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PubMed1975

Descartes' law of reciprocal innervation.

Reciprocal innervation plays a crucial role in the fine motor control exhibited in body movements and this is especially true for the precise ocular rotations demanded of the extrinsic muscles of the eye. Although Galen, in 157 AD, was knowledgeable in human anatomy and muscle function, it was Descarted, who in 1626 first conceived of model for the nervous system controller, of a muscular mechanism for movement of the extra-ocular plant, and of reciprocal innervation as the linking principle to provide for control of agonist and antagonist muscles. Bell, in 1826, and Sherrington in 1893, clearly demonstrated reciprocal innervation in their experimental animals. Additional qualitative neurophysiological evidence supporting the concept of reciprocal innervation has been provided by clinical case reports, by electromyographic recording from the extraocular muscles, and by monitoring single unit activity in the extraocular motor nuclei. Recently the applicatio of bioengineering concepts, such as time optimal control and quantitative models to elucidate the nature of the neural signals sent by the brain to command eye movements have further emphasized the importance of Descartes' "Law of Reciprocal Innervation."

Animals↗
PubMed1997

Relationship between plaque mass and neointimal hyperplasia after stent placement in Yucatan micropigs.

PURPOSE: To determine whether the amount of neointima found after stent placement is related to the preexistent plaque mass in the peripheral arteries in micropigs. MATERIALS AND METHODS: Twenty-six peripheral arteries were studied in 14 Yucatan micropigs in a denudation and diet-induced atherosclerosis model. Quantitative angiographic and intravascular ultrasound (US) analysis were performed before and after stent placement and at follow-up 6 weeks after stent placement. At follow-up, the peripheral arterial tree was fixed by means of pressure perfusion, processed for histologic analysis, and analyzed morphometrically with a computer-based system. RESULTS: Preexistent plaque correlated strongly with intimal hyperplasia measured on US images (r = .81, P < .001) or in histologic sections (r = .53, P = .006). No correlation was found between dilation ratio and intimal hyperplasia or between balloon-to-lesion ratio and intimal hyperplasia. In multivariate models of intimal hyperplasia, preexistent plaque and early gain in lumen diameter depicted at angiography were independent explanatory variables. CONCLUSION: The amount of plaque present before stent placement was a determinant of the amount of intimal hyperplasia present after stent placement.

Angiography↗
PubMed2002

Equilibrium and kinetic folding of hen egg-white lysozyme under acidic conditions.

The equilibrium and kinetic folding of hen egg-white lysozyme was studied by means of circular dichroism spectra in the far- and near-ultraviolet (UV) regions at 25 degrees C under the acidic pH conditions. In equilibrium condition at pH 2.2, hen lysozyme shows a single cooperative transition in the GdnCl-induced unfolding experiment. However, in the GdnCl-induced unfolding process at lower pH 0.9, a distinct intermediate state with molten globule characteristics was observed. The time-dependent unfolding and refolding of the protein were induced by concentration jumps of the denaturant and measured by using stopped-flow circular dichroism at pH 2.2. Immediately after the dilution of denaturant, the kinetics of refolding shows evidence of a major unresolved far-UV CD change during the dead time (<10 ms) of the stopped-flow experiment (burst phase). The observed refolding and unfolding curves were both fitted well to a single-exponential function, and the rate constants obtained in the far- and near-UV regions coincided with each other. The dependence on denaturant concentration of amplitudes of burst phase and both rate constants was modeled quantitatively by a sequential three-state mechanism, U<-->I<-->N, in which the burst-phase intermediate (I) in rapid equilibrium with the unfolded state (U) precedes the rate-determining formation of the native state (N). The role of folding intermediate state of hen lysozyme was discussed.

Acids↗
PubMed2001

A simple model based on mutation and selection explains trends in codon and amino-acid usage and GC composition within and across genomes.

