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Adaptive constraints and the phylogenetic comparative method: a computer simulation test.

Recently, the utility of modern phylogenetic comparative methods (PCMs) has been questioned because of the seemingly restrictive assumptions required by these methods. Although most comparative analyses involve traits thought to be undergoing natural or sexual selection, most PCMs require an assumption that the traits be evolving by less directed random processes, such as Brownian motion (BM). In this study, we use computer simulation to generate data under more realistic evolutionary scenarios and consider the statistical abilities of a variety of PCMs to estimate correlation coefficients from these data. We found that correlations estimated without taking phylogeny into account were often quite poor and never substantially better than those produced by the other tested methods. In contrast, most PCMs performed quite well even when their assumptions were violated. Felsenstein's independent contrasts (FIC) method gave the best performance in many cases, even when weak constraints had been acting throughout phenotypic evolution. When strong constraints acted in opposition to variance-generating (i.e., BM) forces, however, FIC correlation coefficients were biased in the direction of those BM forces. In most cases, all other PCMs tested (phylogenetic generalized least squares, phylogenetic mixed model, spatial autoregression, and phylogenetic eigenvector regression) yielded good statistical performance, regardless of the details of the evolutionary model used to generate the data. Actual parameter estimates given by different PCMs for each dataset, however, were occasionally very different from one another, suggesting that the choice among them should depend on the types of traits and evolutionary processes being considered.

Adaptation, Physiological↗

Restoring unassisted natural gait to paraplegics via functional neuromuscular stimulation: a computer simulation study.

Functional neuromuscular stimulation (FNS) of paralyzed muscles has enabled spinal-cord-injured patients to regain a semblance of lower-extremity control, for example to ambulate while relying heavily on the use of walkers. Given the limitations of FNS, specifically low muscle strengths, high rates of fatigue, and a limited ability to modulate muscle excitations, it remains unclear, however, whether FNS can be developed as a practical means to control the lower extremity musculature to restore aesthetic, unsupported gait to paraplegics. A computer simulation of FNS-assisted bipedal gait shows that it is difficult, but possible to attain undisturbed, level gait at normal speeds provided the electrically-stimulated ankle plantarflexors exhibit either near-normal strengths or are augmented by an orthosis, and at least seven muscle-groups in each leg are stimulated. A combination of dynamic programming and an open-loop, trial-and-error adjustment process was used to find a suboptimal set of discretely-varying muscle stimulation patterns needed for a 3-D, 8 degree-of-freedom dynamic model to sustain a step. An ankle-foot orthosis was found to be especially useful, as it helped to stabilize the stance leg and simplified the task of controlling the foot during swing. It is believed that the process of simulating natural gait with this model will serve to highlight difficulties to be expected during laboratory and clinical trials.

Computer Simulation↗

Movement compatibility for rotary control and circular display--Computer Simulated Test and real Hardware Test.

This experiment studied strength and reversibility of direction-of-motion stereotypes and response times for different configurations of circular displays and rotary knobs. The effect of pointer position, instruction of turn direction, and control plane on movement compatibility was analyzed with precise quantitative measures of strength and reversibility index of stereotype. A comparison of results was made between a Computer Simulated Test and a Hardware Test with real rotary controls. There was consensus in the results of the two tests that strong and significantly reversible clockwise-for-clockwise (CC) and anticlockwise-for-anticlockwise (AA) stereotypes were obtained at the 12 o'clock position. Subjects' response times were found to be generally longer when there were no clear movement stereotypes. Nevertheless, differences of results were observed that while the CC and AA preferences were found to be dominant and reversible at all the planes and pointer positions in the Hardware Test, there was variation in the strength and reversibility of the two stereotypes amongst different testing configurations in the Simulated Test. This phenomenon was explained by the operating of the clockwise-for-right and anticlockwise-for-left principles, as shown in the analysis of contributions of component principles to the overall stereotype. The differences of results from the two tests were discussed with regard to simulation fidelity and it was suggested that a real Hardware Test should be used whenever possible for determination of design parameters of control panels in consideration of movement compatibility. Based on the Hardware Test, a pointer is recommended to be positioned at 12 o'clock position for check reading or resetting purpose, and the frontal plane is the best plane for positioning a rotary control with circular display. The results of this study provided significant implications for the industrial design of control panels used in man-machine interfaces for improved human performance.

