical studies and recent single particle tracking experiments, the early molecular mechanisms involving epidermal growth factor (EGF) binding and EGF receptor (EGFR) dimerization are not as well understood. Herein, we describe a spatially distributed Monte Carlo based simulation framework to enable the simulation of in vivo receptor diffusion and dimerization. RESULTS: Our simulation results are in agreement with the data from single particle tracking and biochemical experiments on EGFR. Furthermore, the simulations reveal that the sequence of receptor-receptor and ligand-receptor reaction events depends on the ligand concentration, receptor density and receptor mobility. CONCLUSION: Our computer simulations reveal the mechanism of EGF binding on EGFR. Overall, we show that spatial simulation of receptor dynamics can be used to gain a mechanistic understanding of receptor activation which may in turn enable improved cancer treatments in the future.

Computer Simulation↗

PubMed1993

Toward a computational model of constraint-driven exploration and haptic object identification.

A conceptual model of the human haptic system in relation to object identification is presented. The model encompasses major architectural elements including representations of haptically accessible object properties and exploratory procedures (EPs)--dedicated movement patterns that are specialized to extract particular properties. These architectural units are related in processing-specific ways. Properties are associated with exploratory procedures in keeping with the extent to which a given procedure delivers information about a given property. The EPs are associated with one another in keeping with their compatibility, as determined by parameters of motor execution and interactions with the object and the workspace. The resulting architecture is treated as a system of constraints which guide the exploration of an object during the course of identification. The selection of the next step in a sequence of exploration requires that constraints be optimally satisfied. A network approach to constraint satisfaction is implemented and shown to account for a number of previous empirical results concerning the time course of exploration, object classification speed, and incidental learning about object properties. This system has potential applications for robotic haptic exploration.

Attention↗

PubMed2005

Effects of abnormal posture on capsular ligament elongations in a computational model subjected to whiplash loading.

Although considerable biomechanical investigations have been conducted to understand the response of the cervical spine under whiplash (rear impact-induced postero-anterior loading to the thorax), studies delineating the effects of initial spinal curvature are limited. This study advanced the hypothesis that abnormal curvatures (straight or kyphotic) of the cervical column affect spinal kinematics during whiplash loading. Specifically, compared to the normal lordotic curvature, abnormal curvatures altered facet joint ligament elongations. The quantifications of these elongations were accomplished using a validated mathematical model of the human head-neck complex that simulated three curvatures. The model was validated using companion experiments conducted in our laboratory that provided facet joint kinematics as a function of cervical spinal level. Regional facet joint ligament elongations were investigated as a function of whiplash loading in the four local anatomic regions of each joint. Under the normal posture, greatest elongations occurred in the dorsal anatomic region at the C2-C3 level and in the lateral anatomic region from C3-C4 to C6-C7 levels. Abnormal postures increased elongation magnitudes in these regions by up to 70%. Excessive ligament elongations induce laxity to the facet joint, particularly at the local regions of the anatomy in the abnormal kyphotic posture. Increased laxity may predispose the cervical spine to accelerated degenerative changes over time and lead to instability. Results from the present study, while providing quantified level- and region-specific kinematic data, concur with clinical findings that abnormal spinal curvatures enhance the likelihood of whiplash injury and may have long-term clinical and biomechanical implications.

Cervical Vertebrae↗

PubMed1991

Hemodynamics of the central nervous system arteriovenous malformation nidus during particulate embolization. A computer model.

We have modelled the hemodynamics of the nidus of the central nervous system (CNS) arteriovenous malformation (AVM) during the process of particulate embolization. The model accurately reproduces the visually apparent incremental slowing observed during such embolization of CNS AVMs. The model is simple and proposes that the nidus is composed of many identical microchannels. As the microchannels are occluded by particles at a constant rate, the rate of change of flow reduction with each bolus of emboli constantly increases exponentially. A rapid reduction in apparent flow rate occurs immediately prior to complete occlusion. With a more accurate understanding of the working of the nidus of CNS AVMs we can increase the safety of therapeutic particulate embolization.

Cerebrovascular Circulation↗

PubMed2005

Computer modeling of acceleration effects on cerebral oxygen saturation.

