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PubMed1995

Fractionated electrograms from a computer model of heterogeneously uncoupled anisotropic ventricular myocardium.

BACKGROUND: The relation between heterogeneously coupled myocardium and fractionated electrograms is incompletely understood. The purpose of this study was to use a detailed computer model of nonuniformly anisotropic myocardium to test the hypothesis that spatial variation of morphology of electrograms recorded simultaneously from multiple sites increases with increasing heterogeneity of intercellular coupling. METHODS AND RESULTS: A sheet of elements with Beeler-Reuter ionic kinetics was coupled with cytoplasmic resistivity to model cells. Gap junctional resistance values were assigned by recursive randomization to produce a fractal pattern of heterogeneous coupling, simulating damage resulting from infarction. The correlation dimension of the pattern, D, measured heterogeneity of intercellular coupling. The peak-to-peak amplitude, duration, minimum derivative (steepest downslope), number of inflections, frequency of peak power, and bandwidth of unfiltered unipolar electrograms were calculated. Linear regressions indicate (P < .001) that the coefficient of variation of five electrogram metrics increases with increasing substrate heterogeneity and that the distance over which electrogram morphology decorrelates decreases with increasing heterogeneity of intercellular coupling. CONCLUSIONS: These findings confirm our hypothesis that the spatial variation of morphology of electrograms recorded simultaneously from multiple sites increases with increasing heterogeneity of intercellular coupling.

Anisotropy↗

PubMed2017

Addressing current challenges in cancer immunotherapy with mathematical and computational modelling.

The goal of cancer immunotherapy is to boost a patient's immune response to a tumour. Yet, the design of an effective immunotherapy is complicated by various factors, including a potentially immunosuppressive tumour microenvironment, immune-modulating effects of conventional treatments and therapy-related toxicities. These complexities can be incorporated into mathematical and computational models of cancer immunotherapy that can then be used to aid in rational therapy design. In this review, we survey modelling approaches under the umbrella of the major challenges facing immunotherapy development, which encompass tumour classification, optimal treatment scheduling and combination therapy design. Although overlapping, each challenge has presented unique opportunities for modellers to make contributions using analytical and numerical analysis of model outcomes, as well as optimization algorithms. We discuss several examples of models that have grown in complexity as more biological information has become available, showcasing how model development is a dynamic process interlinked with the rapid advances in tumour-immune biology. We conclude the review with recommendations for modellers both with respect to methodology and biological direction that might help keep modellers at the forefront of cancer immunotherapy development.

Computer Simulation↗

PubMed1994

Computer modeling of substrate binding to lipases from Rhizomucor miehei, Humicola lanuginosa, and Candida rugosa.

The substrate-binding sites of the triacyl glyceride lipases from Rhizomucor miehei, Humicola lanuginosa, and Candida rugosa were studied by means of computer modeling methods. The space around the active site was mapped by different probes. These calculations suggested 2 separate regions within the binding site. One region showed high affinity for aliphatic groups, whereas the other region was hydrophilic. The aliphatic site should be a binding cavity for fatty acid chains. Water molecules are required for the hydrolysis of the acyl enzyme, but are probably not readily accessible in the hydrophobic interface, in which lipases are acting. Therefore, the hydrophilic site should be important for the hydrolytic activity of the enzyme. Lipases from R. miehei and H. lanuginosa are excellent catalysts for enantioselective resolutions of many secondary alcohols. We used molecular mechanics and dynamics calculations of enzyme-substrate transition-state complexes, which provided information about molecular interactions important for the enantioselectivities of these reactions.

Binding Sites↗

PubMed1994

Entrainment of reentrant tachycardia in a computer model.

