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PubMed2001

Correlating the kinetics of cytokine-induced E-selectin adhesion and expression on endothelial cells.

Many human diseases are mediated through the immune system. In chronic inflammatory disorders, the processes ordinarily involved in tissue healing become destructive. Endothelial cells normally recruit leukocytes to inflamed tissue using cytokine-induced adhesion receptors on the surfaces of interacting cells. Leukocyte capture depends on specialized characteristics of these receptors, particularly the binding kinetics. This study is designed to clarify the relationship between cytokine-induced changes in cell properties and binding kinetics. Here, we measure the kinetics of expression and monoclonal antibody binding for E-selectin in interleukin-1alpha-stimulated microvascular endothelium in vitro and incorporate the data into kinetic models. Quantitative flow cytometry is used to determine molecular density (expression), and micropipette assays are used to find the probability of adhesion (function). Within five hours of interleukin-1alpha stimulation, E-selectin density increases from 0 to 742 sites/microm(2), and antibody-E-selectin adhesion probability increases from a baseline of 6.3% to 64%. A kinetic model is applied to find an apparent association rate constant, k(f), of 3.7 x 10(-14) cm(2)/sec for antibody-E-selectin binding. Although the model successfully predicts experimental results, the rate constant is undervalued for a diffusion-limited process, suggesting that functional adhesion may be modified through cytokine-induced changes in microtopology and receptor localization.

Animals↗
PubMed2004

Identification of own-race and other-race faces: implications for the representation of race in face space.

Own-race faces are recognized more easily than faces of a different, unfamiliar race. According to the multidimensional space (MDS) framework, the poor discriminability of other-race faces is due to their being more densely clustered in face space than own-race faces. Multidimensional scaling analyses of similarity ratings (Caucasian participants, n = 22) showed that other-race (Chinese) faces are more densely clustered in face space. We applied a formal model to test whether the spatial location of face stimuli could account for identification accuracy of another group of Caucasian participants (n = 30). As expected, own-race (Caucasian) faces were identified more accurately (higher hit rate, lower false alarms, and higher A') than other-race faces, which were more densely clustered than own-race faces. A quantitative model successfully predicted identification performance from the spatial locations of the stimuli. The results are discussed in relation to the standard MDS account of race effects and also an alternative "race-feature" hypothesis.

Adult↗
PubMed1985

A model for direction selectivity in threshold motion perception.

Thresholds were measured for a moving line superimposed on moving sinusoidal gratings. When line and grating moved in the same direction significant subthreshold summation was observed over a range of spatial frequencies. For motion of the line and grating in opposite directions, summation was never observed. This supports the hypothesis that direction selective mechanisms are responsible for motion perception at threshold. Further analysis of the data produced estimates of the spatial frequency tuning of these mechanisms. A quantitative model is proposed to interpret the data, and it is suggested that flickering gratings are not decomposed into their moving components by the visual system.

Cybernetics↗
PubMed1991

The comparative biology of genetic variation for conditional sex ratio behavior in a parasitic wasp, Nasonia vitripennis.

Using genetic markers, we tracked the sex ratio behavior of individual females of the parasitic wasp, Nasonia vitripennis, in foundress groups of size 1, 2, 4, 8 and 16. Comparison of 12 isofemale strains extracted from a natural population reveals significant between-strain heterogeneity of sex ratios produced in all sizes of foundress group. Under simple assumptions about population structure, this heterogeneity results in heterogeneity of fitnesses. The strains differ in their conditional sex ratio behavior (the sex ratio response of a female to foundress groups of different sizes). Females of some strains produce more males as foundress group size increases (up to size eight). Females of another strain produce more males when not alone but do not respond differentially to group size otherwise. Females of two other strains show no conditional sex ratio behavior. Females of only two strains behave differently in foundress groups of size 8 and 16. Correlation and regression analyses indicate that the strains differ significantly in their fit to the predictions of an evolutionarily stable strategy (ESS) model of conditional sex ratio behavior. Such heterogeneity contradicts the notion that females of this species possess conditonal sex ratio behavior that is optimal in the ESS sense. The results imply that this ESS model is useful but not sufficient for understanding the causal basis of the evolution of this behavior in this species. This is the first report on the sex ratio behavior of individual females in multiple foundress groups in any species of parasitic wasp. Data of this type (and not foundress group or "patch" sex ratios) are essential for testing evolutionary models that predict the sex ratio behaviors of individuals. We suggest that a test for an ESS model include the answers to two important questions: 1) is the model quantitatively accurate? and 2) is there reasonable evidence to indicate that natural selection has caused individuals to manifest the ESS behavior?

