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PubMed2006

Photophysics of ANS. I. Protein-ANS complexes: Intestinal fatty acid binding protein and single-trp mutants.

We continue investigations into the physical chemistry of intestinal fatty acid binding protein, I-FABP, and its interaction with ANS and other ligands [cf references [Kirk, W., E. Kurian, and F. Prendergast. 1996. Characterization of the sources of protein-ligand affinity: 1-sulfonato-8-anilinonaphthalene binding to intestinal fatty acid binding protein. Biophys. J. 70: 69-83., Kurian, E., W. Kirk, and F. Prendergast. 1996. Affinity of fatty acid for rRat intestinal fatty acid binding protein: Further examination. Biochemistry. 35:3865-74]. The photophysics of the wt protein is compared with that in two mutants which lack respectively one or the other of two trp moieties, one of which, trp 82, is located near the binding region for the polar head group of ligands. These studies afford a look into how the fluorescence of the wt protein is established, that is, as an almost direct sum of the fluorescence of the two individual trp residues, and how this fluorescence is quenched upon binding to ANS. Though we have access to all the relevant spectroscopic and geometric information necessary to specify in detail the Foerster-Dexter energy transfer model, the quenching process is not explicable in terms of very-weak coupling, as is usually assumed in fluorescence studies in protein systems, but in terms of a stronger effect which goes beyond the simple very-weak dipole:dipole formalism. The quenching of trp emission by bound ANS is not as great as that anticipated by ordinary resonance energy transfer, neither is the quenching observed in the reduced lifetimes of the trp emission upon ANS binding as great as that observed in steady-state intensity. However the observed steady-state quenching is explicable in terms derived from the lifetime measurements, together with observed spectral band shifts, by the exciton coupling model we invoke here.

Amino Acid Sequence↗

PubMed2005

Modeling the flow of fluid/particle mixtures in microchannels: encapsulating nanoparticles within monodisperse droplets.

We develop a hybrid computational approach for simulating mixtures of binary fluids and mobile, submicron particles. The model couples a lattice Boltzmann method for the binary fluid with a Brownian dynamics model for the particles. The particles can exhibit preferential wetting interactions with the different components of the fluid. As an illustration of the method, we carry out simulations in two dimensions to compare the spinodal decomposition of a pure binary fluid with the phase separation of binary blends that contain either fixed or mobile particles. We then isolate conditions where the flow of a binary fluid/particle mixture past surfaces with well-defined asperities leads to the formation of monodisperse droplets, which encapsulate the nanoparticles. The findings provide guidelines for creating multiphase emulsions with well-controlled morphologies.

Journal Article↗

PubMed1998

A biomathematical model of time-delayed feedback in the human male hypothalamic-pituitary-Leydig cell axis.

We develop, implement, and test a feedback and feedforward biomathematical construct of the male hypothalamic [gonadotropin-releasing hormone (GnRH)]-pituitary [luteinizing hormone (LH)]-gonadal [testosterone (Te)] axis. This stochastic differential equation formulation consists of a nonstationary stochastic point process responsible for generating episodic release of GnRH, which is modulated negatively by short-loop (GnRH) and long-loop (Te) feedback. Pulsatile GnRH release in turn drives bursts of LH secretion via an agonistic dose-response curve that is partially damped by Te negative feedback. Circulating LH stimulates (feedforward) Te synthesis and release by a second dose response. Te acts via negative dose-responsive feedback on GnRH and LH output, thus fulfilling conditions of a closed-loop control system. Four computer simulations document expected feedback performance, as published earlier for the human male GnRH-LH-Te axis. Six other simulations test distinct within-model coupling mechanisms to link a circadian modulatory input to a pulsatile control node so as to explicate the known 24-h variations in Te and, to a lesser extent, LH. We conclude that relevant dynamic function, internodal dose-dependent regulatory connections, and within-system time-delayed coupling together provide a biomathematical basis for a nonlinear feedback-feedforward control model with combined pulsatile and circadian features that closely emulate the measurable output activities of the male hypothalamic-pituitary-Leydig cell axis.

Circadian Rhythm↗

PubMed1997

An elbow joint movement control model with visual feedback.

A motor program generator control model is proposed to simulate neuromuscular control. Three muscles (Biceps, Triceps, Brachialis) driving elbow joint flexion in a plane are simulated by integrating their nonlinear dynamic property and spinal neural circuitry. The motor descending commands are described by a visual feedback signal from the joint and an excitation signal for the motor neuron pool. The visual feedback signal mimics the gamma command whereas the excitation signal mimics another descending co-activation command. The gamma command is expressed as the output of a PID controller with the visual feedback error signal as the input. The gamma command and the motoneuron pool background activity are the inputs to the motoneuron pool model coupled with the Renshaw cell recurrent inhibitions. The output of the motoneuron pool model mimics the alpha command feeding directly to the muscle dynamics. A movement is produced by reducing the error signal between goal position and actual position and altering excitation signal properly. The simulation results show that a burst pattern of excitation signal and a PID controller can accurately trace the terminal goal and generate a smooth movement with a bell shaped velocity profile. The muscle activation signals have the characteristic similar to the smoothed EMG. Changing different parameters of the PID can cause the same effects as the stimulus pulse intensity or duration modulation.

Elbow Joint↗

PubMed1993

Variable cross-bridge cycling-ATP coupling accounts for cardiac mechanoenergetics.