Adult↗

A computer simulation of conduction block: effects produced by actual block versus interphase cancellation.

A reduction in compound muscle action potential (CMAP) amplitude and area following proximal versus distal stimulation is the accepted clinical hallmark of conduction block; however, quantitative criteria for determining conduction block remain ambiguous. In this study, digitized records of individual motor unit action potentials (MUAPs) elicited by incremental stimulation in vivo were arithmetically combined in a computer simulation of CMAP generation. Through simulation of possible phase interaction patterns of individual MUAPs, we have shown that abnormal temporal dispersion alone can produce reductions in CMAP area of up to 50%, values that are commonly thought to represent conduction block. Furthermore, by simulating conduction block without excessive temporal dispersion in defined subpopulations of axons, we have demonstrated the importance of the fastest conducting (largest MUAP) axons in determining CMAP amplitude and area. In conclusion, measurements of CMAP amplitude and area in determining conduction block may be misleading if there is significant abnormal temporal dispersion, and quantitation of the degree of conduction block is difficult without knowledge of which subpopulations of axons are affected.

Action Potentials↗

Experiments on movement of DNA regions in Escherichia coli evaluated by computer simulation.

During the cell cycle of Escherichia coli DNA is replicated and segregated over two prospective daughter cells. Nucleoids as a whole separate gradually in line with cell elongation, but sub-nucleoid DNA regions may behave differently, separating non-gradually. We tested the ability of three models to predict the outcome of a fluorescent in situ hybridisation (FISH) experiment. We did this by comparing computer-simulated data with experimental data. The first model predicts gradual separation in line with cell elongation. The second model predicts that origins stick together for some time after duplication before one copy jumps to the other side of the cell (non-gradual separation). The simulated data of these models are very similar, indicating that FISH is not a suitable method to distinguish between these two models. The third model predicts that origins may be anywhere within the nucleoid(s). We found that simulated data using the third model resemble the experimental data most. However, DNA regions are not randomly localised in the cell, although their localisation is fuzzy. We propose that movement of DNA regions is the result of a combination of factors. Nucleoid segregation (or the forces behind it) dictates the overall direction of movement. Other factors, of which we show that diffusion could be an important one, move DNA in other directions giving rise to non-gradual movement in individual cells and contributing to variation in intracellular position per cell length in a population of cells.

Cell Cycle↗

Peripheral binding mode and penetration depth of cobra cardiotoxin on phospholipid membranes as studied by a combined FTIR and computer simulation approach.

Cobra cardiotoxin, a cytotoxic beta-sheet basic polypeptide, is known to cause membrane leakage in many cells including human erythrocytes. Herein, we demonstrate that the major cobra cardiotoxin from Naja atra, CTX A3, can cause leakage of vesicle contents in phosphatidylglycerol (PG) and phosphatidylserine containing, but not in pure phosphatidylcholine (PC), membrane bilayers. By the combined polarized attenuated total reflection infrared spectroscopy and computer simulation studies, CTX A3 is shown to peripherally bind to both zwitterionic and anionic monolayers in a similar edgewise manner with a tilted angle of approximately 48 +/- 20 degrees between the beta-sheet plane of the CTX molecule and the normal of the membrane surface. The average surface area expansion induced by CTX A3 binding to the PG monolayer, however, is two times larger than that of the PC monolayer as determined by the Langmuir minitrough method. Interaction energy considerations of CTX A3 on neutral and negatively charged membrane surfaces suggests that the electrostatic interaction between anionic lipid and cationic CTXs plays a role in modulating the penetration depth of CTX molecules on the initial peripheral binding mode and reveals a pathway leading to the formation of an inserted mode in negatively charged membrane bilayers.

Animals↗

Minireview: computer simulations of blood pressure regulation by the renin-angiotensin system.