INTRODUCTION: Failure to effectively regulate BP and cerebral perfusion during high-G aircraft maneuvering may contribute to reduced performance in pilots due to the fact that perfusion to the peripheral cerebral tissues may not be adequate to support the mental demands of flight. Therefore, a critical area of investigation is the study of cortical tissue oxygenation responses to +Gz acceleration. METHODS: Two experiments were used to build two sections of a cerebral oxygen saturation (rSo2) model. Experiment 1: Six subjects participated in the study. A cerebral oximeter (gold standard) provided rSo2. Acceleration profiles (subjects relaxed) included a 0.1 G x s(-1) G onset to central light loss (CLL) and a 3 G x s(-1) onset to a G level that was 1 Gz above CLL to an endpoint of G-LOC. Experiment 2: There were 12 subjects (with G protection) who participated in this study. The rSo2 data were collected during five different simulated aerial combat maneuvers. A model was created that read the Gz profile as input and calculated changes in rSo2. The correlation coefficient, linear best-fit slope, and mean percent error were calculated to determine agreement. RESULTS: The average value for the correlation coefficients, linear best-fit slopes, and mean percent errors for the unprotected subjects were 0.79, 0.87, and 6.08, respectively. These values for the protected subjects were 5 G (0.994, 1.011, 0.384), 6 G (0.994, 0.909, 0.811), 7 G (0.986, 1.061, 0.692), 8 G (0.969, 1.016, 1.300), and 9 G (0.994, 0.979, 0.558), respectively. DISCUSSION: The model is a good predictor of rSo2 values for protected and unprotected subjects under +Gz stress.

Adult↗

PubMedDate not supplied

A computational model for free radicals transport in the microcirculation.

Nitric oxide (NO), superoxide (O(2)(-)), and peroxynitrite (ONOO(-)) interactions in pathophysiologic conditions such as cardiovascular disease, hypertension, and diabetes have been studied extensively in vivo and in vitro. A reduction in bioavailability of NO is a common event that is known as the endothelial dysfunction in these conditions. Despite intense investigation of NO biotransport and O(2)(-) and ONOO(-) biochemical interactions in vasculature, we have very little quantitative knowledge of distributions and concentrations of NO, O(2)(-), and ONOO(-) under normal physiologic and pathophysiologic conditions. Based on fundamental principles of mass balance, vessel geometry, and reaction kinetics, we developed a mathematical model of these free radicals transport in and around an arteriole during oxidative stress. We investigated the role of O(2)(-) and ONOO(-) in inactivating vasoactive NO. The model predictions include (a) NO interactions with oxygen, O(2)(-), and ONOO(-) have relatively little effect on the NO level in the vascular smooth muscle under physiologic conditions; (b) superoxide diffuses only a few microns from its source, whereas peroxynitrite diffuses over a larger distance; and (c) reduced superoxide dismutase levels significantly increase O(2)(-) and peroxynitrite concentrations and decrease NO concentration. Model results indicate that the reduced NO bioavailability and enhanced peroxynitrite formation may vary depending on the location of oxidative stress in the microcirculation, which occurs at diverse vascular cell locations in diabetes, aging, and cardiovascular diseases. The results will have significant implications for our understanding of these free radical interactions in physiologic and pathophysiologic conditions resulting from endothelial dysfunction.

Arterioles↗

PubMed1995

Cardiac tissue geometry as a determinant of unidirectional conduction block: assessment of microscopic excitation spread by optical mapping in patterned cell cultures and in a computer model.

OBJECTIVE: Unidirectional conduction block (UCB) and reentry may occur as a consequence of an abrupt tissue expansion and a related change in the electrical load. The aim of this study was to evaluate critical dimensions of the tissue necessary for establishing UCB in heart cell culture. METHODS: Neonatal rat heart cell cultures with cell strands of variable width emerging into a large cell area were grown using a technique of patterned cell growth. Action potential upstrokes were measured using a voltage sensitive dye (RH-237) and a linear array of 10 photodiodes with a 15 microns resolution. A mathematical model was used to relate action potential wave shapes to underlying ionic currents. RESULTS: UCB (block of a single impulse in anterograde direction - from a strand to a large area - and conduction in the retrograde direction) occurred in narrow cell strands with a width of 15(SD 4) microns (1-2 cells in width, n = 7) and there was no conduction block in strands with a width of 31(8) microns (n = 9, P < 0.001) or larger. The analysis of action potential waveshapes indicated that conduction block was either due to geometrical expansion alone (n = 5) or to additional local depression of conduction (n = 2). In wide strands, action potential upstrokes during anterograde conduction were characterised by multiple rising phases. Mathematical modelling showed that two rising phases were caused by electronic current flow, whereas local ionic current did not coincide with the rising portions of the upstrokes. CONCLUSIONS: (1) High resolution optical mapping shows multiphasic action potential upstrokes at the region of abrupt expansion. At the site of the maximum decrement in conduction, these peaks were largely determined by the electrotonus and not by the local ionic current. (2) Unidirectional conduction block occurred in strands with a width of 15(4) microns (1-2 cells).

