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PubMed2002

Computational model of airway narrowing: mature vs. immature rabbit.

Immature rabbits have greater maximal airway narrowing and greater maximal fold increases in airway resistance during bronchoconstriction than mature animals. We have previously demonstrated that excised immature rabbit lungs have more distensible airways, a lower shear modulus, and structural differences in the relative composition and thickness of anatomically similar airways. In the present study, we incorporated anatomic and physiological data for mature and immature rabbits into a computational model of airway narrowing. We then investigated the relative importance of maturational differences in these factors as determinants of the greater airway narrowing that occurs in the immature animal. The immature model demonstrated greater sensitivity to agonist, as well as a greater maximal fold increase in airway resistance. Exchanging values for airway compliance between the mature and immature models resulted in the mature model exhibiting a greater maximal airway response than the immature model. In contrast, exchanging the shear moduli or the composition of the airway wall relative to the airway size produced relatively small changes in airway reactivity. Our results strongly suggest that the mechanical properties of the airway, i.e., greater compliance of the immature airway, can be an important factor contributing to the greater airway narrowing of the immature animal.

Acetylcholine↗

PubMed2005

Quantification of synchronization during atrial fibrillation by Shannon entropy: validation in patients and computer model of atrial arrhythmias.

Atrial fibrillation (AF), a cardiac arrhythmia classically described as completely desynchronized, is now known to show a certain amount of synchronized electrical activity. In the present work a new method for quantifying the level of synchronization of the electrical activity recorded in pairs of atrial sites during atrial fibrillation is presented. A synchronization index (Sy) was defined by quantifying the degree of complexity of the distribution of the time delays between sites by Shannon entropy estimation. The capability of Sy to discriminate different AF types in patients was assessed on a database of 60 pairs of endocardial recordings from a multipolar basket catheter. The analysis showed a progressive and significant decrease of Sy with increasing AF complexity classes as defined by Wells (AF type I Sy = 0.73 +/- 0.07, type II Sy = 0.56 +/- 0.07, type III Sy = 0.36 +/- 0.04, p < 0.001). The extension of Sy calculation to the whole right atrium showed the existence of spatial heterogeneities in the synchronization level. Moreover, experiments simulated by a computer model of atrial arrhythmias showed that propagation patterns with different complexity could be the basis of different synchronization levels found in patients. In conclusion the quantification of synchronization by Shannon entropy estimation of time delay dispersion may facilitate the identification of different propagation patterns associated with AF, thus enhancing our understanding of AF mechanisms and helping in its treatment.

Algorithms↗

PubMed2005

Interictal to ictal transition in human temporal lobe epilepsy: insights from a computational model of intracerebral EEG.

In human partial epilepsies and in experimental models of chronic and/or acute epilepsy, the role of inhibition and the relationship between the inhibition and excitation and epileptogenesis has long been questioned. Besides experimental methods carried out either in vitro (human or animal tissue) or in vivo (animals), pathophysiologic mechanisms can be approached by direct recording of brain electrical activity in human epilepsy. Indeed, in some clinical presurgical investigation methods like stereoelectroencephalography, intracerebral electrodes are used in patients suffering from drug resistant epilepsy to directly record paroxysmal activities with excellent temporal resolution (in the order of 1 millisecond). The study of neurophysiologic mechanisms underlying such depth-EEG activities is crucial to progress in the understanding of the interictal to ictal transition. In this study, the authors relate electrophysiologic patterns typically observed during the transition from interictal to ictal activity in human mesial temporal lobe epilepsy (MTLE) to mechanisms (at a neuronal population level) involved in seizure generation through a computational model of EEG activity. Intracerebral EEG signals recorded from hippocampus in five patients with MTLE during four periods (during interictal activity, just before seizure onset, during seizure onset, and during ictal activity) were used to identify the three main parameters of a model of hippocampus EEG activity (related to excitation, slow dendritic inhibition and fast somatic inhibition). The identification procedure used optimization algorithms to minimize a spectral distance between real and simulated signals. Results demonstrated that the model generates very realistic signals for automatically identified parameters. They also showed that the transition from interictal to ictal activity cannot be simply explained by an increase in excitation and a decrease in inhibition but rather by time-varying ensemble interactions between pyramidal cells and local interneurons projecting to either their dendritic or perisomatic region (with slow and fast GABAA kinetics). Particularly, during preonset activity, an increasing dendritic GABAergic inhibition compensates a gradually increasing excitation up to a brutal drop at seizure onset when faster oscillations (beta and low gamma band, 15 to 40 Hz) are observed. These faster oscillations are then explained by the model feedback loop between pyramidal cells and interneurons targeting their perisomatic region. These findings obtained from model identification in human temporal lobe epilepsy are in agreement with some results obtained experimentally, either on animal models of epilepsy or on the human epileptic tissue.