Gene targeting experiments in mice have been used by us and others to test whether quantitative changes in gene expression in the renin-angiotensin system affect blood pressure. Surprisingly, these studies showed that blood pressure does not change with mild quantitative changes in the expression of the angiotensin converting enzyme (ACE). Yet, ACE inhibitors are widely used for the treatment of hypertension. This apparent paradox motivated us to develop a simple computer simulation, which qualitatively reconciled the paradox. We have now improved the simulation by including blood pressure as an explicit variable and by adding the kallikrein-kinin system and feedback control of plasma renin via plasma angiotensin II levels. The new simulation now matches quantitative aspects of the experimental data and suggests that a decrease in bradykinin plays an important role in the increased risk of diabetic nephropathy associated with genetically determined higher levels of ACE activity. This emphasizes that the value of these types of simulation lies in the thoughts that they provoke rather than in their ability to replicate experimental data.

Animals↗

Computer simulation of hemodynamic parameter changes by mechanical ventilation and biventricular circulatory support.

When a Bi-Ventricular Assist Device (BVAD) is used in conjunction with mechanical ventilation (MV) of the lungs with positive intrathoracic pressure (Pt), the latter influences hemodynamics. The aim of our study was to assess the simultaneous influence of BVAD and MV on hemodynamics. We assumed ventricular pathological conditions as reduced elastances and increased rest volumes. Peripheral systemic arterial resistance was assumed to have different values. Data were obtained by computer simulation. Trends in main hemodynamic variables were compared with clinical data from literature. Simulation showed that systemic venous, pulmonary arterial and left atrial pressures are very sensitive to Pt (-2 to 5 mmHg).

Computer Simulation↗

Computer simulations of motoneuron firing rate modulation.

1. As a human subject slowly increases the amount of force exerted by a muscle, the discharge rates of low-threshold motor units saturate at a rather low level, whereas higher-threshold units continue to be recruited and undergo increases in their discharge rates. The presently known intrinsic properties of motor units do not produce this "rate limiting." 2. Using computer simulations of a model motoneuron pool, we tested the hypothesis that rate limiting can be accounted for on the basis of the known distributions of synaptic input from different sources. The properties of the simulated motor units and their synaptic inputs were based as closely as possible on the available experimental data. A variety of simulated synaptic input organizations were applied to the pool, and the resulting outputs were compared with the data on rate limiting in human subjects. 3. We found that the data on rate limiting in human subjects greatly constrained the possible organizations of characterized synaptic input systems. Only when the synaptic organization included a gradual "crossover" between two specific types of input systems could the human data be accurately reproduced. Low input/output levels relied on a system organized like the monosynaptic Ia input, which produces greater effective synaptic currents in low- than in high-threshold motor units. Above a sharply defined crossover level, all further increases in output were produced by a system organized like the oligosynaptic rubrospinal input, which generates the opposite pattern.

Computer Simulation↗

Computer simulations of ultrafiltration profiles for an icodextrin-based peritoneal fluid in CAPD.

BACKGROUND: The three-pore model of peritoneal transport has the ability to predict ultrafiltration (UF) profiles rather accurately, even when high molecular weight (MW) solutes are employed as osmotic agents in continuous ambulatory peritoneal dialysis (CAPD). In the present simulations, we wanted to assess, for various theoretical perturbations, the UF properties of a peritoneal dialysis (PD) solution with an osmotic agent having an average MW of 20 kD and a "number average MW" of 6.2 kD, which is similar to that of icodextrin (ICO). METHODS: For a PD solution containing a completely monodispersed 20 kD MW osmotic agent, the degree of UF modeled is much higher than that reported for ICO. Hence, to model the behavior of ICO, we subdivided the ICO molecules into eight or more different MW size fractions. For simulations using six or eight subfractions, we obtained an excellent fit of simulated to reported UF data. More dispersed solutions produced UF profiles similar to that with eight fractions. RESULTS: A 2.05 L 7.5% ICO PD solution, despite being slightly hypotonic, yielded a UF volume of nearly 600 mL in 12 hours, modeled for patients not previously exposed for ICO. After nine hours, the UF volume exceeded that produced by 3.86% glucose. The UF rate and volumes increased in proportion to (1) the ICO concentration, (2) the peritoneal surface area, and (3) the peritoneal UF coefficient, but was almost insensitive to increases in the instilled fluid volume. Simulated for patients previously exposed to ICO, having steady-state plasma concentrations of ICO degradation products, the predicted UF volume at 12 hours was reduced to approximately 400 mL. CONCLUSION: Employing the three-pore model of peritoneal transport and taking into account the polydispersed nature of ICO, it was possible to accurately computer simulate the UF profiles of ICO in accordance with reported data. The simulations suggest an advantage of using ICO in patients with type I UF failure, where UF with a high-MW osmotic agent will exceed that seen in patients not showing UF failure who are on glucose-based PD solutions.