Action Potentials↗

PubMed2000

A discrete-event computer model of feline herpes virus within cat populations.

The purpose of this work was to study the epidemiology of feline herpes virus (FHV), which causes a respiratory disease within natural populations of domestic cats. A stochastic model was constructed using discrete-events simulation. Two habitats (rural vs. urban) were simulated, featuring different demographic, spatial and social patterns. The evolution of immunity in individuals was reproduced, allowing for the random recrudescence of latent infections (influenced by environment and reproduction). Hypotheses concerning the circulation of FHV were examined regarding the role of host density and the possibility of reinfection of host. Uncertainty analyses were performed on the basis of replicated Monte Carlo sampling. The results were in good agreement with serologic data from a long-term study conducted on five populations in France. The model satisfactorily reproduced the variability of natural immunity, and the epidemic features observed. The simulations have shown that FHV can persist in small populations (because of its capacity of reactivation leading to epidemics). However, the impact on demography was not dramatic. The most important parameters in determining change in epidemiology of FHV were: transmission rate corresponding to 'friendly' contacts, and the recrudescence rate of FHV. However, an interaction between these two parameters did not allow estimation of their values.

Animals↗

PubMed2001

A computer model to simulate patellar biomechanics following total knee replacement: the effects of femoral component alignment.

OBJECTIVE: The objective of this study is to analyze the biomechanics of the patellar component following total knee replacement. More specifically we investigated the effect of displacing the femoral component of an Insall-Burstein II total knee replacement on the patellar tracking and patello-femoral contact pressures. DESIGN: We used a validated computer simulation of the knee joint to virtually insert the femoral component with the following four types of placements: (1) no misplacement, (2) 5 degrees of internal rotation, (3) 5 degrees of external rotation and (4) 5 degrees of flexion rotation. The patellar 3D tracking and patello-femoral contact pressures were computed for each femoral component placement as a function of knee flexion angle. BACKGROUND: Complications at the patello-femoral joint are the among most frequent following total knee replacement. RESULTS: Femoral component placement unevenly affected the associated patellar tracking: a 5 degrees internal rotation tilted and rotated the patella laterally by about 5 degrees throughout knee flexion. A 5 degrees external rotation of the femoral component had less effect on patellar tracking. A rotation of 5 degrees in flexion primarily caused patellar rotation (5-10 degrees lateral rotation). Femoral component malalignment had only minor effects on the peak pressure distributions at the patello-femoral interface. CONCLUSION: These results suggest that femoral component positioning primarily affects patellar tracking, with a possible threat for patellar subluxation under external rotation of the femoral component. RELEVANCE: Precise alignment of the prosthetic components is difficult to control during total knee replacement due to the lack of precise anatomical landmarks in the human knee joint. Consequently, the position of each prosthetic component may differ from the ideal one suggested by the manufacturer. Improper alignment of the prosthetic components during total knee replacement may lead to premature implant failure.

Arthroplasty, Replacement, Knee↗

PubMed2004

Changes in foot loading following plantar fasciotomy: a computer modeling study.

Forward dynamic simulations of a toe-rise task were developed to explore the outcomes of plantar fasciotomy, a surgery commonly performed to relieve heel pain. The specific objectives of this study were to develop such a simulation, validate its predictions, and simulate rising on toes using a model from which the plantar fascia had been removed. Root-mean squared differences between the intact model and measurements of healthy subjects were found to be 0.009 body weights (BW) and 0.055 BW for the horizontal and vertical ground reaction forces and 7.1 mm, 11.3 mm, and 0.48 deg for the horizontal, vertical and rotational positions of the pelvis. Simulated plantar fasciotomy increased passive arch torques by 7.4%, increased metatarsal head contact forces by 18%, and resulted in greater toe flexor activity. These simulations may explain the mechanisms behind plantar fasciotomy complications when patients perform activities that require loading of the plantarflexors and the longitudinal arch.

Adaptation, Physiological↗

PubMed2003

Computer modeling of promoter organization as a tool to study transcriptional coregulation.