Algorithms↗

PubMed2000

Metabolically derived potential on the outer membrane of mitochondria: a computational model.

The outer mitochondrial membrane (OMM) is permeable to various small substances because of the presence of a voltage-dependent anion channel (VDAC). The voltage dependence of VDAC's permeability is puzzling, because the existence of membrane potential on the OMM has never been shown. We propose that steady-state metabolically derived potential (MDP) may be generated on the OMM as the result of the difference in its permeability restriction for various charged metabolites. To demonstrate the possibility of MDP generation, two models were considered: a liposomal model and a simplified cell model with a creatine kinase energy channeling system. Quantitative computational analysis of the simplified cell model shows that a MDP of up to -5 mV, in addition to the Donnan potential, may be generated at high workloads, even if the OMM is highly permeable to small inorganic ions, including potassium. Calculations show that MDP and DeltapH, generated on the OMM, depend on the cytoplasmic pH and energy demand rate. Computational modeling suggests that MDP may be important for cell energy metabolism regulation in multiple ways, including VDAC's permeability modulation and the effect of electrodynamic compartmentation. The osmotic pressure difference between the mitochondrial intermembrane space and the cytoplasm, as related to the electrodynamic compartmentation effects, might explain the morphological changes in mitochondria under intense workloads.

Animals↗

PubMed2006

Role of cellular compartmentation in the metabolic response to stress: mechanistic insights from computational models.

The mechanisms controlling ATP generation in the transition from normal resting conditions to either high work states or ischemia are poorly understood. ATP generation depends upon compartmentation between the mitochondria and cytosol of metabolic pathways and key energy transfer species that cannot be easily assessed experimentally. We developed a multicompartment mathematical model of cardiac metabolism to simulate the metabolic responses to ischemia and increased workload. The model is based on mass balances, transport, and metabolic processes in cardiac tissue, and has three distinct compartments (blood, cytosol, and mitochondria). In addition to distinguishing between cytosol and mitochondria, the model includes a cytosolic subcompartment for glycolytic metabolic channeling. The model simulations predict the rapid activation of glycogenolysis and lactate production at the onset of ischemia, and support the concept of localization of glycolysis to a cytosolic subcompartment. In addition, simulations show that mitochondrial NADH/NAD(+) is primarily determined by oxygen consumption during ischemia, while cytosolic NADH/NAD(+) and lactate production are largely a function of glycolytic flux during the initial phase, and is controlled by mitochondrial NADH/NAD(+) and the malate-aspartate shuttle during the steady state. Finally, the model predicts that metabolic activation with an abrupt increase in workload requires parallel activation of ATP hydrolysis, glycolysis, mitochondrial dehydrogenases, the electron transport chain, and ADP phosphorylation. Taken together, these studies demonstrate the importance of metabolic compartmentation in the regulation of cardiac energetics in response to acute stress, and they highlight the usefulness of computational models in this line of investigation.

