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PubMed1998

Form and function of mammalian lung: analysis by scientific computing.

This study approaches the investigation of airway morphology of the lung with a new set of imaging and computer graphical methods, including confocal imaging, computer-guided image acquisition, visualization and fractal graphics. The key result is that, in contrast to the belief that the design of the conductive part of lung of smaller mammals can be described with a trumpet model, the findings reported here document a strongly monopodial branching pattern with the functional consequence of a variation of dead space between the trachea and the acini. This non-dichotomic structural design finds its continuation within the respiratory units as the necessary requirement for an optimal space filling and dense packing which cannot be achieved by a dichotomic branching only. Based on a computer model, computational physics tightly coupled with computer visualistics enables functional simulation of the lung model regarding gas transport. The predicted variance in the ventilation of acini gives rise to an explanation of the well-known difference between the morphologically predicted and physiologically required diffusion capacity.

Bronchi↗

PubMed2003

Self-replicating machines in continuous space with virtual physics.

JohnnyVon is an implementation of self-replicating machines in continuous two-dimensional space. Two types of particles drift about in a virtual liquid. The particles are automata with discrete internal states but continuous external relationships. Their internal states are governed by finite state machines, but their external relationships are governed by a simulated physics that includes Brownian motion, viscosity, and springlike attractive and repulsive forces. The particles can be assembled into patterns that can encode arbitrary strings of bits. We demonstrate that, if an arbitrary seed pattern is put in a soup of separate individual particles, the pattern will replicate by assembling the individual particles into copies of itself. We also show that, given sufficient time, a soup of separate individual particles will eventually spontaneously form self-replicating patterns. We discuss the implications of JohnnyVon for research in nanotechnology, theoretical biology, and artificial life.

Artificial Intelligence↗

PubMed2006

Sampling realistic protein conformations using local structural bias.

The prediction of protein structure from sequence remains a major unsolved problem in biology. The most successful protein structure prediction methods make use of a divide-and-conquer strategy to attack the problem: a conformational sampling method generates plausible candidate structures, which are subsequently accepted or rejected using an energy function. Conceptually, this often corresponds to separating local structural bias from the long-range interactions that stabilize the compact, native state. However, sampling protein conformations that are compatible with the local structural bias encoded in a given protein sequence is a long-standing open problem, especially in continuous space. We describe an elegant and mathematically rigorous method to do this, and show that it readily generates native-like protein conformations simply by enforcing compactness. Our results have far-reaching implications for protein structure prediction, determination, simulation, and design.

Amino Acid Sequence↗

PubMed1993

Simulating the electrical behavior of cardiac tissue using the bidomain model.

The complex microstructure of cardiac muscle comprised of coupled cells, enveloped by an interstitium made up of blood vessels, connective tissue, and fluid, presents some obvious problems to those interested in understanding the tissue as an electrical medium. One approach that has gained considerable favor in recent years views the tissue not as a discrete structure, but rather as two coupled, continuous domains: one for the intracellular space and the other for the interstitial space. For convenience, the averaged potentials and currents in both domains are defined at every point in space. The structure is partially preserved by assigning a conductivity tensor at each point. One advantage of using this space-averaged model is that the governing equations for the electric fields can be described by partial differential equations that on occasion lead to analytical solutions. This formal treatment of cardiac tissue as two coupled continua is referred to as the bidomain model. This article presents a mathematical description of the bidomain model and reviews the use of the model for simulating the electrical behavior of cardiac tissue.

Action Potentials↗

PubMedDate not supplied

Reduced glutamate uptake by retinal glial cells under ischemic/hypoxic conditions.