Absorption↗

The application of size exclusion chromatography and computer simulation to study the thermodynamic and kinetic parameters for short-lived dissociable protein aggregates.

We describe a method to study the monomer-dimer equilibrium of human growth hormone (hGH) making use of a very short size exclusion high-performance liquid chromatographic column and rapid flow rates. By adjusting the flow rate and thus the retention time on the column, the dissociation of the hGH dimer can be observed. Using computer simulation, both the equilibrium constant for dissociation and the dissociation rate constant can be determined directly, followed by the indirect determination of the association rate constant. This method is potentially useful for determining the thermodynamic the kinetic parameters of aggregation of many protein-protein (homodimers and heterodimers) and protein-ligand systems whose rates of interaction are too rapid to be studied by conventional techniques.

Chromatography, High Pressure Liquid↗

Computational simulation of hypertrophic cardiomyopathy mutations in troponin I: influence of increased myofilament calcium sensitivity on isometric force, ATPase and [Ca2+]i.

Familial hypertrophic cardiomyopathy (FHC) is an inherited disease that is characterized by ventricular hypertrophy, cardiac arrhythmias and increased risk of premature sudden death. FHC is caused by autosomal-dominant mutations in genes for a number of sarcomeric proteins; many mutations in Ca(2+)-regulatory proteins of the cardiac thin filament are associated with increased Ca(2+) sensitivity of myofilament function. Computational simulations were used to investigate the possibility that these mutations could affect the Ca(2+) transient and mechanical response of a myocyte during a single cardiac cycle. We used existing experimental data for specific mutations of cardiac troponin I that exhibit increased Ca(2+) sensitivity in physiological and biophysical assays. The simulated Ca(2+) transients were used as input for a three-dimensional half-sarcomere biomechanical model with filament compliance to predict the resulting force. Mutations with the highest Ca(2+) affinity (lowest K(m)) values, exhibit the largest decrease in peak Ca(2+) assuming a constant influx of Ca(2+) into the cytoplasm; they also prolong Ca(2+) removal but have little effect on diastolic Ca(2+). Biomechanical model results suggest that these cTnI mutants would increase peak force despite the decrease in peak [Ca(2+)](i). There is a corresponding increase in net ATP hydrolysis, with no change in tension cost (ATP hydrolyzed per unit of time-integrated tension). These simulations suggest that myofilament-initiated hypertrophic signaling could be associated with decreased [Ca(2+)](i), increased stress/strain, and/or increased ATP flux.

Actin Cytoskeleton↗

Computer simulation of alternative sampling strategies to estimate risk of infection from Cryptosporidium.

Estimation of acceptably safe levels of biological contaminants in drinking water requires fitting a mathematical model to infection rates observed in small samples of human subjects. Because of obvious constraints on exposing human subjects to infective conditions, it is not feasible to compare the utilities of alternative sampling strategies and research designs using data from real experiments. Computer simulation methods were used to generate sample data having known probabilities of infection determined by an exponential or log-linear infectivity model. Experimental conditions that were examined included variations in the total available sample size, strategies for allocating subjects among different test concentrations, and methods for fitting a prediction model to the observed data. Results confirmed that data obtained by exposing most subjects to a concentration that produces an infection rate approximating 50% and calculating the sample regression coefficient for the log-linear model as the average infectivity-to-concentration ratio provided the best estimates of safe concentration. Exposing a single subject to each successively higher test level until an initial infection is observed, and exposing all remaining subjects at that level, or an adjacent log-concentration level is a tactic supported by the empirical results.

Animals↗

A computer simulation of recurrent, excitatory networks of sensory neurons of the gut in guinea-pig.

Intrinsic sensory neurons of the intestine are connected together to form a recurrent network. They interact by slow excitatory post synaptic potentials (EPSPs), which have a complex dependence on the pattern of input. These networks are unstable and unable to give graded responses to sensory input without some form of inhibition, but inhibitory synaptic potentials are rare in this system. Intrinsic sensory neurons have a characteristic after-hyperpolarization (AHP), but this is depressed during slow EPSPs. To test whether AHPs can provide the inhibition necessary for stability, AHPs, slow EPSPs and their interactions were included in a computer simulation of realistic sensory neuron networks. Residual AHPs as small as 1% of control were found to lead to stable networks capable of giving graded responses.

