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Trainable fusion rules. I. Large sample size case.

A wide selection of standard statistical pattern classification algorithms can be applied as trainable fusion rules while designing neural network ensembles. A focus of the present two-part paper is finite sample effects: the complexity of base classifiers and fusion rules; the type of outputs provided by experts to the fusion rule; non-linearity of the fusion rule; degradation of experts and the fusion rule due to the lack of information in the design set; the adaptation of base classifiers to training set size, etc. In the first part of this paper, we consider arguments for utilizing continuous outputs of base classifiers versus categorical outputs and conclude: if one succeeds in having a small number of expert networks working perfectly in different parts of the input feature space, then crisp outputs may be preferable over continuous outputs. Afterwards, we oppose fixed fusion rules versus trainable ones and demonstrate situations where weighted average fusion can outperform simple average fusion. We present a review of statistical classification rules, paying special attention to these linear and non-linear rules, which are employed rarely but, according to our opinion, could be useful in neural network ensembles. We consider ideal and sample-based oracle decision rules and illustrate characteristic features of diverse fusion rules by considering an artificial two-dimensional (2D) example where the base classifiers perform well in different regions of input feature space.

Animals↗

Non-Markovian theory of open systems in classical limit.

A fully classical limit of the recently published quantum-classical approximation [A. A. Neufeld, J. Chem. Phys. 119, 2488 (2003)] is obtained and analyzed. The resulting kinetic equations are capable of describing the evolution of an open system on the entire time axis, including the short-time non-Markovian stage, and are valid beyond linear response regime. We have shown, that proceeding to the classical mechanics limit we restrict the class of allowed correlations between an open system and a canonical bath, so that the initial conditions and the relaxation operator has to be appropriately modified (projected). Disregard of the projection may lead to unphysical behavior, since mechanism of the decay of some correlations is essentially of quantum-mechanical nature, and is not correctly described by classical mechanics. The projection (quantum correction to the kinetics) is particularly important for the non-Markovian regime of relaxation towards canonical equilibrium. The conformity of the developed method to the conventional approaches is demonstrated using a model of Brownian motion (heavy particle in the bath of light ones), for which the obtained non-Markovian equations are reduced to the standard Fokker-Planck equation in phase space.

Computer Simulation↗

An information theory analysis of visual complexity and dissimilarity.

The subjective complexity of a computer-generated bitmap image can be measured by magnitude estimation scaling, and its objective complexity can be measured by its compressed file size. There is a high correlation between these measures of subjective and objective complexity over a large set of marine electronic chart and radar images. The subjective dissimilarity of a pair of bitmap images can be predicted from subjective and objective measures of the complexity of each image, and from the subjective and objective complexity of the image produced by overlaying the two simple images. In addition, the subjective complexity of the image produced by overlaying two simple images can be predicted from the subjective complexity of the simple images and the subjective dissimilarity of the image pair. The results of the experiments that generated these complexity and dissimilarity judgments are consistent with a theory, outlined here, that treats objective and subjective measures of image complexity and dissimilarity as vectors in Euclidean space.

Computer Simulation↗

Effectiveness of the Space Shuttle anti-exposure system in a cold water environment.

The purpose of this study was to evaluate the National Aeronautics and Space Administration (NASA) Space Shuttle Launch Entry Suit (LES) and raft for 24 h of protection against cold water immersion. Two configurations, the LES and the LES with raft (Navy LRU-18/U with NASA spray shield) were evaluated for anti-exposure protection. Conditions were selected to simulate worst case water and air temperatures along projected Space Shuttle ground tracks; i.e., water temperatures = 4.4 degrees C (40 degrees F), air temperature = 5.6 degrees C (42 degrees F), 1 foot waves (chop), and constant spray. Four males, 31-44 years of age, and one 32-year-old female, were studied once in each configuration. Trials with and without a raft were scheduled for up to 24 and 6 h, respectively. Mean LES trial durations were 150 +/- 9 min and final rectal temperature (Tre, f) = 36.5 +/- 0.3 degrees C. Mean LES with raft (LES/r) trial durations were 398 +/- 126 min and final rectal temperature (Tre, f) = 35.6 +/- 0.4 degrees C. LES and LES/r trials were terminated for reaching Tre = 35.0 degrees C or subject-requested termination due to discomfort. The longest LES and LES/r trials were terminated due to subject discomfort. Although not achieving the desired durations, the LES and LES/r did prove capable of protecting individuals, respectively, for up to 3 and 13.5 h. Since the longest LES and LES/r runs were terminated due to subjective tolerance and not physical incapacitation, actual survival times greater than 3 and 13.5 h, respectively, could be expected for individuals in these ensembles.