Animals↗
PubMed1999

A possible neurophysiological basis of the octave enlargement effect.

Although the physical octave is defined as a simple ratio of 2:1, listeners prefer slightly greater octave ratios. Ohgushi [J. Acoust. Soc. Am. 73, 1694-1700 (1983)] suggested that a temporal model for octave matching would predict this octave enlargement effect because, in response to pure tones, auditory-nerve interspike intervals are slightly larger than the stimulus period. In an effort to test Ohgushi's hypothesis, auditory-nerve single-unit responses to pure-tone stimuli were collected from Dial-anesthetized cats. It was found that although interspike interval distributions show clear phase-locking to the stimulus, intervals systematically deviate from integer multiples of the stimulus period. Due to refractory effects, intervals smaller than 5 msec are slightly larger than the stimulus period and deviate most for small intervals. On the other hand, first-order intervals are smaller than the stimulus period for stimulus frequencies less than 500 Hz. It is shown that this deviation is the combined effect of phase-locking and multiple spikes within one stimulus period. A model for octave matching was implemented which compares frequency estimates of two tones based on their interspike interval distributions. The model quantitatively predicts the octave enlargement effect. These results are consistent with the idea that musical pitch is derived from auditory-nerve interspike interval distributions.

Algorithms↗
PubMed1997

Distribution of mixtures of bile salt taurine conjugates between lecithin-cholesterol vesicles and aqueous media: an empirical model.

Bile salts are surfactants that partition into phospholipid bilayers. When liposomes or membranes are exposed to mixed solutions of bile salts, the more hydrophobic bile salt species associate preferentially with the lipid bilayer. As a consequence, in the aqueous phase, the free monomeric concentration of bile salt declines and the more hydrophilic species become relatively enriched. Above a critical saturating concentration of lecithin-associated bile salt, a phase transition occurs with loss of membrane integrity and formation of mixed micelles. In this paper we present a quantitative model which, for mixed solutions of bile salt taurine conjugates, predicts the distribution of bile salt monomers between large unilamellar vesicles composed of lecithin and cholesterol and the aqueous phase. The model is based on association isotherms for individual bile salts, determined by an ultrafiltration method with empirical curve fitting, and is critically dependent upon the observation that association coefficients of each bile salt are a function of the total bound bile salt/lecithin mole ratio. Given the concentrations of individual bile salts, lecithin and cholesterol, the model permits calculation of the membrane-bound bile salt/lecithin ratio and the concentration of each bile salt remaining free as soluble monomer in the aqueous phase, as well as the overall hydrophilic-hydrophobic balance (hydrophobicity index) of the bile salts remaining free in aqueous solution. Distribution data determined empirically for a variety of mixtures of bile salt taurine conjugates and large unilamellar vesicles of varying cholesterol:lecithin ratio agree closely with predictions. This model may be of value in predicting the physical, biological and toxic properties of mixed bile salt solutions.

Animals↗
PubMed2003

Mefenamate, an agent that fails to attenuate experimental cerebral infarction.

BACKGROUND: Blockade of nonselective cation channels is a potential therapeutic approach that has not been attempted in cerebral ischemia, in spite of the ability of these channels to allow cellular calcium influx into neurons. Fenamates are a class of molecules that block these channels, and many congeners are also anti-inflammatory and free radical scavenging. These three mechanisms may contribute to brain damage in ischemia. METHODS: Pretreatment or posttreatment with mefenamate (30 mg/kg) was evaluated in a temperature-controlled rat transient focal ischemia model. Quantitative histopathology on 26 coronal sections allowed determination of tissue necrosis and tissue atrophy at one week survival. RESULTS: Neither pre- nor postischemic administration of a dose previously shown effective in preventing epileptic neuronal necrosis was found to reduce necrosis in cortex, nor in any subcortical structures. CONCLUSIONS: We conclude that nonselective cation channel blockade with mefenamate affords no neuroprotection in this model. Publication bias against negative studies exists in the literature, but we here report negative findings due to the multiple potentially positive actions of the drug. Closer examination of the effects of the molecule, however, reveals several potentially negative effects as well. We conclude there may be inherent weakness in pharmacologic monotherapy, even with molecules having protean potentially beneficial effects. This conclusion seems to have been borne out by the results of recent clinical trials.