The high-affinity uptake of glutamate by glial cells and neurons of the central nervous system, including the retina, serves to inactivate synaptically released glutamate and maintains glutamate at low concentrations in the extracellular space. This uptake prevents accumulation of glutamate extracellularly and thus minimizes the possibility of glutamate neurotoxicity secondary to ischemic insult. One mechanism whereby glutamate neurotoxicity may occur in ischemic/hypoxic insult is through increased extracellular K+ reversing the electrogenic glutamate uptake into retinal glial (Müller) cells. We investigated glial uptake of the amino acids glutamate, GABA, and D-aspartate in the intact isolated rat retina under high extracellular K+ conditions and under conditions simulating ischemia. Immunocytochemical findings showed that uptake of glutamate and GABA by MIller cells in the intact isolated rat retina continues under conditions simulating ischemia and high extracellular K+ conditions, and uptake of D-aspartate also continues under high K+ conditions. However, under high K+ conditions, the glutamate uptake system saturates at a lower concentration of exogenous glutamate than in the normal K+ condition. These findings provide evidence that disruption of glutamate uptake by Müller cells is likely to be a significant contributing factor to excess glutamate accumulation in the extracellular space which can lead to neurotoxicity.

Animals↗

PubMedDate not supplied

Reduction of partial-volume artifacts with zero-filled interpolation in three-dimensional MR angiography.

Partial-volume artifacts reduce vessel contrast and continuity (especially in small vessels) in magnetic resonance (MR) angiography. The authors applied zero-filled (band-limited) interpolation to three-dimensional (3D) MR angiograms to reduce partial-volume artifacts. They demonstrated that zero-filled interpolation can also be implemented by means of voxel shifting in real space. Voxel-shifted interpolation is much less computer memory intensive than conventional zero-filled interpolation. They numerically simulated the contrast loss due to partial-volume artifacts and contrast recovery obtained with zero-filled interpolation. Zero-filled interpolation in all three orthogonal directions was applied to 3D MR angiography data sets from 29 human studies. These studies were obtained with the three commonly used 3D MR angiography techniques: 3D time of flight, multislab 3D time of flight, and 3D phase contrast. A substantial improvement in vessel contrast and vessel continuity was observed in all cases.

Adult↗

PubMed1980

Computer studies of the spatial structure and temporal growth of tumor cells.

In the present paper we attempt to determine the spatial structure and the time behaviour of cell renewal systems, continuing previous studies in which tumor diseases were interpreted as unstable control loops. A computer model wa developed for the two-dimensional cell space, which is described by a set of specifications and growth statements. Selected case studies are then simulated by means of a digital computer (CYBER 76). In the development of this model special emphasis was given to (i) the existence of several cell systems with different mean life spans, growing in competition; (ii) the variability of the mean life spans of a cell and of the initial configuration of cell patterns; (iii) the description of the cell-to-cell interactions; (iv) the perturbation of normal cell growth by tumor cells and their elimination in medicine comparable with a direct irradiation or removal by surgery; (v) the consideration of the loss of tumor cells. The development of this model enables a deeper insight into the structure and function of disturbed cell renewal processes. Systematic studies were made on the influence of the size of a tumor nucleus and the mean life span of a tumor cell on the tumor growth assuming constant cell loss. Furthermore it is possible with this computer model to simulate simple basic cases which are difficult to test in real life.

Cell Division↗

PubMed1984

[Bilateral coronaro-pulmonary fistula. Apropos of a new case with review of the literature].

Two coronary pulmonary fistulae were demonstrated between the right coronary and left anterior descending arteries and the main pulmonary artery at coronary angiography, in a 66 year old woman with a continuous murmur in the third left intercostal space. This double malformation, though uncommon is not rare (18 previously published cases). It is usually diagnosed late (17 to 76 years) and the presentation is limited in half the cases to a localised continuous murmur, the localisation of which may simulate a patent ductus arteriosus. The hypothesis of a supernumerary coronary artery arising from the main pulmonary artery is suggested by the constancy of the anatomical characteristics of the reported cases. Eight patients presented typical attacks of angina which were due to severe coronary atherosclerosis, affecting two or three main vessels except in one case. Therefore, it is unlikely that these fistulae cause coronary insufficiency by a coronary steal syndrome. However, this mechanism may aggravate symptoms in patients with coronary artery disease and necessitate surgical cure of the fistulae at the same time as coronary bypass surgery. On the other hand, surgery does not seem to be indicated in asymptomatic patients.