Adult↗

Analysis of electrode configurations for measuring cardiac tissue conductivities and fibre rotation.

: This paper describes a multi-electrode grid, which could be used to determine cardiac tissue parameters by direct measurement. A two pass process is used, where potential measurements are made, during the plateau phase of the action potential, on a subset of these electrodes and these measurements are used to determine the bidomain conductivities. In the first pass, the potential measurements are made on a set of 'closely-spaced' electrodes and the parameters are fitted to the potential measurements in an iterative process using a bidomain model and a solver based on a modified Shor's r-algorithm. This first pass yields the extracellular conductivities. The second pass is similar except that a 'widely-spaced' electrode set is used and this time the intracellular conductivities are recovered. In addition, it is possible to determine the fibre rotation throughout the tissue, since the bidomain model used here is able to include the effects of fibre rotation. In the simulation studies presented here, the model is solved with known conductivities, on each of the two subsets of electrodes, to generate two sets of 'measured potentials.' Conductivities are then recovered by solving an inverse problem based on the measured potentials, to which various levels of noise are added. For example, simulations in the first pass are performed using an electrode spacing of 500 mum, for a situation where the longitudinal and transverse space constants are 769 and 308 mum, respectively. These give very accurate average percentage relative errors for the longitudinal and transverse extracellular conductivities, over five simulations with 1% noise added, of 0.3 and 0.2%. Twenty-five second pass simulations, on a 1 mm grid, yield average percentage relative errors of 3.8, 2.6 and 1.4% for the corresponding intracellular values and the fibre rotation angle, respectively.

Animals↗

Simulating the impact of a molecular 'decision-process' on cellular phenotype and multicellular patterns in brain tumors.

Experimental evidence indicates that human brain cancer cells proliferate or migrate, yet do not display both phenotypes at the same time. Here, we present a novel computational model simulating this cellular decision-process leading up to either phenotype based on a molecular interaction network of genes and proteins. The model's regulatory network consists of the epidermal growth factor receptor (EGFR), its ligand transforming growth factor-alpha (TGF alpha), the downstream enzyme phospholipaseC-gamma (PLC gamma) and a mitosis-associated response pathway. This network is activated by autocrine TGF alpha secretion, and the EGFR-dependent downstream signaling this step triggers, as well as modulated by an extrinsic nutritive glucose gradient. Employing a framework of mass action kinetics within a multiscale agent-based environment, we analyse both the emergent multicellular behavior of tumor growth and the single-cell molecular profiles that change over time and space. Our results show that one can indeed simulate the dichotomy between cell migration and proliferation based solely on an EGFR decision network. It turns out that these behavioral decisions on the single cell level impact the spatial dynamics of the entire cancerous system. Furthermore, the simulation results yield intriguing experimentally testable hypotheses also on the sub-cellular level such as spatial cytosolic polarization of PLC gamma towards an extrinsic chemotactic gradient. Implications of these results for future works, both on the modeling and experimental side are discussed.

Brain Neoplasms↗

Hindlimb-suspension and spaceflight both alter cGMP levels in rat choroid plexus.