BACKGROUND: Correlations between genome composition (in terms of GC content) and usage of particular codons and amino acids have been widely reported, but poorly explained. We show here that a simple model of processes acting at the nucleotide level explains codon usage across a large sample of species (311 bacteria, 28 archaea and 257 eukaryotes). The model quantitatively predicts responses (slope and intercept of the regression line on genome GC content) of individual codons and amino acids to genome composition. RESULTS: Codons respond to genome composition on the basis of their GC content relative to their synonyms (explaining 71-87% of the variance in response among the different codons, depending on measure). Amino-acid responses are determined by the mean GC content of their codons (explaining 71-79% of the variance). Similar trends hold for genes within a genome. Position-dependent selection for error minimization explains why individual bases respond differently to directional mutation pressure. CONCLUSIONS: Our model suggests that GC content drives codon usage (rather than the converse). It unifies a large body of empirical evidence concerning relationships between GC content and amino-acid or codon usage in disparate systems. The relationship between GC content and codon and amino-acid usage is ahistorical; it is replicated independently in the three domains of living organisms, reinforcing the idea that genes and genomes at mutation/selection equilibrium reproduce a unique relationship between nucleic acid and protein composition. Thus, the model may be useful in predicting amino-acid or nucleotide sequences in poorly characterized taxa.

Amino Acids↗
PubMed1992

Protein control of iron-sulfur cluster redox potentials.

The relationship between the three-dimensional structures of iron-sulfur proteins and the redox potentials of their iron-sulfur clusters is of fundamental importance. We report calculations of the redox potentials of the [Fe4S4(S-cys)4]-2/-3 couple in four crystallographically characterized proteins: Azotobacter vinelandii ferredoxin I, Peptococcus aerogenes ferredoxin, Bacillus thermoproteolyticus ferredoxin, and Chromatium vinosum high potential iron protein (HiPIP). Our calculations use the "protein dipoles Langevin dipoles" microscopic electrostatic model, which includes both protein and solvent water. The variations in calculated redox potentials are in excellent agreement with experimental data. In particular, our results confirm the important role of amide groups close to the cluster in separating the potential of C. vinosum HiPIP from those of the other three proteins. However, the potentials of these latter exhibit a substantial range despite extremely similar amide group environments of their clusters. Our results show that the potentials in these proteins are tuned in part by varying the access of solvent water to the neighborhood of the cluster. Our calculations provide the first successful quantitative modeling of the protein control of iron-sulfur cluster redox potentials.

Azotobacter vinelandii↗
PubMed2005

Prospect theory on the brain? Toward a cognitive neuroscience of decision under risk.

Most decisions must be made without advance knowledge of their consequences. Economists and psychologists have devoted much attention to modeling decisions made under conditions of risk in which options can be characterized by a known probability distribution over possible outcomes. The descriptive shortcomings of classical economic models motivated the development of prospect theory (D. Kahneman, A. Tversky, Prospect theory: An analysis of decision under risk. Econometrica, 4 (1979) 263-291; A. Tversky, D. Kahneman, Advances in prospect theory: Cumulative representation of uncertainty. Journal of Risk and Uncertainty, 5 (4) (1992) 297-323) the most successful behavioral model of decision under risk. In the prospect theory, subjective value is modeled by a value function that is concave for gains, convex for losses, and steeper for losses than for gains; the impact of probabilities are characterized by a weighting function that overweights low probabilities and underweights moderate to high probabilities. We outline the possible neural bases of the components of prospect theory, surveying evidence from human imaging, lesion, and neuropharmacology studies as well as animal neurophysiology studies. These results provide preliminary suggestions concerning the neural bases of prospect theory that include a broad set of brain regions and neuromodulatory systems. These data suggest that focused studies of decision making in the context of quantitative models may provide substantial leverage towards a fuller understanding of the cognitive neuroscience of decision making.

Animals↗
PubMed2006

Population clinical pharmacology of children: modelling covariate effects.

