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Results for “computational modelling”

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PubMed1987

Computer modelling of measurement error in longitudinal lung function data.

The effect of measurement error on the accuracy of results in two epidemiological study designs involving longitudinal lung function data was assessed using computer modelling. Five realistic data sets (cohorts) were created, each of 400 subjects, half of whom were exposed to an agent whose effects approximated in magnitude that of cigarette smoking. In each cohort, FEV1 decline was modelled after 6, 4 and 2 years of observation with and without error in the measurement of level of FEV1. For each length of observation the effect of exposure on decline was estimated using a follow-up design comparing the FEV1 decline between exposure groups, and a case-control design comparing risk of exposure in subjects in the top 20th percentile of FEV1 decline (cases) to exposure in those in the bottom 20th percentile (controls). For both study designs an exposure effect at p less than or equal to 0.01 could only be consistently detected after 6 years of observation.

Computer Simulation↗

PubMed2004

A computational model of monkey cortical grating cells.

Grating cells were discovered in the V1 and V2 areas of the monkey visual cortex by von der Heydt et al. (1992). These cells responded vigorously to grating patterns of appropriate orientation and periodicity. Computational models inspired by these findings were used as texture operator (Kruzinga and Petkov 1995, 1999; Petkov and Kruzinga 1997) and for the emergence and self-organization of grating cells (Brunner et al. 1998; Bauer et al. 1999). The aim of this paper is to create a grating cell operator that demonstrates similar responses to monkey grating cells by applying operator to the same stimuli as in the experiments carried out by von der Heydt et al. (1992). Operator will be tested on images that contain periodic patterns as suggested by De Valois (1988). In order to learn more about the role of grating cells in natural vision, operator is applied to 338 real-world images of textures obtained from three different databases. The results suggest that grating cells respond strongly to regular alternating periodic patterns of a certain orientation. Such patterns are common in images of human-made structures, like buildings, fabrics, and tiles, and to regular natural periodic patterns, which are relatively rare in nature.

Animals↗

PubMed1999

A computational model of selective deficits in first and second-order motion processing.

Recent neurological studies of selective impairments in first and second-order motion processing are of considerable relevance in elucidating the mechanisms of motion perception in normal human observers. We examine the stimuli which have been used to assess first and second-order motion processing capabilities in clinical subjects, and discuss the nature of the computations necessary to extract their motion. We find that a simple computational model of first and second-order motion processing is able to account for the data. The model consists of a first-order channel computing motion at coarse and fine scales, and a coarse scale second-order channel. The second-order channel is sensitive to motion information defined by variations in luminance, contrast, spatial frequency and flicker. When elements of the model are disabled, its performance on either first or second-order motion can be selectively impaired in line with the neurological data.

Brain Diseases↗

PubMed1983

Simultaneous differentiation of three opiate receptor subpopulations by computer modelling.

[3H]-(-)-bremazocine was displaced from guinea-pig brain membrane homogenates by three compounds having different specificity to opiate receptor subpopulations. A three site receptor model showed the best fit of the calculated to the measured value for the opiate mu (DAla2,MePhe4,Gly(ol)5-enkephalin) and the delta specific compound (DAla2,DLeu5-enkephalin). Computer modelling of data from displacement curves with the opiate kappa specific compound U-50.488H favored a two site receptor model.

Animals↗

PubMed1997

A Computer Model for the Pore of Potassium Channel: Oxygen Cage Mechanism.

We have constructed a structural motif for the pore of voltage-gated K(+) channel by computer modeling. The model developed here predicts that the narrowest part of the pore is formed by the four carbonyl oxygens of Gly444 or Gly446, and that the ion selectivity is achieved through "oxygen cage" mechanism. Residues 447, 448 and 449 make the external entrance to the narrowest part of the pore. Of these residues, 449 and 447 are believed to interact directly with TEA. This model agrees well with many available experimental data.

Journal Article↗

PubMed2006

Computational models with thermodynamic and composition features improve siRNA design.