Aged↗

PubMed1997

Changes in the immune system during and after spaceflight.

The results of immunological analyses before, during and after spaceflight, have established the fact that spaceflight can result in a blunting of the immune mechanisms of human crew members and animal test species. There is some evidence that the immune function changes in short-term flights resemble those occurring after acute stress, while the changes during long-term flights resemble those caused by chronic stress. In addition, this blunting of the immune function occurs concomitant with a relative increase in potentially infectious microorganisms in the space cabin environment. This combination of events results in an increased probability of inflight infectious events. The realization of this probability has been shown to be partially negated by the judicious use of a preflight health stabilization program and other operational countermeasures. The continuation of these countermeasures, as well as microbial and immunological monitoring, are recommended for continued spaceflight safety.

Acute Disease↗

PubMed1998

Fine-scale spatial genetic structure with nonuniform distribution of individuals.

This paper presents the first theoretical study of spatial genetic structure within nonuniformly distributed continuous plant populations. A novel individual-based model of isolation by distance was constructed to simulate genetic evolution within such populations. We found larger values of spatial genetic autocorrelations in highly clumped populations than in uniformly distributed populations. Most of this difference was caused by differences in mean dispersal distances, but aggregation probably also produced a slight increase in spatial genetic structure. Using an appropriate level of approximation of the continuous distribution of individuals in space, we assessed the potential effects of density, seed and pollen dispersal, generation overlapping, and overdominance selection at an independent locus, on fine-scale genetic structure, by varying them separately in a few particular cases with extreme clumping. When selfing was allowed, all these input variables influenced both aggregation and spatial genetic structure. Most variations in spatial genetic structure were closely linked to variations in clumping and/or local density. When selfing was not allowed, spatial genetic structure was lower in most cases.

Biological Evolution↗

PubMed1999

Time-resolved analysis and visualization of dynamic processes in living cells.

Recent development of in vivo microscopy techniques, including green fluorescent proteins, has allowed the visualization of a wide range of dynamic processes in living cells. For quantitative and visual interpretation of such processes, new concepts for time-resolved image analysis and continuous time-space visualization are required. Here, we describe a versatile and fully automated approach consisting of four techniques, namely highly sensitive object detection, fuzzy logic-based dynamic object tracking, computer graphical visualization, and measurement in time-space. Systematic model simulations were performed to evaluate the reliability of the automated object detection and tracking method. To demonstrate potential applications, the method was applied to the analysis of secretory membrane traffic and the functional dynamics of nuclear compartments enriched in pre-mRNA splicing factors.

Animals↗

PubMed2005

A Bayesian approach to jointly modeling toxicity and biomarker expression in a phase I/II dose-finding trial.

In this article, we propose a Bayesian approach to phase I/II dose-finding oncology trials by jointly modeling a binary toxicity outcome and a continuous biomarker expression outcome. We apply our method to a clinical trial of a new gene therapy for bladder cancer patients. In this trial, the biomarker expression indicates biological activity of the new therapy. For ethical reasons, the trial is conducted sequentially, with the dose for each successive patient chosen using both toxicity and activity data from patients previously treated in the trial. The modeling framework that we use naturally incorporates correlation between the binary toxicity and continuous activity outcome via a latent Gaussian variable. The dose-escalation/de-escalation decision rules are based on the posterior distributions of both toxicity and activity. A flexible state-space model is used to relate the activity outcome and dose. Extensive simulation studies show that the design reliably chooses the preferred dose using both toxicity and expression outcomes under various clinical scenarios.

Algorithms↗

PubMed1991

Propagation of dendritic spikes mediated by excitable spines: a continuum theory.