INTRODUCTION: Population modelling using mixed effects models provides a means to study variability in paediatric drug responses among individuals representative of those in whom the drug will be used clinically. DISCUSSIONS: Explanatory covariates explain the predictable part of the between-individual variability. Growth and development are two major aspects of children not seen in adults. These aspects can be investigated by using size and age as covariates. Problems attributable to co-linearity can be approached by using size as the first covariate. Size standardisation is achieved using allometric scaling, a mechanistic approach that has a strong theoretical and empirical basis. Age is used to describe the maturation of clearance. The quantitative models (linear, exponential, first-order, variable slope sigmoidal) used to describe this maturation process vary depending on the span of the ages under investigation. Measures of response are not always straightforward and can be more difficult to quantify in children. CONCLUSION: Covariate investigation in children is improving the understanding of developmental aspects of drug disposition and effects in the paediatric population, ultimately leading to more effective use of medications.

Body Surface Area↗
PubMed2001

Photooxidation of organic mixtures on biased TiO2 films.

Processes that occur in the TiO2-photocatalysis of binary aqueous solutions containing model photolytes with different affinity for the TiO2 surface (methanol and oxalic and salicylic acids) are analyzed from the photoelectrochemical response of TiO2 films under bias in a time window of 1-100 s. Long-lived oxidized intermediates produced upon illumination at 0.6 VSCE are detected by cathodic sweep run in the dark after irradiation. The main conclusion derived from this work is that a scheme of competitive kinetics describes only those cases in which one of the components is weakly or nonadsorbed on TiO2, whereas for two photolytes with high affinity for the surface cooperative effects may occur. The methanol-oxalate system is quantitatively modeled by considering that oxalate forms surface complexes with different reactivity and a parallel pathway for hole transfer to -OH and adsorbed oxalate. In this case as well as for electrolytes containing methanol and salicylate photooxidation of methanol (with low affinity for the surface) via intermediates formed by reaction with trapped holes (-*OH) is partially or fully suppressed. For electrolytes containing oxalic and salicylic acids in which both components chemisorb on TiO2 the photoelectrochemical response depends on preadsorption, the photooxidation pathways deviates those of single component systems, and there is remotion of salicylate adsorbed byproducts assigned to cooperative effects.

Adsorption↗
PubMed2007

Macromolecular transport in heart valves. II. Theoretical models.

This paper proposes a new, two-dimensional convection-diffusion model for macromolecular transport in heart valves based on horseradish peroxidase (HRP) experiments on rats presented in the first of the papers in this series (Part I; Zeng Z, Yin Y, Huang AL, Jan KM, Rumschitzki DS. Am J Physiol Heart Circ Physiol 292: H2664-H2670, 2007). Experiments require two valvular intimae, one underneath each endothelium. Tompkins et al. (Tompkins RG, Schnitzer JJ, Yarmush ML. Circ Res 64: 1213-1223, 1989) found large variations in shape and magnitude in transvalvular (125)I-labeled low-density lipoprotein (LDL) profiles from identical experiments on four squirrel monkeys. Their one-dimensional, uniform-medium diffusion-only model fit three parameters independently for each profile; data variability resulted in large parameter spreads. Our theory aims to explain their data with one parameter set. It uses measured parameters and some aortic values but fits the endothelial mass transfer coefficient (k(a)=k(v)=1.63 x 10(-8) cm/s, where subscripts a and v indicate aortic aspect and ventricular aspect, respectively) and middle layer permeability (K(p(2))=2.28 x 10(-16)cm(2)) and LDL diffusion coefficient [D(2)(LDL)=5.93 x 10(-9) cm(2)/s], using one of Tompkins et al.'s profiles, and fixes them throughout. It accurately predicts Part I's rapid localized HRP leakage spot growth rate in rat leaflets that results from the intima's much sparser structure, dictating its far larger transport parameters [K(p(1))= 1.10 x 10(-12)cm(2), D(1)(LDL/HRP)=1.02/4.09 x 10(-7)cm(2)/s] than the middle layer. This contrasts with large arteries with similarly large HRP spots, since the valve has no internal elastic lamina. The model quantitatively explains all of Tompkins et al.'s monkey profiles with these same parameters. Different numbers and locations of isolated macromolecular leaks on both aspects and different section-leak(s) distances yield all profiles.