Capture of the cardiac rate by pacing followed by an immediate return to the original rate after pacing has been proposed as characteristic of reentrant rhythms. In this study, such entrainment has been demonstrated using computer-model simulations of propagated excitation and of reentry associated with structural and functional obstacles. With structural obstacles, the mechanism of entrainment was bidirectional propagation of paced excitation in reentry circuits, with collision of the reentrant and paced excitation in one direction and continued propagation of paced excitation in the other direction. The time of pacing onset, rate, and location all affected the QRS waveform during entrainment. With a particular time of onset and rate of pacing, the duration of time during which the QRS waveform underwent dynamic change was directly related to the distance between the pacing site and reentrant circuit. The location of reentry associated with functional obstacles moved so that the relationship between pacing-induced and reentrant excitation varied. In some cycles, pacing did not alter reentrant circuits, that is, entrainment did not occur, while other cycles were entrained, but by a different mechanism than that with structural obstacles. Leading circle reentry circuits, consisting of propagation away from and returning to reentry sites, did not have an excitable gap and paced excitation did not enter those circuits. Paced excitation did, however, enter the propagation paths between leading circle reentry circuits and modified the circuits by affecting the recovery of excitability.

Cardiac Pacing, Artificial↗

PubMedDate not supplied

Clubfoot analysis with three-dimensional computer modeling.

Which way are the bones rotated in a clubfoot? This question has long been debated by clubfoot surgeons. Opinions have been based on observations from surgery, radiographs, and autopsies. These methods all have pitfalls and are subject to misinterpretation. We used three-dimensional computer modeling to analyze histologic sections of a newborn clubfoot and a newborn normal foot. Relative to the bimalleolar axis in the axial plane, the normal talus demonstrated 5 degrees of internal rotation of its body and 25 degrees internal rotation of its neck. The clubfoot talus showed 14 degrees of external rotation of its body and 45 degrees of internal rotation of its neck. The calcaneus was externally rotated 5 degrees in the normal foot and internally rotated 22 degrees in the clubfoot.

Calcaneus↗

PubMed2005

Wavelength and vulnerability to atrial fibrillation: Insights from a computer model of human atria.

AIM: To explain the contradictory results related to the concept of critical cardiac wavelength in the initiation and perpetuation of atrial fibrillation (AF). METHODS: A biophysically based computer model was used to: (1) study the relationship between wavelength and AF perpetuation in the presence of multiple re-entrant wavelets, (2) evaluate the performance of different existing methods for wavelength estimation in the presence of different arrhythmogenic substrates, and (3) document the impact of either heterogeneities in refractoriness or the presence of a mother rotor on wavelength estimation. RESULTS: The simulations confirmed that the wavelength must be below a critical value for AF to be sustained, when the perpetuation mechanism relies on multiple re-entrant wavelets. The estimated value of wavelength was not the same for all methods tested and depended in part on the nature of the spatio-temporal organization of the AF dynamics. CONCLUSION: A priori information about the underlying wavelet dynamics is needed for a correct interpretation of the cardiac wavelength as estimated by the current clinical methods.

Atrial Fibrillation↗

PubMed1982

Electrotonic interactions across an inexcitable region as a cause of ectopic activity in acute regional myocardial ischemia. A study in intact porcine and canine hearts and computer models.

We recorded 60 DC simultaneous electrograms from isolated porcine and canine hearts in the first minutes after coronary occlusion. Ventricular premature beats (VPB) originated from the normal side of the ischemic border, which was frequently separated from the central ischemic area showing delayed activity by a small zone of inexcitable tissue. We attempted in a computer model to generate VPB's at one side of an area showing conduction block. In computer simulations,,, the presence of elements capable of automatic activity greatly facilitated the induction of VPB's. By coupling automatic elements to nonautomatic elements, overt pacemaking activity could be suppressed. Subthreshold depolarizations transmitted through a zone of conduction block could, when properly timed, trigger the latent automatic elements into overt automatic activity, resulting in single or repetitive VPB's. The ventricular premature beats in the intact hearts with acute regional ischemia may be caused by "triggered automaticity" in which the trigger is provided by the "injury current" flowing from ischemic cells showing delayed repolarization via a segment of inexcitable ischemic cells in the border zone to normally perfused cells with suppressed automaticity.

Animals↗

PubMed2002

Application of biologically based computer modeling to simple or complex mixtures.