Action Potentials↗

Reactions of OH-radicals with procarbazine. A pulse radiolysis and computer simulation study.

Pulse radiolysis was applied to study the reactivity of *OH radicals with procarbazine (PC), a cytostatic agent widely used in radiation- and chemotherapy. An overall rate constant of k(*OH+PC) = 3.7 x 10(9) l.mol(-1).s(-1) was determined. The thereby formed transients had a strong absorption at 350 nm, epsilon350 = 4.46 x 10(3) l.mol(-1).cm(-1), and a weak absorption band around 530 nm. Computer simulation studies to elucidate the most probable sites of *OH attack on the PC molecule showed that *OH radical addition to the aromatic ring had the highest probability. These transients decayed by a first order reaction, k = 1.75 x 10(3) s(-1), whereby species having a maximum absorption at 300 nm and broad shoulder at 340-380 nm were formed. Similar absorptions were observed after gamma radiolysis of PC. A reaction mechanism is suggested. For the reaction of H-atoms with PC, a rate constant k(*H+PC) = 6.4 x 10(8) l.mol(-1).s(-1) was determined.

Antineoplastic Agents↗

Computer simulation of the baroregulation in response to moderate dynamic exercise.

A baroregulation model, based on a previous pulsatile non-linear multielement cardiovascular model, is extended and used to study short-term regulation mechanisms. Using this model, the responses of several cardiovascular variables to different exercise levels are simulated and compared with the experimental data reported in the literature. The impact of physiological or pathological changes on the short-term regulation of arterial pressure under the stimulus of moderate dynamic exercise is then studied. The simulation results indicate that baroreflex feedback plays a critical role in the short-term regulation of arterial pressure. When the baroreflex gain decreases to one-third of the normal value, the response of the mean arterial pressure to moderate dynamic exercise and post-exercise recovery time increases by factors of 1.7 and 2.3, respectively. Clinical data from 36 subjects (two groups: normal and hypertensive) are collected to validate the model. Computer simulations for the hypertensive group show that the elastic modulus of the arterial vessel wall is increased by 1.5 times, and peripheral resistance is increased by 1.3 times the normal value, and the baroreflex gain decreases from 0.55 (for the normal group) to 0.40. The simulation results for normal and hypertensive groups agree well with the clinical data.

Adult↗

Computer simulations of nuclear reactions by protons with incident energies of 250, 300 and 500 MeV in a human body.

Computer simulations of nuclear reactions by protons in a human body were carried out at the incident energies of 250, 300 and 500 MeV. About 20% of the incident protons are absorbed by the body with nuclear interactions and the rest of the protons pass through the body at these energies. Radiation of gamma rays from the body and radioactivity of the body were estimated as a function of the time after irradiation with the proton beam.

Body Composition↗

Computer simulation of stepping in the hind legs of the cat: an examination of mechanisms regulating the stance-to-swing transition.

Physiological studies in walking cats have indicated that two sensory signals are involved in terminating stance in the hind legs: one related to unloading of the leg and the other to hip extension. To study the relative importance of these two signals, we developed a three-dimensional computer simulation of the cat hind legs in which the timing of the swing-to-stance transition was controlled by signals related to the force in ankle extensor muscles, the angle at the hip joint, or a combination of both. Even in the absence of direct coupling between the controllers for each leg, stable stepping was easily obtained using either a combination of ankle force and hip position signals or the ankle force signal alone. Stable walking did not occur when the hip position signal was used alone. Coupling the two controllers by mutual inhibition restored stability, but it did not restore the correct timing of stepping of the two hind legs. Small perturbations applied during the swing phase altered the movement of the contralateral leg in a manner that tended to maintain alternating stepping when the ankle force signal was included but tended to shift coordination away from alternating when the hip position signal was used alone. We conclude that coordination of stepping of the hind legs depends critically on load-sensitive signals from each leg and that mechanical linkages between the legs, mediated by these signals, play a significant role in establishing the alternating gait.

Animals↗