BACKGROUND: Small interfering RNAs (siRNAs) have become an important tool in cell and molecular biology. Reliable design of siRNA molecules is essential for the needs of large functional genomics projects. RESULTS: To improve the design of efficient siRNA molecules, we performed a comparative, thermodynamic and correlation analysis on a heterogeneous set of 653 siRNAs collected from the literature. We used this training set to select siRNA features and optimize computational models. We identified 18 parameters that correlate significantly with silencing efficiency. Some of these parameters characterize only the siRNA sequence, while others involve the whole mRNA. Most importantly, we derived an siRNA position-dependent consensus, and optimized the free-energy difference of the 5' and 3' terminal dinucleotides of the siRNA antisense strand. The position-dependent consensus is based on correlation and t-test analyses of the training set, and accounts for both significantly preferred and avoided nucleotides in all sequence positions. On the training set, the two parameters' correlation with silencing efficiency was 0.5 and 0.36, respectively. Among other features, a dinucleotide content index and the frequency of potential targets for siRNA in the mRNA added predictive power to our model (R = 0.55). We showed that our model is effective for predicting the efficiency of siRNAs at different concentrations. We optimized a neural network model on our training set using three parameters characterizing the siRNA sequence, and predicted efficiencies for the test siRNA dataset recently published by Novartis. On this validation set, the correlation coefficient between predicted and observed efficiency was 0.75. Using the same model, we performed a transcriptome-wide analysis of optimal siRNA targets for 22,600 human mRNAs. CONCLUSION: We demonstrated that the properties of the siRNAs themselves are essential for efficient RNA interference. The 5' ends of antisense strands of efficient siRNAs are U-rich and possess a content similarity to the pyrimidine-rich oligonucleotides interacting with the polypurine RNA tracks that are recognized by RNase H. The advantage of our method over similar methods is the small number of parameters. As a result, our method requires a much smaller training set to produce consistent results. Other mRNA features, though expensive to compute, can slightly improve our model.

Artificial Intelligence↗

PubMed1992

Computer model of ethosuximide's effect on a thalamic neuron.

Ethosuximide appears to have a specific effect on the low-threshold calcium current in thalamic cells. This may be related to its efficacy in the treatment of absence epilepsy. We used a computer model of an individual thalamocortical neuron to better understand the alteration in the low-threshold calcium current under voltage clamp and to predict response to current injection in the presence of ethosuximide. The full model included nine voltage-sensitive ionic channels and a realistic dendritic morphology. The model reproduced the two major responses seen in tissue slices: repetitive spiking with depolarization and the low-threshold calcium spike elicited on release from hyperpolarization. The alteration in low-threshold calcium current with ethosuximide can be explained by a 10-mV depolarizing shift in the steady-state activation curve for this channel with a 10% reduction in maximum channel permeability. Simulations of current injection showed that ethosuximide diminished the low-threshold calcium spike while leaving the tonic firing pattern unaffected. Our results support the hypothesis that ethosuximide's effects on low-threshold calcium current might selectively alter the dynamics of slow bursting in thalamic cells.

Action Potentials↗

PubMed1992

Computer modeling studies on the subsite interactions of ribonuclease T1.

The modes of binding of pGp,ApG,CpG and UpG to the enzyme ribonuclease T1 were determined by computer modeling. Essentially two binding modes are possible for all the four ligands--one with the 3'-phosphate group occupying the phosphate binding site (substrate mode of binding) and the second with the 5'-phosphate group occupying the phosphate binding site (inhibitor mode of binding). The latter binding mode is energetically favoured over the former and in this mode the base (G) and the 5'-phosphate moieties occupy the same sites on the enzyme as 5'-GMP when bound to RNase T1. The ribose moiety of pGp adopts a C3'-endo pucker form when bound to the enzyme and the glycosyl torsion angle will be in -syn range as 5'-GMP in the RNase T1-5'-GMP complex. Based on these results, a mechanism for the release of the product subsequent to cleavage of the substrate by the enzyme has been proposed. The amino acid residues Asn98 and Tyr45 are shown to form the subsites for the phosphate and the base respectively on the 5'-side of the guanine occupying the primary binding site. These studies also provide a stereochemical explanation for the specificity of the 1N subsite for adenine.