The complexity and the astronomic number of possible chemical mixtures preclude any systematic experimental assessment of toxicology of all potentially troublesome chemical mixtures. Thus, the use of computer modeling and mechanistic toxicology for the development of a predictive tool is a promising approach to deal with chemical mixtures. In the past 15 years or so, physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling has been applied to the toxicologic interactions of chemical mixtures. This approach is promising for relatively simple chemical mixtures; the most complicated chemical mixtures studied so far using this approach contained five or fewer component chemicals. In this presentation we provide some examples of the utility of PBPK/PD modeling for toxicologic interactions in chemical mixtures. The probability of developing predictive tools for simple mixtures using PBPK/PD modeling is high. Unfortunately, relatively few attempts have been made to develop paradigms to consider the risks posed by very complex chemical mixtures such as gasoline, diesel, tobacco smoke, etc. However, recent collaboration between scientists at Colorado State University and engineers at Rutgers University attempting to use reaction network modeling has created hope for the possible development of a modeling approach with the potential of predicting the outcome of toxicology of complex chemical mixtures. We discuss the applications of reaction network modeling in the context of petroleum refining and its potential for elucidating toxic interactions with mixtures.

Computer Simulation↗

PubMed1986

Structures attached to doublet microtubules of cilia: computer modeling of thin-section and negative-stain stereo images.

With a single set of positional coordinates for longitudinal and transverse attachment of the inner and outer rows of dynein arms with respect to the doublet microtubules of Tetrahymena ciliary axonemes, a computer model has been constructed at 4-nm resolution that reconciles negative-stain en face stereo images of arm and spoke positions to traditional images of tannic acid/glutaraldehyde-fixed sections. In this model, inner and outer arms correspond in substructure; both repeat with a 24-nm periodicity without stagger between rows, and a pair of arms is in exact alignment with the first spoke (S1) in each doublet spoke group. The model and the supporting micrographs suggest that each arm cycles in three dimensions and that, during cycling, the inner and outer arms move in opposite directions with respect to the center of subfiber A of the doublet (N). Attachment is off-center with respect to subfiber B of the adjacent doublet (N + 1), causing the sliding doublets to skew with respect to one another.

Adenosine Triphosphatases↗

PubMed2002

A comparison between tandem and ovoids and interstitial gynecologic template brachytherapy dosimetry using a hypothetical computer model.

PURPOSE: To evaluate the dose distribution within the clinical target volume between two gynecologic brachytherapy systems---the tandem and ovoids and the Syed-Neblett gynecologic template---using a hypothetical computer model. METHODS AND MATERIALS: Source positions of an intracavitary system (tandem and ovoids) and an interstitial system (GYN template) were digitized into the Nucletron Brachytherapy Planning System. The GYN template is composed of a 13-catheter implant (12 catheters plus a tandem) based on the Syed-Neblett gynecologic template. For the tandem and ovoids, the dwell times of all sources were evenly weighted to produce a pear-shaped isodose distribution. For the GYN template, the dwell times were determined using volume optimization. The prescribed dose was then normalized to point A in the intracavitary system and to a selected isodose line in the interstitial system. The treated volume in the two systems was kept approximately the same, and a cumulative dose-volume histogram of the treated volume was then generated with the Nucletron Brachytherapy Planning System to use for comparison. To evaluate the dose to a hypothetical target, in this case the cervix, a 2-cm-long, 3-cm-diameter cylinder centered along the tandem was digitized as the clinical target volume. The location of this hypothetical cervix was based on the optimal application of the brachytherapy system. A visual comparison of clinical target coverage by the treated volume on three different orthogonal planes through the treated volume was performed. The percentage dose-volume histograms of the target were generated for comparison. Multiple midline points were also placed at 5-mm intervals away from the tandem in the plane of the cervix to simulate the location of potential bladder and rectal dose points. Doses to these normal structures were calculated for comparison. RESULTS: Although both systems covered the hypothetical cervix adequately, the interstitial system had a better coverage of the region lateral to the cervix. Smaller volumes of the vagina and uterine fundus received the full dose from the interstitial implant. The cumulative dose-volume histograms revealed larger high-dose regions within the treatment volume for the intracavitary system. The volumes receiving > or = 180% of the prescription dose were 31 cc and 17 cc for the intracavitary system and interstitial system, respectively. The isodose lines showed that most of this difference results from the high-dose region around the tandem. The percentage dose-volume histograms showed that a larger percentage of cervix received a higher dose in the intracavitary system. Fifty-two percent of the target volume received 200% or higher of the prescription dose with tandem and ovoids, compared with only 20% with the template system. Analysis of dose points outside of the 100% isodose lines showed a slightly more rapid dose drop-off with the interstitial system compared to the intracavitary system. Point doses at 20, 25, and 30 mm from the tandem in the interstitial system were 100%, 69%, and 51% of prescribed dose, and from the intracavitary system were 101%, 76%, and 58%, respectively. CONCLUSIONS: Our dosimetric analysis revealed a better coverage in the parametrial regions, but underdosage of the central cervical region, for the interstitial system. On the other hand, because of the increased distance of source to dose point, there is a more rapid dose drop-off outside the treated volume with the interstitial system, which has the potential to improve tissue sparing. Based on this analysis, we caution against using a radiotherapy system with a homogeneous central dose distribution when treating cervical cancer with an intact uterus. We recommend differential loading of the implant catheters with the majority of dose delivered from the tandem when using an interstitial GYN template with remote afterloader.