1. Neuroscientists are currently hypothesizing on how voltage-dependent channels, in dendrites with spines, may be spatially distributed or how their numbers may divide between spine heads and the dendritic base. A new cable theory is formulated to investigate electrical interactions between many excitable and/or passive dendritic spines. The theory involves a continuum formulation in which the spine density, the membrane potential in spine heads, and the spine stem current vary continuously in space and time. The spines, however, interact only indirectly by voltage spread along the dendritic shaft. Active membrane in the spine heads is modeled with Hodgkin-Huxley (HH) kinetics. Synaptic currents are generated by transient conductance increases. For most simulations the membrane of spine stems and dendritic shaft is assumed passive. 2. Action-potential generation and propagation occur as localized excitatory synaptic input into spine heads causes a few excitable spines to fire, which then initiates a chain reaction of spine firings along a branch. This sustained wavelike response is possible for a certain range of spine densities and electrical parameters. Propagation is precluded for spine stem resistance (Rss) either too large or too small. Moreover, even if Rss lies in a suitable range for the local generation of an action potential (resulting from local synaptic excitatory input), this range may not be suitable to initiate a chain reaction of spine firings along the dendrite; success or failure of impulse propagation depends on an even narrower range of Rss values. 3. The success or failure of local excitation to spread as a chain reaction depends on the spatial distribution of spines. Impulse propagation is unlikely if the excitable spines are spaced too far apart. However, propagation may be recovered by redistributing the same number of equally spaced spines into clusters. 4. The spread of excitation in a distal dendritic arbor is also influenced by the branching geometry. Input to one branch can initiate a chain reaction that accelerates into the sister branch but rapidly attenuates as it enters the parent branch. In branched dendrites with many excitable and passive spines, regions of decreased conductance load (e.g., near sealed ends) can facilitate attenuating waves and enhance waves that are successfully propagating. Regions of increased conductance load (e.g., near common branch points) promote attenuation and tend to block propagation. Non-uniform loading and/or nonuniform spine densities can lead to complex propagation characteristics. 5. Some analytic results of classical cable theory are generalized for the case of a passive spiny dendritic cable.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗

PubMed1994

"Simulated molecular evolution" or computer-generated artifacts?

1. The authors define a function with value 1 for the positive examples and 0 for the negative ones. They fit a continuous function but do not deal at all with the error margin of the fit, which is almost as large as the function values they compute. 2. The term "quality" for the value of the fitted function gives the impression that some biological significance is associated with values of the fitted function strictly between 0 and 1, but there is no justification for this kind of interpretation and finding the point where the fit achieves its maximum does not make sense. 3. By neglecting the error margin the authors try to optimize the fitted function using differences in the second, third, fourth, and even fifth decimal place which have no statistical significance. 4. Even if such a fit could profit from more data points, the authors should first prove that the region of interest has some kind of smoothness, that is, that a continuous fit makes any sense at all. 5. "Simulated molecular evolution" is a misnomer. We are dealing here with random search. Since the margin of error is so large, the fitted function does not provide statistically significant information about the points in search space where strings with cleavage sites could be found. This implies that the method is a highly unreliable stochastic search in the space of strings, even if the neural network is capable of learning some simple correlations. 6. Classical statistical methods are for these kind of problems with so few data points clearly superior to the neural networks used as a "black box" by the authors, which in the way they are structured provide a model with an error margin as large as the numbers being computed.7. And finally, even if someone would provide us with a function which separates strings with cleavage sites from strings without them perfectly, so-called simulated molecular evolution would not be better than random selection.Since a perfect fit would only produce exactly ones or zeros,starting a search in a region of space where all strings in the neighborhood get the value zero would not provide any kind of directional information for new iterations. We would just skip from one point to the other in a typical random walk manner.

Amino Acid Sequence↗

PubMed1999

Conformal self-organization for continuity on a feature map.

The self-organization model with a conformal-mapping adaptation is studied in this work. This model is designed to provide conformal transformation to meet the conformality requirement in biological morphology and geometrical surface mapping. This model spans the network field in the input space where topological conformality is preserved. The converged network provides not only the organized clustering features of the input but also a specific mapping representation. This facilitates the Kohonen's self-organization model in exploring the input in a continuous conformality sense. Simulations for morphing applications are described.

Journal Article↗

PubMed2005

Bed rest effects on human calf hemodynamics and orthostatic intolerance: a model-based analysis.