Animals↗

PubMed2003

Whale (Balaenoptera physalus) haemoglobin: primary structure, functional characterisation and computer modelling studies.

The functional properties of haemoglobin from the Mediterranean whale Balaenoptera physalus have been studied as functions of heterotropic effector concentration and temperature. Particular attention has been given to the effect of carbon dioxide and lactate since the animal is specialised for prolonged dives often in cold water. The molecular basis of the functional behaviour and in particular of the weak interaction with 2,3-diphosphoglycerate is discussed in the light of the primary structure and of computer modelling. On these bases, it is suggested that the A2 (Pro-->Ala) substitution observed in the beta chains of whale haemoglobin may be responsible for the displacement of the A helix known to be a key structural feature in haemoglobins that display an altered interaction with 2,3-diphosphoglycerate as compared with human haemoglobin. The functional and structural results, discussed in the light of a previous study on the haemoglobin from the Arctic whale Balaenoptera acutorostrata, give further insights into the regulatory mechanisms of the interactive effects of temperature, carbon dioxide and lactate.

Amino Acid Sequence↗

PubMed2005

A dynamic, stochastic, computational model of preference reversal phenomena.

Preference orderings among a set of options may depend on the elicitation method (e.g., choice or pricing); these preference reversals challenge traditional decision theories. Previous attempts to explain these reversals have relied on allowing utility of the options to change across elicitation methods by changing the decision weights, the attribute values, or the combination of this information--still, no theory has successfully accounted for all the phenomena. In this article, the authors present a new computational model that accounts for the empirical trends without changing decision weights, values, or combination rules. Rather, the current model specifies a dynamic evaluation and response process that correctly predicts preference orderings across 6 elicitation methods, retains stable evaluations across methods, and makes novel predictions regarding response distributions and response times.

Humans↗

PubMed2006

Computational modeling of the Plasmodium falciparum interactome reveals protein function on a genome-wide scale.

Many thousands of proteins encoded by the genome of Plasmodium falciparum, the causal organism of the deadliest form of human malaria, are of unknown function. It is of utmost importance that these proteins be characterized if we are to develop combative strategies against malaria based on the biology of the parasite. In an attempt to infer protein function on a genome-wide scale, we computationally modeled the P. falciparum interactome, elucidating local and global functional relationships between gene products. The resulting interaction network, reconstructed by integrating in silico and experimental functional genomics data within a Bayesian framework, covers approximately 68% of the parasite genome and provides functional inferences for more than 2000 uncharacterized proteins, based on their associations. Network reconstruction involved the use of a novel strategy, where we incorporated continuously updated, uniform reference priors in our Bayesian model. This method for generating interaction maps is thus also well suited for application to other genomes, where pre-existing interactome knowledge is sparse. Additionally, we superimposed this map on genomes of three apicomplexan pathogens--Plasmodium yoelii, Toxoplasma gondii, and Cryptosporidium parvum--describing relationships between these organisms based on retained functional linkages. This comparison provided a glimpse of the highly evolved nature of P. falciparum; for instance, a deficit of nearly 26% in terms of predicted interactions is observed against P. yoelii, because of missing ortholog partners in pairs of functionally linked proteins.

Animals↗

PubMed2006

Computational model explains high activity and rapid cycling of Rho GTPases within protein complexes.