Effects of actual and simulated weightlessness on choroidal guanylate cyclase activity were evaluated by assaying the production of cyclic guanosine monophosphate (cGMP), a second messenger involved in mechanisms regulating the secretion of cerebrospinal fluid (CSF) in choroid plexus. Cyclic cGMP was measured, using radio-immunoassay, in choroidal extracts of hindlimb-suspended rats (HLS rats), adapted to an anti-orthostatic restraint for 30 min., or for 3, 9 or 14 days and after a 17-day spaceflight (Life and Microgravity SpaceLab experiment; LMS). Basal cGMP levels were slightly but significantly decreased in the first 30 min. of the HLS experiment, whereas they were significantly increased in rats adapted to longer anti-orthostatic restraints. LMS flight rats demonstrated a similar increase in the choroidal cGMP baseline. After natriuretic peptide stimulation, i.e. using ANP (atrial natriuretic peptide) or BNP (brain natriuretic peptide), choroidal cGMP contents were typically increased (by 1.5-2 times; p<0.05) in control rats (LMS and HLS experiments), but not significantly elevated in suspended rats, except for those adapted to HLS for 14 days. In these animals the ANP-dependent cGMP production was significantly increased (by about 3 times; p<0.005). The ANP- or BNP-dependent responses were similarly abolished in LMS flight rats, which were dissected 4-6 hours after return to Earth's gravity. The role of corticosteroids was also investigated during the LMS experiment. Results on choroidal functions revealed a lack of significant change of cGMP levels between adrenalectomized and sham-operated rats. For the first time, it is reported that both basal and ANP- stimulated cGMP levels are dramatically changed over the first 14 days of suspension, i.e. with experiments known to simulate some effects of weightlessness. Basal choroidal cGMP levels are also increased after 17 days in space, suggesting that space adaptation also impacts choroidal guanylate cyclase activities. However, the absence of ANP-dependent cGMP increase, observed in LMS flight animals, suggests that HLS could not simulate all the spaceflight effects. Thus, these preliminary results seem to show that a natriuretic peptides-independent s stem is involved in choroidal adaptation to spaceflight.

Adaptation, Physiological↗

Simulation of gentamicin delivery for the local treatment of osteomyelitis.

In order to understand the effect of antibiotics delivery to bone tissue, by biodegradable polymeric drug disc, for the treatment of osteomyelitis, a three-dimensional simulation model is developed. The simulation investigates the effect of pressure-induced convection on drug distribution, by taking into account the pressure gradient that exists between capillaries and interstitial space, and also as a result of the surgical opening. The clotting process at the surgical opening is incorporated into the simulation, and the effect of clotting duration is investigated. The clotting duration for the baseline simulation is 2 days and it is observed that increasing this duration depresses the mean drug concentration in the marrow and cortical bone. The effect of double burst release profile is also studied and it is observed that drug concentration drops too rapidly after the first burst to provide any therapeutic effect. However, it is shown that the drug concentration after the second burst stays above the minimum inhibitory concentration of the bacteria for a longer period of time, than would have been observed for a mono-burst release. Inserting non-biodegradable polymethylmethacrylate (PMMA) beads into bone seems to cause a higher average concentration of drug in the marrow. However, this could be brought about by the difference in the geometry between the disc and the bead, and the amount of drug packed in each bead. Further simulations on the management of dead space shows the ineffectiveness of having the void filled up with surgical gel as it becomes an additional barrier to drug delivery to the infected tissues.

Animals↗

The effect of microgravity on the development of plant protoplasts flown on Biokosmos 9.

An experiment using plant protoplasts has been accepted for the IML-1 Space Shuttle mission scheduled for 1991. Preparatory experiments have been performed using both fast and slow rotating clinostats and in orbit to study the effect of simulated and real weightlessness on protoplast regeneration. Late access to the space vehicles before launch has required special attention since it is important to delay cell wall regeneration until the samples are in orbit. On a flight on Biokosmos 9 ("Kosmos-2044") in September 1989 some preliminary results were obtained. Compared to the ground control, the growth of both carrot and rapeseed protoplasts was decreased by 18% and 44% respectively, after 14 days in orbit. The results also indicated that there is less cell wall regeneration under micro-g conditions. Compared to the ground controls the production of cellulose in rapeseed and carrot flight samples was only 46% and 29% respectively. The production of hemicellulose in the flight samples was 63% and 67% respectively of that of the ground controls. In both cases all samples reached the stage of callus development. The peroxidase activity was also found to be lower in the flight samples than in the ground controls, and the number of different isoenzymes was decreased in the flight samples. In general, the regeneration processes were retarded in the flight samples with respect to the ground controls. From a simulation experiment for IML-1 performed in January 1990 at ESTEC, Holland, regenerated plants have been obtained. These results are discussed and compared to the results obtained on Biokosmos 9. Protoplast regeneration did not develop beyond the callus stage in either the flight or the ground control samples from the Biokosmos 9 experiment.