Animals↗
PubMed2005

Antibacterial activity of linezolid and vancomycin in an in vitro pharmacodynamic model of gram-positive catheter-related bacteraemia.

OBJECTIVES: The aim of this study was to compare the activity of linezolid and vancomycin in an in vitro pharmacodynamic model to assess potential differences in activity against biofilm-embedded organisms. METHODS: Single-lumen central venous catheters colonized with biofilm-embedded Staphylococcus aureus, Staphylococcus epidermidis or vancomycin-resistant Enterococcus faecium (VRE) were treated with simulated clinical dosing regimens of linezolid 600 mg every 12 h or vancomycin 1 g every 12 h in a one-compartment in vitro pharmacodynamic model. Quantitative cultures were sampled through the catheter and peripheral ports over 48 h to dynamically assess changes in the burden of catheter colonization and organism seeding, respectively. At 24 and 48 h catheters were removed, sonicated and cultured for adherent organisms. RESULTS: Both linezolid and vancomycin suppressed bacterial growth on the catheter and release of S. aureus and S. epidermidis into the model compared with controls (P < 0.05), while linezolid also suppressed counts compared with control and vancomycin versus VRE. Neither agent completely eradicated bacterial colonization of the catheters. MICs for the isolates recovered from the model did not increase over time with linezolid or vancomycin exposure. CONCLUSIONS: Lack of activity against biofilm-embedded organisms appeared to be the primary reason for microbiological failure of both drugs in the model.

Acetamides↗
PubMed2001

An analytically solvable model for biomechanical response of the cornea to refractive surgery.

An analttically solvable model that considers the elasticity of the cornea is developed for use in the current and novel corneal refractive surgery procedures. The model assumes that the cornea is a thin spheroid shell with an elastic response to intraocular pressure. The value of the Young's modulus of the post-operative cornea and its dependence on the geometric parameters of the ablation zone are estimated employing "best-fit" approach to nomograms currently used in corneal refractive surgery. These elasticity parameters are applied for quantitative modeling of different types of refractive surgery for myopia.

Biomechanical Phenomena↗
PubMed1995

Comparison of cost-effectiveness and utility of exercise ECG, single photon emission computed tomography, positron emission tomography, and coronary angiography for diagnosis of coronary artery disease.

BACKGROUND: To compare cost-effectiveness and utility of four clinical algorithms to diagnose obstructive coronary atherosclerotic heart disease (CAD), we compared exercise ECG (ExECG), stress single photon emission computed tomography (SPECT), positron emission tomography (PET), and coronary angiography. METHODS AND RESULTS: Published data and a straightforward mathematical model based on Bayes' theorem were used to compare strategies. Effectiveness was defined as the number of patients with diagnosed CAD, and utility was defined as the clinical outcome, ie, the number of quality-adjusted life years (QALY) extended by therapy after the diagnosis of CAD. Our model used published values for costs, accuracy, and complication rates of tests. Analysis of the model indicates the following results. (1) The direct cost (fee) for each test differs considerably from total cost per delta QALY. (2) As pretest likelihood of CAD (pCAD) in the population increases, there is a linear increase in cost per patient tested but a hyperbolic decrease in cost per effect and cost per utility unit, ie, increased cost-effectiveness and decreased cost per utility unit. (3) At pCAD < 0.70, analysis of the model indicates that stress PET is the most cost-effective test, with the lowest cost per utility, followed by SPECT, ExECG, and angiography, in that order. (4) Above a threshold value of pCAD of 0.70 (for example, middle-aged men with typical angina), proceeding directly to angiography as the first test showed the lowest cost per effect or utility. This quantitative model has the advantage of estimating a threshold value of pCAD (0.70) at which the rank order of cost-effectiveness and cost per utility unit change. The model also allows substitution of different values for any variable as a way to account for the uncertainties of clinical data, ie, changing costs, test accuracy and risk, etc. This procedure, called sensitivity analysis, showed that the rank order of cost-effectiveness did not change despite changes in several variables. CONCLUSIONS: (1) Estimation of total costs of diagnostic tests for CAD requires consideration not only of the direct cost of the test per se (eg, test fees) but also of the indirect and induced costs of management algorithms based on the test (eg, cost/delta QALY). (2) It is essential to consider the clinical history (pCAD) when selecting the clinical algorithm to make a diagnosis with the lowest cost per effect or cost per utility unit. (3) Stress PET shows the lowest cost per effect or cost per utility unit in patients with pCAD < 0.70. (4) Angiography shows the lowest cost per effect or cost per utility unit in patients with pCAD > 0.70.