Formation of multiprotein complexes on cellular membranes is critically dependent on the cyclic activation of small GTPases. FRAP-based analyses demonstrate that within protein complexes, some small GTPases cycle nearly three orders of magnitude faster than they would spontaneously cycle in vitro. At the same time, experiments report concomitant excess of the activated, GTP-bound form of GTPases over their inactive form. Intuitively, high activity and rapid turnover are contradictory requirements. How the cells manage to maximize both remains poorly understood. Here, using GTPases of the Rab and Rho families as a prototype, we introduce a computational model of the GTPase cycle. We quantitatively investigate several plausible layouts of the cycling control module that consist of GEFs, GAPs, and GTPase effectors. We explain the existing experimental data and predict how the cycling of GTPases is controlled by the regulatory proteins in vivo. Our model explains distinct and separable roles that the activating GEFs and deactivating GAPs play in the GTPase cycling control. While the activity of GTPase is mainly defined by GEF, the turnover rate is a sole function of GAP. Maximization of the GTPase activity and turnover rate places conflicting requirements on the concentration of GAP. Therefore, to achieve a high activity and turnover rate at once, cells must carefully maintain concentrations of GEFs and GAPs within the optimal range. The values of these optimal concentrations indicate that efficient cycling can be achieved only within dense protein complexes typically assembled on the membrane surfaces. We show that the concentration requirement for GEF can be dramatically reduced by a GEF-activating GTPase effector that can also significantly boost the cycling efficiency. Interestingly, we find that the cycling regimes are only weakly dependent on the concentration of GTPase itself.

Amino Acid Sequence↗

PubMed2006

[Computer modeling correlation between the entering wound and the final position of the metallic intraocular foreign body].

AIM: The aim of this study was to establish the correlation coefficient between given parameters of the entering wound and final position of the metallic intraocular foreign body. MATERIAL AND METHODS: Fifty patients (50 eyes) with a penetrating injury of the eye and present metallic intraocular foreign body were included in this study. Clinically found data of the entering wound and final position of the intraocular foreign body (IFB) as well were transformed with a computer model into the three-dimensional parameters. Both parameters were statistically evaluated by means of correlation analysis, and correlation coefficient and determination coefficient were calculated. RESULTS: The extent of correlation between two variables is called correlation coefficient. The coefficient values range between -1 to +1. The closer is the calculated value to ranges (to -1 or to +1) the more are the two variables more correlated. The coefficient of determination values range from 0 to +1. The closer the results are to +1, the better the model describes the dependence between the two variables. The results obtained by means of correlation analysis were for the correlation coefficient 0.454, and for the coefficient of determination 0.6411 respectively. CONCLUSION: Results of the correlation analysis show that the knowledge of coordinates of the entering wound has no prediction value for final position of the foreign body in the eye. These two variables are not correlated and so the accurate final position of the foreign body cannot be predicted. The final position of the intraocular metallic foreign body is probably influenced by biophysical factors not included in this study.

Biomechanical Phenomena↗

PubMed1989

Compensating conduction times as a mechanism of alternating reentry tachycardia: computer modelling experiments.

This article concerns a currently reported hypothesis explaining the alternations of conduction time during intra atrioventricular (AV) nodal reentrant tachycardia (AVNRT). This hypothesis supposes simple mutual influence of sequences of intranodal conduction during reentry tachycardia that use the same circuit in different tachycardia cycles. It has been suggested that delayed conduction prolongs the recovery time of the circuit, thus making it possible to transmit the excitation wave with a faster speed in the next tachycardia loop; this less delayed loop shortens the recovery interval of the pathway and results in subsequently delayed conduction of the following tachycardia cycle. A computer model simulating intra-AV nodal reentrant conduction was used to imitate and prove this hypotheses. The results are negative, showing that the suggested mechanism is too simplistic and that either the pathophysiologic background of the AVNRT cycle length oscillations must be different or additional phenomena must be considered to improve the hypothesis.

Computer Simulation↗

PubMed1999

Cognition and control in schizophrenia: a computational model of dopamine and prefrontal function.