Brassica↗

Potential of genetic algorithms in protein folding and protein engineering simulations.

Genetic algorithms are very efficient search mechanisms which mutate, recombine and select amongst tentative solutions to a problem until a near optimal one is achieved. We introduce them as a new tool to study proteins. The identification and motivation for different fitness functions is discussed. The evolution of the zinc finger sequence motif from a random start is modelled. User specified changes of the lambda repressor structure were simulated and critical sites and exchanges for mutagenesis identified. Vast conformational spaces are efficiently searched as illustrated by the ab initio folding of a model protein of a four beta strand bundle. The genetic algorithm simulation which mimicked important folding constraints as overall hydrophobic packaging and a propensity of the betaphilic residues for trans positions achieved a unique fold. Cooperativity in the beta strand regions and a length of 3-5 for the interconnecting loops was critical. Specific interaction sites were considerably less effective in driving the fold.

Algorithms↗

Dynamic properties of regulatory motifs associated with induction of three temporal domains of memory in aplysia.

A model was developed to examine dynamical properties of regulatory motifs correlated with different temporal domains of memory. The model represents short-, intermediate-, and long-term phases of protein kinase A (PKA) activation, which appear related to corresponding phases of facilitation of the Aplysia sensorimotor synapse. The model also represents phosphorylation of the transcription factor CREB1 by PKA and consequent induction of the immediate-early gene Aplysia ubiquitin hydrolase (Ap-uch), which is essential for long-term synaptic facilitation (LTF). Simulations suggest mechanisms responsible for differing profiles of synaptic facilitation following massed vs. spaced exposures to 5-HT, and suggest a novel regulatory motif (gated positive feedback) is important for LTF. Simulations suggest zero-order ultrasensitivity may underlie a requirement of a threshold number of exposures to 5-HT for LTF induction. The model makes predictions for the dynamics of PKA activation and Ap-uch induction when MAP kinase is activated, or when repression of Ap-uch is relieved by inhibiting the transcription factor CREB2. This model may therefore be useful for understanding processes underlying memory formation in Aplysia and other systems.

Amino Acid Motifs↗

An operator splitting method for solving the bidomain equations coupled to a volume conductor model for the torso.

In this paper we present a numerical method for the bidomain model, which describes the electrical activity in the heart. The model consists of two partial differential equations (PDEs), which are coupled to systems of ordinary differential equations (ODEs) describing electrochemical reactions in the cardiac cells. Many applications require coupling these equations to a third PDE, describing the electrical fields in the torso surrounding the heart. The resulting system is challenging to solve numerically, because of its complexity and very strict resolution requirements in time and space. We propose a method based on operator splitting and a fully coupled discretization of the three PDEs. Numerical experiments show that for simple simulation cases and fine discretizations, the algorithm is second-order accurate in space and time.

Algorithms↗

Does the forest filter effect prevent semivolatile organic compounds from reaching the Arctic?