Asparagine↗

PubMed1997

A computational model of acute focal cortical lesions.

BACKGROUND AND PURPOSE: Determining how cerebral cortex adapts to sudden focal damage is important for gaining a better understanding of stroke. In this study we used a computational model to examine the hypothesis that cortical map reorganization after a simulated infarct is critically dependent on perilesion excitability and to identify factors that influence the extent of poststroke reorganization. METHODS: A previously reported artificial neural network model of primary sensorimotor cortex, controlling a simulated arm, was subjected to acute focal damage. The perilesion excitability and cortical map reorganization were measured over time and compared. RESULTS: Simulated lesions to cortical regions with increased perilesion excitability were associated with a remapping of the lesioned area into the immediate perilesion cortex, where responsiveness increased with time. In contrast, when lesions caused a perilesion zone of decreased activity to appear, this zone enlarged and intensified with time, with loss of the perilesion map. Increasing the assumed extent of intracortical connections produced a wider perilesion zone of inactivity. These effects were independent of lesion size. CONCLUSIONS: These simulation results suggest that functional cortical reorganization after an ischemic stroke is a two-phase process in which perilesion excitability plays a critical role.

Animals↗

PubMedDate not supplied

Computational model for effects of ligand/receptor binding properties on interleukin-2 trafficking dynamics and T cell proliferation response.

Multisubunit cytokine receptors such as the heterotrimeric receptor for interleukin-2 (IL-2) are ubiquitous in hematopoeitic cell types of importance in biotechnology and are crucial regulators of cell proliferation and differentiation behavior. Dynamics of cytokine/receptor endocytic trafficking can significantly impact cell responses through effects of receptor down-regulation and ligand depletion, and in turn are governed by ligand/receptor binding properties. We describe here a computational model for trafficking dynamics of the IL-2 receptor (IL-2R) system, which is able to predict T cell proliferation responses to IL-2. This model comprises kinetic equations describing binding, internalization, and postendocytic sorting of IL-2 and IL-2R, including an experimentally derived dependence of cell proliferation rate on these properties. Computational results from this model predict that IL-2 depletion can be reduced by decreasing its binding affinity for the IL-2R betagamma subunit relative to the alpha subunit at endosomal pH, as a result of enhanced ligand sorting to recycling vis-à-vis degradation, and that an IL-2 analogue with such altered binding properties should exhibit increased potency for stimulating the T cell proliferation response. These results are in agreement with our recent experimental findings for the IL-2 analogue termed 2D1 [Fallon, E. M. et al. J. Biol. Chem. 2000, 275, 6790-6797]. Thus, this type of model may enable prediction of beneficial cytokine/receptor binding properties to aid development of molecular design criteria for improvements in applications such as in vivo cytokine therapies and in vitro hematopoietic cell bioreactors.

Biological Transport↗

PubMedDate not supplied

A computer model study of the ventricular fibrillation vulnerable window: sensitivity to regional conduction depressions.

The cardiac vulnerable window is typically defined to be that portion of the cardiac cycle during which ectopic stimuli can induce ventricular fibrillation (VF). We have used cardiac electrophysiological computer modeling to investigate how the size and shape of the cardiac vulnerable window is affected by regional conduction velocity depressions (RCVDs), as might be found in ischemia. Computer simulations were performed on a three-dimensional finite-state, discrete-element model of the ventricles of a dog heart, with simulated RCVDs of 0% (normal) to 100% (infarcted) isolated to the apical region of this heart. Using a programmed electrical stimulation protocol, vulnerability was quantified as the number of ectopic stimuli necessary to induce VF. We observed a nonlinear and nonmonotonic relation between increases in RCVD and the vulnerability of the heart to ectopic stimuli. The size and shape of the vulnerable window remained stable through RCVDs of 30%, expanded rapidly thereafter through RCVDs of 90%, and then contracted significantly at the RCVD of 100%. These increases in vulnerability were manifest as both a lowering of the overall stimulus thresholds necessary for fibrillation (window "deepening"), and an increase in the fraction of the cardiac cycle susceptible to these ectopic stimuli (window "widening"). In all cases of induced VF, the mechanism of induction was through reentry facilitated by temporary functional block. Moreover, the ability to form such a block--and thus the likelihood of subsequent VF--was enhanced as the RCVD increased. Taken together, these results demonstrate the complex relation between vulnerability and RCVD and, at the very least, suggest that the entire shape of the vulnerable window, rather than just its minimum threshold, is important when determining a heart's electrical stability. These conclusions are supported by results obtained from an experimental study--which utilized a similar programmed stimulation protocol--of normal and ischemic canine hearts.