Adult↗
PubMed1995

[The role of the Aedes aegypti vector in the epidemiology of dengue in Mexico].

The role of Aedes aegypti (Lineo) in the epidemiology of dengue fever in Mexico is herein discussed based on the vectorial capacity model. Comments on the advantages and disadvantages of each model component at the time of field determinations are also presented. Emphasis is made on the impact of sampling and method bias on the results of vectorial capacity studies. The paper also addresses the need to increase vector biology knowledge as an input for epidemiological work to explain and predict dengue fever outbreaks. Comments on potential entomological variables not considered by the quantitative model are included. Finally, we elaborate on the introduction of Aedes albopictus (Skuse) in Mexico as a new risk factor and on its implications for the understanding of dengue fever transmission in Mexico.

Aedes↗
PubMed2006

Bayesian model of human color constancy.

Vision is difficult because images are ambiguous about the structure of the world. For object color, the ambiguity arises because the same object reflects a different spectrum to the eye under different illuminations. Human vision typically does a good job of resolving this ambiguity-an ability known as color constancy. The past 20 years have seen an explosion of work on color constancy, with advances in both experimental methods and computational algorithms. Here, we connect these two lines of research by developing a quantitative model of human color constancy. The model includes an explicit link between psychophysical data and illuminant estimates obtained via a Bayesian algorithm. The model is fit to the data through a parameterization of the prior distribution of illuminant spectral properties. The fit to the data is good, and the derived prior provides a succinct description of human performance.

Algorithms↗
PubMed1989

A model for fluid secretion in the exocrine pancreas.

Fluid secretion by the isolated rabbit pancreas is strongly dependent on the presence of Na+ in the bathing medium. Substitution of Na+ by another cation such as Li+ or K+ causes an inhibition of fluid secretion rate and a change in the composition of the secreted fluid which is dependent on the nature of the substituent cation. Stimulation of the pancreas by CCK-8 or carbachol increases paracellular ion permeability and, in some cases, also fluid secretion rate. We present a simple, quantitative model for ion and water secretion which accounts for the effects observed upon Na+ substitution and stimulation. The main features are active, Na+-dependent transcellular HCO3- transport and passive, paracellular cation and anion permeation. The activity of the HCO3- pump is dependent on the energy status of the cell and on the Na+ concentration in the bathing medium, and is competitively inhibited by K+. The paracellular ion permeabilities can be modulated by stimulatory agonists. We examine the extent to which, according to the model, fluid secretion is controlled by the various system parameters such as ion permeabilities and ion pump activity, and by external parameters such as the ion concentrations in the bathing medium. In addition, calculation of the effects of changes in these parameters are carried out in order to gain more insight in the mechanisms of secretion.

Animals↗
PubMed2005

Linear free energy relationship for 4-substituted (o-phenylenediamine)platinum(II) dichloride derivatives using quantum mechanical descriptors.

In the present work quantum mechanical methods were used to calculate the rate constants for the first step of the aquation of a set of 4-substituted (o-phenylenediamine)platinum(II) dichloride derivatives containing electron-donating and withdrawing substituents at the 4-position of the aromatic ring. A linear free energy relationship was obtained for log(k(X)/k(H)), k being the rate constant for the first step of hydrolysis, and the electronic Hammett constants sigma(m) and sigma(p). The results showed that electron-donating groups promote the hydrolysis reaction. The quantitative models described here may be useful for the rational design of new, less mutagenic drugs based on platinum complexes.

Antineoplastic Agents↗
PubMed1999

Coupled cellular trafficking and diffusional limitations in delivery of immunotoxins to multicell tumor spheroids.