Forests act as efficient filters for many airborne semivolatile organic compounds (SOCs). However, most simulations of an organic chemical's long-range transport in the atmosphere do not account for this filter effect. In this study, forests are introduced into an existing zonally averaged global distribution model (Globo-POP) to investigate how such a change affects a chemical's potential to undergo long range transport and accumulation in the Arctic, as quantified by the Arctic contamination potential (ACP). Simulation results indicate that the ACP of a "space" of perfectly persistent hypothetical organic chemicals, defined by log KOA and log KAW, is reduced by introducing forests in the global model. Depending on partition characteristics, this reduction can be as large as a factor of 2. Model calculations also indicate that it is mostly the boreal forests, specifically boreal deciduous forests, which play a key role in this respect. Sensitivity analyses establish the deposition velocity to boreal forests, especially for gaseous compounds, as one of the most influential parameters controlling this global forest filter effect. The extent of the effect is further sensitive to the forest density and precipitation rate in the boreal zone, and the degradation rates of the chemical. Specifically, degradation in the forest canopy may enhance the effect and further reduce an SOC's long range transport to remote regions. Simulations for three PCB congeners suggest that forests may reduce concentrations in air, ocean, and freshwater at the expense of increased concentrations in forest soils and may lead to substantially increased overall global residence times.

Air↗

Accurate characterization of Monte Carlo calculated electron beams for radiotherapy.

Monte Carlo studies of dose distributions in patients treated with radiotherapy electron beams would benefit from generalized models of clinical beams if such models introduce little error into the dose calculations. Methodology is presented for the design of beam models, including their evaluation in terms of how well they preserve the character of the clinical beam, and the effect of the beam models on the accuracy of dose distributions calculated with Monte Carlo. This methodology has been used to design beam models for electron beams from two linear accelerators, with either a scanned beam or a scattered beam. Monte Carlo simulations of the accelerator heads are done in which a record is kept of the particle phase-space, including the charge, energy, direction, and position of every particle that emerges from the treatment head, along with a tag regarding the details of the particle history. The character of the simulated beams are studied in detail and used to design various beam models from a simple point source to a sophisticated multiple-source model which treats particles from different parts of a linear accelerator as from different sub-sources. Dose distributions calculated using both the phase-space data and the multiple-source model agree within 2%, demonstrating that the model is adequate for the purpose of Monte Carlo treatment planning for the beams studied. Benefits of the beam models over phase-space data for dose calculation are shown to include shorter computation time in the treatment head simulation and a smaller disk space requirement, both of which impact on the clinical utility of Monte Carlo treatment planning.

Biophysical Phenomena↗

Simulation of surface EMG signals for a multilayer volume conductor with triangular model of the muscle tissue.

This study analytically describes surface electromyogram (sEMG) signals generated by a model of a triangular muscle, i.e., a muscle with fibers arranged in a fan shape. Examples of triangular muscles in the human body are the deltoid, the pectoralis major, the trapezius, the adductor pollicis. A model of triangular muscle is proposed. It is a sector of a cylindrical volume conductor (with the fibers directed along the radial coordinate) bounded at the muscle/fat interface. The muscle conductivity tensor reflects the fan anisotropy. Edge effects have been neglected. A solution of the nonspace invariant problem for a triangular muscle is provided in the Fourier domain. An approximate analytical solution for a two plane layer volume conductor model is obtained by introducing a homogeneous layer (modeling the fat) over the triangular muscle. The results are implemented in a complete sEMG generation model (including the finite length of the fibers), simulating single fiber action potentials. The model is not space invariant due to the changes of the volume conductor along the direction of action potential propagation. Thus the detected potentials at the skin surface change shape as they propagate. This determines problems in the extraction and interpretation of parameters. As a representative example of application of the simulation model, the influence of the inhomogeneity of the volume conductor in conduction velocity (CV) estimation is addressed (for two channels; maximum likelihood and reference point methods). Different fiber depths, electrode placements and small misalignments of the detection system with respect to the fiber have been simulated. The error in CV estimation is large when the depth of the fiber increases, when the detection system is not aligned with the fiber and close to the innervation point and to the tendons.

Action Potentials↗

Human cerebral autoregulation before, during and after spaceflight.