INTRODUCTION: Microgravity-induced orthostatic intolerance continues to be a primary problem after space missions. Its etiology remains uncertain despite significant research efforts over the past years. We hypothesized that calf hemodynamic parameters (compliance and resistance) are significantly affected by 14 to 16-d head-down bed rest (simulated microgravity), and their alterations play a role in the pathogenesis of orthostatic intolerance (OI) following bed rest. METHODS: To estimate these parameters, we developed a model-based approach to quantitatively simulate calf vascular response to venous occlusion, which only necessitates measurement of plethysmography data. In this study, plethysmography data were obtained from 29 subjects before and after 14-16 d of head-down bed rest. The subjects also underwent a tilt/stand test before and after bed rest. RESULTS: Statistical analyses demonstrated an increase in calf compliance (1.87 +/- 0.08, mean +/- SE, pre-bed rest; 2.16 +/- 0.10, end-bed rest) but no significant change in vascular resistance following bed rest. Compared with the tilt-intolerant subjects, those who were tilt-tolerant before bed rest had significantly higher calf compliance [2.00 +/- 0.09 (tolerant); 1.58 +/- 0.09 (intolerant)] and higher vascular resistance [7.79 +/- 0.18 (tolerant); 6.91 +/- 0.40 (intolerant)]. After bed rest, no such difference was detected. DISCUSSION: Based on these results, we validated the hypothesis that, instead of causing orthostatic intolerance, higher calf compliance before bed rest leads to recruitment of compensatory mechanisms (validated by the enhanced vascular resistance during venous occlusion) for a better toleration of orthostatic stress. With the absence of orthostatic challenge during bed rest, the difference in calf hemodynamic parameters is attenuated between the tilt-tolerant and tilt-intolerant groups.

Adaptation, Physiological↗

PubMed1989

Modeling adaptive biological systems.

During the evolution of many systems found in nature, both the system composition and the interactions between components will vary. Equating the dimension with the number of different components, a system which adds or deletes components belongs to a class of dynamical systems with a finite dimensional phase space of variable dimension. We present two models of biochemical systems with a variable phase space, a model of autocatalytic reaction networks in the prebiotic soup and a model of the idiotypic network of the immune system. Each model contains characteristic meta-dynamical rules for constructing equations of motion from component properties. The simulation of each model occurs on two levels. On one level, the equations of motion are integrated to determine the state of each component. On a second level, algorithms which approximate physical processes in the real system are employed to change the equations of motion. Models with meta-dynamical rules possess several advantages for the study of evolving systems. First, there are no explicit fitness functions to determine how the components of the model rank in terms of survivability. The success of any component is a function of its relationship to the rest of the system. A second advantage is that since the phase space representation of the system is always finite but continually changing, we can explore a potentially infinite phase space which would otherwise be inaccessible with finite computer resources. Third, the enlarged capacity of systems with meta-dynamics for variation allows us to conduct true evolution experiments. The modeling methods presented here can be applied to many real biological systems. In the two studies we present, we are investigating two apparent properties of adaptive networks. With the simulation of the prebiotic soup, we are most interested in how a chemical reaction network might emerge from an initial state of relative disorder. With the study of the immune system, we study the self-regulation of the network including its ability to distinguish between species which are part of the network and those which are not.

Adaptation, Biological↗

PubMed2003

Helical MR: continuously moving table axial imaging with radial acquisitions.

A technique for extended field of view MRI is presented. Similar to helical computed tomography, the method utilizes a continuously moving patient table, a 2D axial slice that remains fixed relative to the MRI magnet, and a radial k-space trajectory. A fully refocused SSFP acquisition enables spatial resolution comparable to current clinical protocols in scan times that are sufficiently short to allow a reasonable breathhold duration. RF transmission and signal reception are performed using the RF body coil and the images are reconstructed in real time. Experimental results are presented that illustrate the technique's ability to resolve small structures in the table-motion direction. Simulation experiments to study the steady-state response of the fully refocused SSFP acquisition during continuous table motion are also presented. Finally, whole body images of healthy volunteers demonstrate the high image quality achieved using the helical MRI approach.

Artifacts↗