Immunotoxins have the potential to be powerful tools for selective cell killing, but their lack of clinical success against solid tumors indicates a need to better understand factors which limit immunotoxin transport in three-dimensional systems. In this work, a previously developed model which related immunotoxin toxicity to cellular trafficking in a single cell was coupled with a term accounting for diffusive transport of immunotoxin in a solid tumor sphere. This created a mathematical model which is capable of simulating the biological response of multicell tumor spheroids (MTS) to immunotoxin treatment. The model was used to predict the kinetics of protein synthesis inhibition in MTS treated with transferrin receptor-targeted immunotoxins as a function of immunotoxin concentration and toxin choice. HeLa cells were grown as MTS and treated with immunotoxins constructed from the anti-transferrin receptor antibody OKT9 and the toxins gelonin or CRM107, and the average protein synthesis inhibition and growth rates were measured. With no fitted parameters, the mathematical model quantitatively predicted the experimental observations. Immunotoxins were generally less effective against MTS than monolayer cells at equivalent conditions; for OKT9-gelonin at high concentrations this decrease in efficacy was attributed primarily to heterogeneous receptor distribution in MTS whereas for OKT9-CRM107 the decrease was caused primarily by a large barrier to penetration of the immunotoxin into the spheroid. The experimentally verified model was used to define the conditions which lead to large penetration barriers. In general, transport barriers in MTS become more important as immunotoxins become more effective against cells grown as monolayers. The proposed model is unique in its ability to predict toxicity in MTS directly, and is an important step toward understanding immunotoxin effect on tumors in vivo.

Animals↗
PubMed1991

A quantitative comparison of the TERA modeling and DFT magnetic resonance image reconstruction techniques.

The resolution of magnetic resonance images reconstructed using the discrete Fourier transform (DFT) algorithm is limited by the effective window generated by the finite data length. The transient error reconstruction approach (TERA) is an alternative reconstruction method based on autoregressive moving average (ARMA) modeling techniques. Quantitative measurements comparing the truncation artifacts present during DFT and TERA image reconstruction show that the modeling method substantially reduces these artifacts on "full" (256 X 256), "truncated" (256 X 192), and "severely truncated" (256 X 128) data sets without introducing the global amplitude distortion found in other modeling techniques. Two global measures for determining the success of modeling are suggested. Problem areas for one-dimensional modeling are examined and reasons for considering two-dimensional modeling discussed. Analysis of both medical and phantom data reconstructions are presented.

Algorithms↗
PubMed2006

A unifying model for activity-dependent and activity-independent mechanisms predicts complete structure of topographic maps in ephrin-A deficient mice.

Axons of retinal ganglion cells establish orderly projections to the superior colliculus of the midbrain. Axons of neighboring cells terminate proximally in the superior colliculus thus forming a topographically precise representation of the visual world. Coordinate axes are encoded in retina and in the target through graded expression of chemical labels. Additional sharpening of projections is provided by electric activity, which is correlated between neighboring axons. Here we propose a quantitative model, which allows combining the effects of chemical labels and correlated activity in a single approach. Using this model we study a complete structure of two-dimensional topographic maps in mutant mice, in which the label encoding the horizontal retinal coordinate ephrin-A is reduced/eliminated. We show that topographic maps in ephrin-A deficient mice display a granular structure, with the regions of smooth mapping separated by linear discontinuities reminiscent of fractures observed in the maps of preferred orientation.

Animals↗
PubMed2004

Asynchronous adaptive time step in quantitative cellular automata modeling.

BACKGROUND: The behaviors of cells in metazoans are context dependent, thus large-scale multi-cellular modeling is often necessary, for which cellular automata are natural candidates. Two related issues are involved in cellular automata based multi-cellular modeling: how to introduce differential equation based quantitative computing to precisely describe cellular activity, and upon it, how to solve the heavy time consumption issue in simulation. RESULTS: Based on a modified, language based cellular automata system we extended that allows ordinary differential equations in models, we introduce a method implementing asynchronous adaptive time step in simulation that can considerably improve efficiency yet without a significant sacrifice of accuracy. An average speedup rate of 4-5 is achieved in the given example. CONCLUSIONS: Strategies for reducing time consumption in simulation are indispensable for large-scale, quantitative multi-cellular models, because even a small 100 x 100 x 100 tissue slab contains one million cells. Distributed and adaptive time step is a practical solution in cellular automata environment.

Animals↗