Exposure to microgravity alters the distribution of body fluids and the degree of distension of cranial blood vessels, and these changes in turn may provoke structural remodelling and altered cerebral autoregulation. Impaired cerebral autoregulation has been documented following weightlessness simulated by head-down bed rest in humans, and is proposed as a mechanism responsible for postspaceflight orthostatic intolerance. In this study, we tested the hypothesis that spaceflight impairs cerebral autoregulation. We studied six astronauts approximately 72 and 23 days before, after 1 and 2 weeks in space (n = 4), on landing day, and 1 day after the 16 day Neurolab space shuttle mission. Beat-by-beat changes of photoplethysmographic mean arterial pressure and transcranial Doppler middle cerebral artery blood flow velocity were measured during 5 min of spontaneous breathing, 30 mmHg lower body suction to simulate standing in space, and 10 min of 60 deg passive upright tilt on Earth. Dynamic cerebral autoregulation was quantified by analysis of the transfer function between spontaneous changes of mean arterial pressure and cerebral artery blood flow velocity, in the very low- (0.02-0.07 Hz), low- (0.07-0.20 Hz) and high-frequency (0.20-0.35 Hz) ranges. Resting middle cerebral artery blood flow velocity did not change significantly from preflight values during or after spaceflight. Reductions of cerebral blood flow velocity during lower body suction were significant before spaceflight (P < 0.05, repeated measures ANOVA), but not during or after spaceflight. Absolute and percentage reductions of mean (+/- s.e.m.) cerebral blood flow velocity after 10 min upright tilt were smaller after than before spaceflight (absolute, -4 +/- 3 cm s(-1) after versus -14 +/- 3 cm s(-1) before, P = 0.001; and percentage, -8.0 +/- 4.8% after versus -24.8 +/- 4.4% before, P < 0.05), consistent with improved rather than impaired cerebral blood flow regulation. Low-frequency gain decreased significantly (P < 0.05) by 26, 23 and 27% after 1 and 2 weeks in space and on landing day, respectively, compared with preflight values, which is also consistent with improved autoregulation. We conclude that human cerebral autoregulation is preserved, and possibly even improved, by short-duration spaceflight.

Adaptation, Physiological↗

A realistic kinetic Monte Carlo simulation of the faceting of a Pt(110) surface under reaction conditions.

The faceting process on Pt(110) is studied with the help of a kinetic Monte Carlo model taking into account realistic Pt-Pt, Pt-CO, and Pt-O interactions. The activation energies of the allowed atomic steps are estimated using available computational and experimental data. The model well reproduces the region in the parameter space where faceting occurs. Under kinetic instability conditions, the simulated faceted pattern forms a periodic hill and valley structure with a lateral periodicity of approximately 140-170 A, which is comparable with experimental data. The simulations reproduce the development of faceting on a realistic time scale.

Journal Article↗

A comparison of solute-transport solution techniques and their effect on sensitivity analysis and inverse modeling results.

Five common numerical techniques for solving the advection-dispersion equation (finite difference, predictor corrector, total variation diminishing, method of characteristics, and modified method of characteristics) were tested using simulations of a controlled conservative tracer-test experiment through a heterogeneous, two-dimensional sand tank. The experimental facility was constructed using discrete, randomly distributed, homogeneous blocks of five sand types. This experimental model provides an opportunity to compare the solution techniques: the heterogeneous hydraulic-conductivity distribution of known structure can be accurately represented by a numerical model, and detailed measurements can be compared with simulated concentrations and total flow through the tank. The present work uses this opportunity to investigate how three common types of results--simulated breakthrough curves, sensitivity analysis, and calibrated parameter values--change in this heterogeneous situation given the different methods of simulating solute transport. The breakthrough curves show that simulated peak concentrations, even at very fine grid spacings, varied between the techniques because of different amounts of numerical dispersion. Sensitivity-analysis results revealed: (1) a high correlation between hydraulic conductivity and porosity given the concentration and flow observations used, so that both could not be estimated; and (2) that the breakthrough curve data did not provide enough information to estimate individual values of dispersivity for the five sands. This study demonstrates that the choice of assigned dispersivity and the amount of numerical dispersion present in the solution technique influence estimated hydraulic conductivity values to a surprising degree.

Bromides↗