Animals↗
PubMed1998

Strong precursor-pore interactions constrain models for mitochondrial protein import.

Mitochondrial precursor proteins are imported from the cytosol into the matrix compartment through a proteinaceous translocation pore. Import is driven by mitochondrial Hsp70 (mHsp70), a matrix-localized ATPase. There are currently two postulated mechanisms for this function of mHsp70: 1) The "Brownian ratchet" model proposes that the precursor chain diffuses within the pore, and that binding of mHsp70 to the lumenal portion of the chain biases this diffusion. 2) The "power stroke" model proposes that mHsp70 undergoes a conformational change that actively pulls the precursor chain through the pore. Here we formulate these two models quantitatively, and compare their performance in light of recent experimental evidence that precursor chains interact strongly with the walls of the translocation pore. Under these conditions the simulated Brownian ratchet is inefficient, whereas the power stroke mechanism seems to be a plausible description of the import process.

Adenosine Triphosphatases↗
PubMed2004

On the mechanism of stomatocyte-echinocyte transformations of red blood cells: experiment and theoretical model.

This study represents an attempt to achieve a better understanding of the stomatocyte-echinocyte transition in the shape of red blood cells. We determined experimentally the index of cell shape at various ionic strengths and osmolarities for native and trypsin-treated human erythrocytes. For every given composition of the outer phase, we calculated the ionic strength in the cells and the transmembrane electric potential using a known theoretical model. Next, we described theoretically the electric double layers formed on both sides of the cell membrane, and derived expressions for the tensions of the two membrane leaflets. Taking into account that the cell-shape index depends on the tension difference between the two leaflets, we fitted the experimental data with the constructed physicochemical model. The model, which agrees well with the experiment, indicates that the tension difference between the two leaflets is governed by the different adsorptions of counterions at the two membrane surfaces, rather than by the direct contribution of the electric double layers to the membrane tension. Thus, with the rise of the ionic strength, the counterion adsorption increases stronger at the outer leaflet, whose stretching surface pressure becomes greater, and whose area expands relative to that of the inner leaflet. Hence, there is no contradiction between the bilayer-couple hypothesis and the electric double layer theory, if the latter is upgraded to account for the effect of counterion-adsorption on the membrane tension. The developed quantitative model can be applied to predict the shape index of cells upon a stomatocyte-discocyte-echinocyte transformation at varying composition of the outer medium.

Adsorption↗
PubMed2003

Stochastic model of T cell proliferation: a calculus revealing IL-2 regulation of precursor frequencies, cell cycle time, and survival.

The outcome of Ag exposure is dictated by complex regulation of T cell proliferation. The rates of proliferation and survival are altered by numerous signals that the cell receives and integrates to achieve a net response. We have illustrated previously how small changes in kinetic parameters can lead to large differences, even under conditions of saturating IL-2. In this study, we examine the effect of varying IL-2 concentration on T cell response and develop a model incorporating additional parameters of proliferation and survival. Strikingly, the proportion of cells that enter the first division, but not the time at which they enter, is dramatically altered by IL-2. Furthermore, the survival and average division time of cells in later divisions are also altered by IL-2 concentration. Together, the small simultaneous effects on these parameters result in large differences in total cell number. These results reveal how in vitro systems may exaggerate the contribution of IL-2, and thus how costimuli or additional helper cells that alter IL-2 concentration, even by relatively small amounts, will generate large in vitro differences in cell number and therefore appear obligatory. Furthermore, they illustrate how a quantitative model of T cell activation can clarify how complex signal integration is handled by T cells in situ, and therefore more appropriately aid development of a theory of behavior.