Behavioral deficits suffered by patients with schizophrenia in a wide array of cognitive domains can be conceptualized as failures of cognitive control, due to an impaired ability to internally represent, maintain, and update context information. A theory is described that postulates a single neurobiological mechanism for these disturbances, involving dysfunctional interactions between the dopamine neurotransmitter system and the prefrontal cortex. Specifically, it is hypothesized that in schizophrenia, there is increased noise in the activity of the dopamine system, leading to abnormal "gating" of information into prefrontal cortex. The theory is implemented as an explicit connectionist computational model that incorporates the roles of both dopamine and prefrontal cortex in cognitive control. A simulation is presented of behavioral performance in a version of the Continuous Performance Test specifically adapted to measure critical aspects of cognitive control function. Schizophrenia patients exhibit clear behavioral deficits on this task that reflect impairments in both the maintenance and updating of context information. The simulation results suggest that the model can successfully account for these impairments in terms of abnormal dopamine activity. This theory provides a potential point of contact between research on the neurobiological and psychological aspects of schizophrenia, by illustrating how a particular physiological disturbance might lead to precise and quantifiable consequences for behavior.

Cognition Disorders↗

PubMed2004

[Virtual simulation of dental surgery using a three-dimensional computer model with a force feedback system].

BACKGROUND: Selective reduction of bone without injuring inner structures is an essential part of surgical techniques, especially during dental surgery. Virtual drilling is possible using a new simulator. The following illustrates simulation of an apicectomy. MATERIAL AND METHODS: Using the VOXEL-MAN system, a virtual three-dimensional model of a skull was created based on CT data. Both inferior alveolar nerves and apical inflammations of teeth 23, 25, 36, and 35 were virtually simulated. To achieve a realistic drilling effect with the force feedback system, special tools were integrated into VOXEL-MAN to obtain a high resolution of collision recognition. Adding drilling noises further improved the simulation. Spatial 3D perception was possible with the help of shutter glasses. RESULTS: The presented computer model enabled the visual and haptic observation of complex volume-based models and virtual interaction with them. The haptic feeling proved to be convincing because of collision recognition, consideration of drilling parameters, and addition of drilling noises. Via postoperative reconstructions, polydimensional verification of performed drilling routes is possible. CONCLUSION: Using apicectomies as examples, realistic simulation of dental surgical procedures, even in complex anatomical models, is possible. Generally, it is possible to add virtual pathologies in data sets and/or to use anonymous patient data sets to extend the range of simulated surgical procedures.

Apicoectomy↗

PubMed2001

Functional and computer modelling studies of haemoglobin from horse. The haemoglobin system of the Sardinian wild dwarf horse.

A study was made of the haemoglobin (Hb) system from the Sardinian dwarf horse (Equus caballus jara), one of the last surviving wild horse species in Europe. The oxygen binding properties of the whole haemolysate and of the four different horse Hbs, separated by ion-exchange chromatography, were studied with special regard to the effect of chloride, 2,3-diphosphoglycerate and lactate. Results indicate that no significant functional differences exist between the four Hb components of horse haemolysate. Moreover, the molecular basis of the intrinsically low oxygen affinity and of the weak interaction of horse Hb with 2,3-diphosphoglycerate is discussed in the light of the primary structure of the molecule and of the results of a computer modelling approach. On these bases, it is suggested that the A1 (Thr-->Ser) and A2 (Pro-->Gly) substitutions observed in the beta chains from horse Hb may be responsible for the displacement of the A helix that is known to be a key structural feature of those Hbs that display an altered interaction with 2,3-diphosphoglycerate as compared with human Hb.

Adult↗

PubMedDate not supplied

A computer model for evaluating the costs of cholecystectomy or ursodiol treatment in the management of cholelithiasis.

Over 500,000 cholecystectomies are performed each year in the United States. The procedure has its risks (mortality is 1.2% in the general population and 3% in patients aged 75 years or over) and it is expensive: the average direct cost of each cholecystectomy is about $10,000, for a national total of $5 billion annually. An alternative to surgery is to dissolve the stone with ursodiol, a naturally occurring bile acid, which has been successfully used for cholesterol gallstones with a diameter less than 20 mm. A computer model was developed to compare the costs of surgery for gallstones and treatment with ursodiol. In a hypothetical health maintenance organization with one million enrollees, use of ursodiol treatment rather than cholecystectomy would result in cumulative savings of $8.5 million after one year, $30.7 million after five years, and $57.8 million after ten years.