Brachytherapy↗

PubMed1992

A computer model for the study of electrical current flow in the human thorax.

Electrocardiography has played an important role in the detection and characterization of heart function, both in normal and abnormal states. In this paper we present an inhomogeneous, anisotropic computer model of the human thorax for use in electrocardiography with emphasis on the calculation of transthoracic potential and current distributions. Knowledge of the current pathways in the thorax has many applications in electrocardiography and has direct utility in studies pertaining to cardiac defibrillation, forward and inverse problems, impedance tomography, and electrode placement in electrocardiography.

Computer Simulation↗

PubMed2004

The role of cell death during neocortical neurogenesis and synaptogenesis: implications from a computational model for the rat and mouse.

We are quantitatively evaluating the acquisition of neocortical neurons through key stages of development including neurogenesis, migration, and synaptogenesis. Here we expand upon a previous computational model describing neocortical neurogenesis in the rat and mouse [Dev. Neurosci. 24 (2002) 467], to include the period of synaptogenesis (P0-P14) when programmed cell death (PCD) is known to play a major role in shaping the neocortex. We also quantitatively evaluate differing hypotheses on the role of cell death during neurogenesis. This new model construct allows prediction of acquisition of adult neuronal number in the rat and mouse neocortex from the beginning of neurogenesis through synaptogenesis. The mathematical model output is validated by independently derived stereologically determined neuron number estimates in the adult rat and mouse. Simulations suggest cell death during synaptogenesis reduces the neocortical neuronal population by 20-30%, while cell death of progenitor cells and newly formed neurons during neurogenesis may reduce output by as much as 24%. However, higher death rates during neurogenesis as suggested by some research would deplete the progenitor population, not allowing for the vast expansion that is the hallmark of the mammalian neocortex. Furthermore, our simulations suggest the clearance time of dying neurons labeled by TUNEL or pyknosis is relatively short, between 1 and 4 h, corroborating experimental research. This novel mathematical model for adult neocortical neuronal acquisition allows for in silico analysis of normal and perturbed states of neocortical development as well as interspecies and evolutionary analyses of neocortical development.

Animals↗

PubMed2006

Computational models of the hippocampal region: implications for prediction of risk for Alzheimer's disease in non-demented elderly.