Animals↗
PubMed2004

TOMOCOMD-CARDD, a novel approach for computer-aided 'rational' drug design: I. Theoretical and experimental assessment of a promising method for computational screening and in silico design of new anthelmintic compounds.

In this work, the TOMOCOMD-CARDD approach has been applied to estimate the anthelmintic activity. Total and local (both atom and atom-type) quadratic indices and linear discriminant analysis were used to obtain a quantitative model that discriminates between anthelmintic and non-anthelmintic drug-like compounds. The obtained model correctly classified 90.37% of compounds in the training set. External validation processes to assess the robustness and predictive power of the obtained model were carried out. The QSAR model correctly classified 88.18% of compounds in this external prediction set. A second model was performed to outline some conclusions about the possible modes of action of anthelmintic drugs. This model permits the correct classification of 94.52% of compounds in the training set, and 80.00% of good global classification in the external prediction set. After that, the developed model was used in virtual in silico screening and several compounds from the Merck Index, Negwer's handbook and Goodman and Gilman were identified by models as anthelmintic. Finally, the experimental assay of one organic chemical (G-1) by an in vivo test coincides fairly well (100%) with model predictions. These results suggest that the proposed method will be a good tool for studying the biological properties of drug candidates during the early state of the drug-development process.

Animals↗
PubMed2000

Development of stereotactically guided laser interstitial thermotherapy of breast cancer: in situ measurement and analysis of the temperature field in ex vivo and in vivo adipose tissue.

BACKGROUND AND OBJECTIVE: The size (0.5-1.0 cm) of early nonpalpable breast tumors currently detected by mammography and confirmed by stereotactic core biopsy is of the order of the penetration depth of near infrared photons in breast tissue. In principle, stereotactically biopsied tumors, therefore, could be safely and efficiently treated with laser thermotherapy. The aim of the current study is to confirm the controlled heating produced by clinically relevant power levels delivered with an interstitial laser fiber optic probe adapted for use with stereotactic mammography and biopsy procedures. STUDY DESIGN/MATERIALS AND METHODS: Temperature increases and the resultant thermal field produced by the irradiation of ex vivo (porcine and human) and in vivo (porcine) tissue models appropriate to the treatment of human breast tissue by using cw Nd:YAG laser radiation delivered with a interstitial fiber optic probe with a quartz diffusing tip, were recorded with an array of fifteen 23-gauge needle thermocouple probes connected to a laboratory computer-based data acquisition system. RESULTS: By using a stepwise decreasing power cycle to avoid tissue charring, acceptably symmetric thermal fields of repeatable volumetric dimensions were obtained. Reproducible thermal gradients and predictable tissue necrosis without carbonization could be induced in a 3-cm-diameter region around the fiber probe during a single treatment lasting only 3 minutes. The time-dependences of the temperature rise of the thermocouples surrounding the LITT probe were quantitatively modeled with simple linear functions during the applied laser heating cycles. CONCLUSION: Analysis of our experimental results show that reproducible, symmetric and predictable volumetric temperature increases in time can be reliably produced by interstitial laser thermotherapy.

Adipose Tissue↗
PubMedDate not supplied

Optimization of an assay for baculovirus titer and design of regimens for the synchronous infection of insect cells.

We have previously described a quantitative model of the trafficking of baculovirus in insect cells that considers the various infection steps such as attachment, internalization, endosomal fusion, and nuclear accumulation. Concepts from the model were used to design synchronous infection regimens for various cell lines, to analyze the inherent inefficiency of existing assays for virus titer, and to develop a modified end-point dilution assay optimized to measure more completely the concentration of intrinsically infectious particles in a virus inoculum. The titer obtained from existing assays incompletely counts infectious virus particles due primarily to the incomplete adsorption of the virus during the short, standard 1-h incubation period. For representative assays, the calculated bound virus is generally about 10% of the added virus, but could be as low as 1.4%, underestimating actual titers by 3-70-fold. A modified end-point dilution assay involving centrifugation has been developed from both quantitative and qualitative analyses. The ratio of particle to plaque-forming unit with the optimized assay was 4-6 compared to 100-300 for typical assays, representing a significant improvement in the measurement of total infectious virus concentration.