Cholecystectomy↗

PubMed2005

Developmental analysis and computer modelling of bioengineered teeth.

Here we present the developmental progression of bioengineered pig teeth from 1 to 25 weeks of development. We demonstrate that 2-25 week implants contained embryonic tooth bud- and cap-stage tooth structures consisting of dental epithelium expressing the sonic hedgehog gene and condensed dental mesenchyme. Implants harvested at 18-25 weeks also contained tooth bud-like structures, as well as mature tooth structures containing enamel, dentin and pulp tissues. Immunohistochemical analyses confirmed the expression of dentin- and enamel-specific proteins in differentiated bioengineered tooth tissues. Three-dimensional computer modelling further demonstrated a spatial organization of enamel, dentin and pulp tissues resembling that of natural teeth. We conclude that bioengineered teeth commonly exhibit morphological stages characteristic of naturally forming teeth. Furthermore, the presence of immature tooth buds at all times assayed and increased numbers of bioengineered tooth structures over time suggests that porcine dental progenitor cells maintain the ability to form teeth for at least 25 weeks.

Animals↗

PubMed2003

Computational model of the ventricular action potential in adult spontaneously hypertensive rats.

INTRODUCTION: Cardiac hypertrophy has substantial clinical significance because many hypertrophic cells have markedly prolonged repolarization behavior, which may lead to increased risk for cardiac arrhythmias. Spontaneously hypertensive rat (SHR) is one model of hypertension that is studied extensively and is considered to be the best laboratory model of human hypertension. We extended our previously published model of the rat ventricular myocyte to simulate the effects of hypertrophy in SHR. METHODS AND RESULTS: In SHR it has been shown that the membrane capacitance is increased, the density of transient outward K+ current is decreased, the sarcoplasmic reticulum Ca2+ ATPase activity is reduced, and the cell volumes are increased compared to those of the normal rat. We introduced these changes into our previous model of the rat ventricular myocyte and simulated the ventricular action potential of SHR. Our results demonstrated increased action potential duration (APD) and increased peak systolic value of the intracellular calcium transient in SHR. Simulations with reduced extracellular K+ concentration ([K+]o) have shown that there is increased APD shortening in SHR compared to that of the normal rat. CONCLUSIONS: Our computational model qualitatively simulated the electrophysiologic changes observed in SHR and provided the plausible mechanistic linkage between the prolonged APD and increased inotropy. Our model results also demonstrated the electrophysiologic changes observed with reduced [K+]o in SHR, a finding that is clinically significant in hypertensive patients with left ventricular hypertrophy undergoing diuretic treatment.

Action Potentials↗

PubMed2006

A computational model of visual marking using an inter-connected network of spiking neurons: the spiking search over time & space model (sSoTS).

In the real world, visual information is selected over time as well as space, when we prioritise new stimuli for attention. Watson and Humphreys [Watson, D., Humphreys, G.W., 1997. Visual marking: prioritizing selection for new objects by top-down attentional inhibition of old objects. Psychological Review 104, 90-122] presented evidence that new information in search tasks is prioritised by (amongst other processes) active ignoring of old items - a process they termed visual marking. In this paper we present, for the first time, an explicit computational model of visual marking using biologically plausible activation functions. The "spiking search over time and space" model (sSoTS) incorporates different synaptic components (NMDA, AMPA, GABA) and a frequency adaptation mechanism based on [Ca(2+)] sensitive K(+) current. This frequency adaptation current can act as a mechanism that suppresses the previously attended items. We show that, when coupled with a process of active inhibition applied to old items, frequency adaptation leads to old items being de-prioritised (and new items prioritised) across time in search. Furthermore, the time course of these processes mimics the time course of the preview effect in human search. The results indicate that the sSoTS model can provide a biologically plausible account of human search over time as well as space.

Action Potentials↗