We have pursued an interdisciplinary research program to develop novel behavioral assessment tools for evaluating specific memory impairments following damage to the medial temporal lobe, including the hippocampus and associated structures that show pathology early in the course of Alzheimer's disease (AD). Our approach uses computational models to identify the functional consequences of hippocampal-region damage, leading to testable predictions in both rodents and humans. Our modeling argues that hippocampal-region dysfunction may selectively impair the ability to generalize when familiar information is presented in novel recombinations. Previous research has shown that specific reductions in hippocampal volume in non-demented elderly individuals correlate with future development of AD. In two previous studies, we tested non-demented elderly with and without mild hippocampal atrophy (HA) on stimulus-response learning tasks. Individuals with and without HA could learn the initial information, but the HA group was selectively impaired on transfer tests where familiar features and objects were recombined. This suggests that such generalization deficits may be behavioral markers of HA, and an early indicator of risk for subsequent cognitive decline. Converging support for the relevance of these tasks to aging and Alzheimer's disease comes from our recent fMRI studies of individuals with mild cognitive impairment (MCI). Activity in the hippocampus declines with progressive training on these tasks, suggesting that the hippocampus is important for learning new stimulus representations that support subsequent transfer. Individuals with HA may be able to learn, but in a more hippocampal-independent fashion that does not support later transfer. Ultimately, this line of research could lead to a novel battery of behavioral tests sensitive to very mild hippocampal atrophy and risk for decline to AD, allowing early diagnosis and also allowing researchers to test new Alzheimer's drugs that target individuals in the earliest stages of the disease - before significant cognitive decline. A new mouse version of one of our tasks shows promise for translating these paradigms into rodents, allowing for future studies of therapeutic interventions in transgenic mouse models of AD.

Aged↗

PubMed2002

Computer modelling of hooks for use as intra-operative force sensors.

There are a number of forces applied during scoliosis surgery, the magnitude and direction of which remains unknown. There is little literature concerning the in vivo distribution of forces along the spine. Computer modelling (ANSYS) was used to investigate the possibility of using an instrumented hook to intra-operatively measure the antero-posterior and distraction/compression forces applied by the surgeon during corrective scoliosis surgery. Three hook designs were evaluated based on specific design criteria. ANSYS provided the preliminary analysis to determine the strain distribution in these hooks. One design, the "membrane" design, was selected and a prototype was manufactured. Preliminary tests demonstrate that this prototype will be able to differentiate between the four major forces applied during the surgical correction.

Biomechanical Phenomena↗

PubMed2005

Computational models for detection of erectile dysfunction.

PURPOSE: Vascular comorbidities are well known to correlate with erectile dysfunction (ED) but a correlation with hypogonadism and depression is less clear. Using several linear and nonlinear mathematical models we investigated the correlation of age, hypogonadism and depression with ED using the Sexual Health Inventory for Men (SHIM) as a surrogate marker for ED. MATERIALS AND METHODS: A data set of 140 exemplars containing the input features age, total testosterone in ng/dl, Center for Epidemiologic Studies Depression scale score and output SHIM score (thresholded to 10 for moderate ED) was randomized into a modeling (training) set of 105 and a cross-validation (test) set of 35 with similar outcome frequencies preserved in each set. Using neUROn++, a set of C++ programs that we developed using the Cygwin (Red Hat, Raleigh, North Carolina) GNU C++ port for Windows (Microsoft, Redmond, Washington) distributed across Pentium (Intel, Santa Clara, California) platforms we modeled the data set using the linear methods, linear and quadratic discriminant function analysis, and logistic regression, and the nonlinear method of neural computation with several investigated architectures. RESULTS: A 4 hidden node network was found to have the highest accuracy compared to linear and quadratic discriminant function analyses, and logistic regression. ROC areas for the test set were 0.702, 0.645, 0.676 and 0.618, respectively. Analysis of the neural network demonstrated that moderate ED correlated with patient age and depression score. Forward and reverse regression of the neural network based on Wilk's generalized likelihood ratio test revealed that age was most significant (p <0.001), followed by Center for Epidemiologic Studies Depression Scale score (p <0.03), followed by testosterone (p >0.6). CONCLUSIONS: We investigated linear and nonlinear computational models of moderate ED. To our knowledge this is the first demonstration that SHIM correlates with age and a depression metric. Furthermore, moderate ED based on SHIM with a correlation with age may now provide a rationale and basis for future investigation into the understanding of age related erectile pathophysiology.