Animals↗

PubMed2000

Computer model for glucose-limited growth of a single cell of Escherichia coli B/r-A. Reprinted from Biotechnology and Bioengineering, Vol. 26, Issue 3, Pp 203-216 (1984).

A computer model is described which is capable of predicting changes in cell composition, cell size, cell shape, and the timing of chromosome synthesis in response to changes in external glucose limitation. The model is constructed primarily from information on unrestricted growth in glucose minimal medium. The ability of the model to make reasonable quantitative predictions under glucose-limitation is a test of the plausibility of the basic biochemical mechanisms included in the model. Such a model should be of use in differentiating among competing hypotheses for biological mechanisms and in suggesting as yet unobserved phenomena. The last two points are illustrated with the testing of a mechanism for the control of the initiation of DNA synthesis and predictions on cell-width variations during the division cycle.

Computer Simulation↗

PubMed2006

Integrated neural processes for defining potential actions and deciding between them: a computational model.

To successfully accomplish a behavioral goal such as reaching for an object, an animal must solve two related problems: to decide which object to reach and to plan the specific parameters of the movement. Traditionally, these two problems have been viewed as separate, and theories of decision making and motor planning have been developed primarily independently. However, neural data suggests that these processes involve the same brain regions and are performed in an integrated manner. Here, a computational model is described that addresses both the question of how different potential actions are specified and how the brain decides between them. In the model, multiple potential actions are simultaneously represented as continuous regions of activity within populations of cells in frontoparietal cortex. These representations engage in a competition for overt execution that is biased by modulatory influences from prefrontal cortex. The model neural populations exhibit activity patterns that correlate with both the spatial metrics of potential actions and their associated decision variables, in a manner similar to activities in parietal, prefrontal, and premotor cortex. The model therefore suggests an explanation for neural data that have been hard to account for in terms of serial theories that propose that decision making occurs before action planning. In addition to simulating the activity of individual neurons during decision tasks, the model also reproduces key aspects of the spatial and temporal statistics of human choices and makes a number of testable predictions.

Computational Biology↗

PubMed2006

A computational model of intracellular oxygen sensing by hypoxia-inducible factor HIF1 alpha.

Hypoxia-inducible factor-1, HIF1, transcriptionally activates over 200 genes vital for cell homeostasis and angiogenesis. We developed a computational model to gain a detailed quantitative understanding of how HIF1 acts to sense oxygen and respond to hypoxia. The model consists of kinetic equations describing the intracellular variation of 17 compounds, including HIF1, iron, prolyl hydroxylase, oxygen, ascorbate, 2-oxoglutarate, von Hippel Lindau protein and associated complexes. We tested an existing hypothesis of a switch-like change in HIF1 expression in response to a gradual decrease in O2 concentration. Our model predicts that depending on the molecular environment, such as intracellular iron levels, the hypoxic response varies considerably. We show HIF1-activated cellular responses can be divided into two categories: a steep, switch-like response to O2 and a gradual one. Discovery of this dual response prompted comparison of two therapeutic strategies, ascorbate and iron supplementation, and prolyl hydroxylase targeting, to predict under what microenvironments either effectively increases HIF1alpha hydroxylation. Results provide crucial insight into the effects of iron and prolyl hydroxylase on oxygen sensing. The model advances quantitative molecular level understanding of HIF1 pathways--an endeavor that will help elucidate the diverse responses to hypoxia found in cancer, ischemia and exercise.

Ascorbic Acid↗

PubMed2003

Ligand screening by exoproteolysis and mass spectrometry in combination with computer modelling.