Understanding how the regulation of gene networks is orchestrated is an important challenge for characterizing complex biological processes. Gene transcription is regulated in part by nuclear factors that recognize short DNA sequence motifs, called transcription factor binding sites, in most cases located upstream of the gene coding sequence in promoter and enhancer regions. Genes expressed in the same tissue under similar conditions often share a common organization of at least some of these regulatory binding elements. In this way the organization of promoter motifs represents a "footprint" of the transcriptional regulatory mechanisms at work in a specific biologic context and thus provides information about signal and tissue specific control of expression. Analysis of promoters for organizational features as demonstrated here provides a crucial link between the static nucleotide sequence of the genome and the dynamic aspects of gene regulation and expression.

Animals↗

PubMed2005

Vessel maturation effects on tumour growth: validation of a computer model in implanted human ovarian carcinoma spheroids.

We analysed measurements of tumour growth, neovascular maturation and function in human epithelial ovarian carcinoma xenografts, studied noninvasively by magnetic resonance imaging. Results suggest that vascular maturation and mature and immature vessel regression occur continuously during tumour neovascularisation. Moreover, in these spheroids, a high tumour growth-rate is associated with monotonic changes in vessel density (VD) and with large proportions of mature blood vessels, whereas a lower tumour growth-rate is associated with fluctuating VD and lower proportions of mature vessels. These results corroborate a mathematical model for tumour dynamics, including vascular maturation and immature and mature vessel regression. The model predicts that rapid tumour growth may result from a high maturation-rate of neo-vasculatures, due to substantial mature VD in the microenvironment, while a slower tumour growth is an outcome of a lower background VD, leading to a lower vessel maturation-rate, larger proportion of immature vessels and, consequently, to regression-driven instabilities. The generality of these results for other tumour types should be validated.

Animals↗

PubMed1992

Computer modeling of fibrin polymerization kinetics correlated with electron microscope and turbidity observations: clot structure and assembly are kinetically controlled.

Although much is known about fibrin polymerization, because it is complex, the effects of various modifications are not intuitively obvious and many experimental observations remain unexplained. A kinetic model presented here that is based on information about mechanisms of assembly accounts for most experimental observations and allows hypotheses about the effects of various factors to be tested. Differential equations describing the kinetics of polymerization were written and then solved numerically. The results have been related to turbidity profiles and electron microscope observations. The concentrations of intermediates in fibrin polymerization, and fiber diameters, fiber and protofibril lengths have been calculated from these models. The simplest model considered has three steps; fibrinopeptide A cleavage, protofibril formation, and lateral aggregation of protofibrils to form fibers. The average number of protofibrils per fiber, which is directly related to turbidity, can be calculated and plotted as a function of time. The lag period observed in turbidity profiles cannot be accurately simulated by such a model, but can be simulated by modifying the model such that oligomers must reach a minimum length before they aggregate. Many observations, reported here and elsewhere, can be accounted for by this model; the basic model may be modified to account for other experimental observations. Modeling predicts effects of changes in the rate of fibrinopeptide cleavage consistent with electron microscope and turbidity observations. Changes only in the rate constants for initiation of fiber growth or for addition of protofibrils to fibers are sufficient to account for a wide variety of other observations, e.g., the effects of ionic strength or fibrinopeptide B removal or thrombospondin. The effects of lateral aggregation of fibers has also been modeled: such behavior has been observed in turbidity curves and electron micrographs of clots formed in the presence of platelet factor 4. Thus, many aspects of clot structure and factors that influence structure are directly related to the rates of these steps of polymerization, even though these effects are often not obvious. Thus, to a large extent, clot structure is kinetically determined.

Biophysical Phenomena↗

PubMed1986

Computer modeling of the reaction between antigen and heterogeneous antibody in fixed antigen excess: a new method for measuring antibody affinity.

Antigen-antibody binding experiments were performed by choosing antigen excess starting conditions and then diluting both the 125I-BSA antigen and anti-BSA proportionately so that the ratio between the reactants remained constant. The fraction antigen bound was measured at each dilution. Binding data were analyzed by computer using non-linear least squares regression to determine the affinity and affinity distribution of different antisera. Early anti-BSA was found to have a unimodal distribution with a binding constant in the range of 10(6)M-1. Intermediate anti-BSA had a bimodal distribution: 1/3 high affinity (1.0 X 10(9] and 2/3 low affinity (3.4 X 10(6)M-1). Late and hyperimmune rabbit BSA antibodies had unimodal affinity distributions with binding constants varying between 1.7 and 2.9 X 10(10)M-1. Antibody affinity can be readily determined by computer analysis of binding curves obtained in constant antigen excess conditions.

Animals↗