Adult↗

PubMed1979

Metabolism of palmitate in perfused rat liver. Computer models of subcellular triacylglycerol metabolism.

1. In the preceding paper [Kondrup (1979) Biochem. J.184, 63-71] the separation of two major fractions of hepatic triacylglycerol was described. One fraction contained triacylglycerol from the endoplasmic reticulum and from the Golgi apparatus. The other fraction contained triacylglycerol from the cytoplasmic lipid droplets. In the present paper possible precursor-product relationships between the two fractions were investigated by means of computer models. 2. The fatty acids present in di- and tri-acylglycerol in the fractions isolated in the time studies were analysed by gas chromatography. From this analysis the relative specific radioactivities, and contents, of palmitate in acylglycerols in the two fractions at the various time points were calculated. 3. A computer was used to predict relative specific radioactivities of pools in defined models of hepatic triacylglycerol metabolism. The acceptability of the models was evaluated by comparing predicted with measured relative specific radioactivities. 4. It is suggested that triacylglycerol in cytoplasmic lipid droplets does not originate (a) directly from triacylglycerol in the endoplasmic reticulum, (b) from a sub-pool of it or (c) directly from non-esterified fatty acids entering the cell. Rather, it is formed from diacylglycerol (and acyl-CoA) in the endoplasmic reticulum. Diacylglycerol, on the other hand, is furnished in part by hydrolysis of triacylglycerol in the endoplasmic reticulum. 5. This suggestion is discussed in relation to previous models of hepatic fatty acid metabolism.

Animals↗

PubMed2004

Intersection of microwire electrodes with proximal CA1 stratum-pyramidale neurons at insertion for multiunit recordings predicted by a 3-D computer model.

It is of broad interest in the context of neuronal multiunit extracellular recordings to understand electrode-tissue interactions in order to maximize the number of recordable units and to minimize experimental artifacts due to mechanical tissue alteration. Toward this goal, a computer model of microwire electrode insertion in hippocampus CA1 area was developed, firstly to provide estimates of the number of electrode-neuron intersections affecting recordable (local) neurons and, secondly, to determine optimal insertion/electrode parameters that minimize the number of intersections. The model predicts that in hippocampus CA1 area, using an electrode 50 microm in diameter, only 10% of the recordable neurons (those within 50 microm of the electrode), would remain collision free. Moreover, the model also predicts that inhibitory neurons are less prone to be intersected by the electrode, resulting in a 2 to threefold higher percentage of collision-free interneurons than expected from the relative densities of pyramidal cells and interneurons. Furthermore, the model confirms, in agreement with experimental observations, that electrode tilting with respect to the main neuronal axis increases the number of intact neurons (fourfold for a 50-microm electrode at 45 degrees when compared to 0 degrees , i.e., an insertion normal to the cell body layer).

Animals↗

PubMedDate not supplied

On structural aspects of peptidoglycan of bacterial cell wall with special attention on mycobacteria by computer modelling.

The cell wall components of mycobacteria are said to be vitally linked with their pathogenicity. Peptidoglycan, one of the major cell wall component in most of the bacteria are multilayered in gram positive bacteria and it is diverse in nature for the Gram positive strain rather than gram negative. The cell wall of bacteria are primary targets for many drugs and antibiotics and conformation of the major cell wall components provide invaluable information and understanding at molecular level to medicinal chemists and drug designers. Mycobacterial peptidoglycan has been studied critically by computer modelling on various aspects. A plausible structure and conformation has been identified and glycan chain is found to have a pseudo two fold symmetry taking disaccharide unit as monomer with Knox & Murthy H-bond scheme. This paper attempts to clarify the understanding of organisation and possible interaction mode of peptidoglycan of organisation in complex mycobacterial cell wall structure.

Amino Acid Sequence↗