Here, we present a new approach for protein ligand screening based on the use of limited exoproteolysis coupled to MALDI-TOF mass spectrometry, combined with computational modelling and prediction of binding energies. As a test for this combined approach, we have screened a combinatorial library containing 8000 peptides (organized in 60 peptide samples) based on positional scanning format. This library is attached to a poly-Pro framework, and screened against the Abl-SH3 domain. The results obtained demonstrated the validity of the experimental and theoretical approaches in identifying better ligands and in rationalizing the changes in affinity. Exoproteolysis coupled to MALDI-TOF mass spectrometry could be used to screen complex libraries in a fast and efficient way.

Algorithms↗

PubMed1996

A Computational Model for Color Constancy by Separating Reflectance and Illuminant Edges within a Scene.

Several psychophysical experiments have revealed that color constancy exists even in shadowed scenes where the spatial power distribution of the illuminant has abrupt step changes, while previous models for color constancy fail to distinguish shadows and reflectance changes. This article addresses this problem and proposes a computational model for color constancy which separates reflectance and illuminant edges by two modules recovering both the spatial power distribution of the illuminant and surface reflectances of an object from an input scene. Each module has a line process which interprets whether a given edge is derived from a reflectance or illuminant change based on prior knowledge of shadows: it is mainly luminance that changes at the boundry of a shadowed area. Simulation results show that the proposed model correctly detects reflectance and illuminant edges and illuminant colors, and successfully removes the illuminant from the input scene. This suggests that recovering both surface reflectance and the spatial power distribution of the illuminant is one of the possible ways to achieve color constancy in shadows. Copyright 1996 Elsevier Science Ltd.

Journal Article↗

PubMedDate not supplied

High frequency stimulation of the subthalamic nucleus eliminates pathological thalamic rhythmicity in a computational model.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) or the internal segment of the globus pallidus (GPi) has recently been recognized as an important form of intervention for alleviating motor symptoms associated with Parkinson's disease, but the mechanism underlying its effectiveness remains unknown. Using a computational model, this paper considers the hypothesis that DBS works by replacing pathologically rhythmic basal ganglia output with tonic, high frequency firing. In our simulations of parkinsonian conditions, rhythmic inhibition from GPi to the thalamus compromises the ability of thalamocortical relay (TC) cells to respond to depolarizing inputs, such as sensorimotor signals. High frequency stimulation of STN regularizes GPi firing, and this restores TC responsiveness, despite the increased frequency and amplitude of GPi inhibition to thalamus that result. We provide a mathematical phase plane analysis of the mechanisms that determine TC relay capabilities in normal, parkinsonian, and DBS states in a reduced model. This analysis highlights the differences in deinactivation of the low-threshold calcium T -current that we observe in TC cells in these different conditions. Alternative scenarios involving convergence of thalamic signals in the cortex are also discussed, and predictions associated with these results, including the occurrence of rhythmic rebound bursts in certain TC cells in parkinsonian states and their drastic reduction by DBS, are stated. These results demonstrate how DBS could work by increasing firing rates of target cells, rather than shutting them down.

Action Potentials↗

PubMedDate not supplied

[Widening of the sub-acromial space using a wedge osteotomy of the scapular spine. Anatomical bases, measurements on the preparation, studies of the kinematics of the acromion movements on a computer model].

We describe the theoretical principles of a new kind of decompression of subacromial impingement syndrome by means of a wedge osteotomy at the transition between acromion and spine of the scapula. The operation on cadaver bone and the simulation of acromion movement in a computer model demonstrate an increase of subacromial space more than 1 cm after wedge excision with cranial base of 5 mm and ventral base of 3 mm. After the excision of an anterior based wedge the resection of the coracoacromial ligament is not necessary. An angle between 50 and 60 degrees from mediocranial to laterocaudal referred to the transverse plane has been calculated as optimal. We regard the sparing of the abducting parts of deltoid muscle, the better approach to the cuff with the possibility to mobilize the supraspinate muscle in cases of greater cuff-tears and the possibility to obtain a smooth undersurface of the acromion as further advantages of this procedure. Further biomechanic experiments will be necessary to optimize osteosynthesis.

Acromion↗