Adsorption↗
PubMed2000

The resonant dynamics of speech perception: interword integration and duration-dependent backward effects.

How do listeners integrate temporally distributed phonemic information into coherent representations of syllables and words? For example, increasing the silence interval between the words "gray chip" may result in the percept "great chip," whereas increasing the duration of fricative noise in "chip" may alter the percept to "great ship" (B. H. Repp, A. M. Liberman, T. Eccardt, & D. Pesetsky, 1978). The ARTWORD neural model quantitatively simulates such context-sensitive speech data. In ARTWORD, sequentially stored phonemic items in working memory provide bottom-up input to unitized list chunks that group together sequences of items of variable length. The list chunks compete with each other. The winning groupings feed back to establish a resonance which temporarily boosts the activation levels of selected items and chunks, thereby creating an emergent conscious percept whose properties match such data.

Cues↗
PubMed2005

A new approach to spatial covariance modeling of functional brain imaging data: ordinal trend analysis.

In neuroimaging studies of human cognitive abilities, brain activation patterns that include regions that are strongly interactive in response to experimental task demands are of particular interest. Among the existing network analyses, partial least squares (PLS; McIntosh, 1999; McIntosh, Bookstein, Haxby, & Grady, 1996) has been highly successful, particularly in identifying group differences in regional functional connectivity, including differences as diverse as those associated with states of awareness and normal aging. However, we address the need for a within-group model that identifies patterns of regional functional connectivity that exhibit sustained activity across graduated changes in task parameters. For example, predictions of sustained connectivity are commonplace in studies of cognition that involve a series of tasks over which task difficulty increases (Baddeley, 2003). We designed ordinal trend analysis (OrT) to identify activation patterns that increase monotonically in their expression as the experimental task parameter increases, while the correlative relationships between brain regions remain constant. Of specific interest are patterns that express positive ordinal trends on a subject-by-subject basis. A unique feature of OrT is that it recovers information about functional connectivity based solely on experimental design variables. In particular, there is no requirement by OrT to provide either a quantitative model of the uncertain relationship between functional brain circuitry and subject variables (e.g., task performance and IQ) or partial information about the regions that are functionally connected. In this letter, we provide a step-by-step recipe of the computations performed in the new OrT analysis, including a description of the inferential statistical methods applied. Second, we describe applications of OrT to an event-related fMRI study of verbal working memory and H(2)15O-PET study of visuo-motor learning. In sum, OrT has potential applications to not only studies of young adults and their cognitive abilities, but also studies of normal aging and neurological and psychiatric disease.

Adult↗
PubMed2004

Modelling how ribavirin improves interferon response rates in hepatitis C virus infection.

Nearly 200 million individuals worldwide are currently infected with hepatitis C virus (HCV). Combination therapy with pegylated interferon and ribavirin, the latest treatment for HCV infection, elicits long-term responses in only about 50% of patients treated. No effective alternative treatments exist for non-responders. Consequently, significant efforts are continuing to maximize response to combination therapy. However, rational therapy optimization is precluded by the poor understanding of the mechanism(s) of ribavirin action against HCV. Ribavirin alone induces either a transient early decline or no decrease in HCV viral load, but in combination with interferon it significantly improves long-term response rates. Here we present a model of HCV dynamics in which, on the basis of growing evidence, we assume that ribavirin decreases HCV infectivity in an infected individual in a dose-dependent manner. The model quantitatively predicts long-term response rates to interferon monotherapy and combination therapy, fits observed patterns of HCV RNA decline in patients undergoing therapy, reconciles conflicting observations of the influence of ribavirin on HCV RNA decline, provides key insights into the mechanism of ribavirin action against HCV, and establishes a framework for rational therapy optimization.

Dose-Response Relationship, Drug↗