Cardiac twitch contractions were simulated by Huxley's sliding filament cross-bridge muscle model coupled with parallel and series elastic components. The energetics of the contraction were based on the ATP hydrolysis for the cross-bridge cycling. Force-length area (FLA), as a measure of the total mechanical energy, was computed for both isometric and isotonic contractions in a manner similar to the pressure-volume area (PVA) (Suga, H. Physiol. Rev. 70: 247-277, 1990). PVA correlates linearly with cardiac oxygen consumption, and since FLA is analogous to PVA, FLA should correlate with the ATP expended. Simulations comparing FLA with the cross-bridge cycling ATP usage showed that at lower muscle fiber activation levels (shorter initial fiber lengths and lower preload levels) FLA decreased more rapidly than the number of muscle fiber cross-bridge cycles in both isometric and isotonic contraction cases. This suggests that one ATP can cause more than one cross-bridge cycle at lower activation levels as was proposed by Yanagida, Arata, and Oosawa (Nature 316: 366-369, 1985). If the number of cross-bridge cycles to ATP ratio is allowed to increase at lower activation levels as suggested by Yanagida et al., Huxley's model is compatible with the experimental findings on FLA and PVA.

Adenosine Triphosphate↗

PubMed1999

The effect of slow allosteric transitions in a coupled biochemical oscillator model.

The effect of slowed allosteric transitions in a coupled biochemical oscillator model showing complex dynamic behavior is investigated. When the allosteric transitions are sufficiently fast one can obtain a low-dimensional asymptotic approximation for the dynamics of the species that evolve on a slow time-scale. Such low-dimensional models are common in studies of biological control systems and little attention has, so far, been given to the dynamic effect of the large number of species usually eliminated from more biochemically detailed models. Here we investigate the dynamic effect of explicit inclusion of allosteric transitions having finite time-scales of equilibration. It is found that slowed allosteric transitions suppress complex dynamic modes such a bursting, quasi-periodicity and chaos. The effect arises as the enzyme of consideration becomes trapped in an active state where it is unable to respond to changes in effector concentration on the time-scale necessary to support the modes of complex dynamics. Slow allosteric transitions may be favourable in biological systems in which complex oscillations are not desirable but which, at the same time, may benefit from the presence of positive feedbacks. Our findings suggest that slow allosteric transitions and finite internal rates in general may contribute significantly to the dynamics of biological control mechanisms.

Allosteric Regulation↗

PubMed1983

Thermodynamic studies of the protein-protein interactions between cytochrome P-450 and cytochrome b5. Evidence for a central role of the cytochrome P-450 spin state in the coupling of substrate and cytochrome b5 binding to the terminal hemoprotein.

The interactions between purified rat hepatic microsomal cytochrome P-450 and the type I ligands benzphetamine and cytochrome b5 have been studied in the presence of phospholipid using difference spectrophotometry. Cytochrome b5 was shown to interact with cytochrome P-450 to form a tight 1:1 complex (Kd = 275 nM), in which the proportion of high spin cytochrome P-450 was increased from 7 to 30%. The presence of saturating cytochrome b5 was shown to cause a decrease in the apparent Kd for benzphetamine binding from 111 microM to 40 microM. Likewise, the presence of benzphetamine was shown to cause a decrease in the apparent dissociation constant for cytochrome b5 binding to cytochrome P-450 (Kd = 90 nM). The above interactions were resolved into the basic equilibria inter-relating the various ligation states of the hemoprotein in an energetically closed eight-state free energy coupling model and the relative magnitudes of the microequilibria were analyzed to determine the degree of coupling of the interactions between cytochrome P-450 and both benzphetamine and cytochrome b5. Consequently, the spin state changes in cytochrome P-450 induced by benzphetamine and cytochrome b5 binding were shown to arise because these ligands interact 7 and 4 times more tightly with high spin cytochrome P-450, respectively. Furthermore, the data revealed that these ligands interact at independent sites on cytochrome P-450. Thus the effects of cytochrome b5 upon benzphetamine binding and vice versa were rationalized simply in terms of an increase in the proportion of a high spin (high affinity) conformation of cytochrome P-450 brought about by pre-equilibration with the effector ligand, with the intrinsic binding affinities of the two ligands for the low or high spin states remaining relatively unaltered. The thermodynamic parameters associated with the interactions between cytochrome P-450 and cytochrome b5, determined from the temperature dependence of these interactions, revealed that these protein interactions are entropy driven and probably occur by a hydrophobic mechanism.

Animals↗

PubMed2005

Kinetic mechanism for predicting secondary organic aerosol formation from the reaction of d-limonene with ozone.

A semi-explicit mechanism of d-limonene was developed and tested against experimental results obtained from large outdoor Teflon film chambers at the University of North Carolina (UNC) smog chamber facility. The model couples gas-phase reactions with partitioning processes and possible particle-phase reactions. The model not only tracks the gas-phase ozonolysis reaction of d-limonene, but also provides a reasonable prediction of the secondary aerosol mass production under different conditions. Limononaldehyde was the major identified product, followed by limona-ketone, referred to here as keto-limonene, keto-limononaldehyde, limononic acid, and keto-limononic acid. Identified particle-phase products accounted for about 60% of the observed particle mass in the initial stages of the reaction. Model sensitivity was tested and discussed with respect to effects of temperature, humidity, water uptake, and reactant concentrations.

Aerosols↗

PubMed2006

[Effect of latrunculin B, jasplakinolide and brefeldin A on the store-dependent Ca2+ entry in macrophages].

Using Fura-2AM microfluorimetry, effect of actin filament modifiers and vesicular trafficking inhibitor on the store-dependent Ca2+ entry induced by purinergic agonists (ATP, UTP) and endoplasmic Ca2+-ATPase inhibitors (thapsigargin, cyclopiazonic acid) in rat peritoneal macrophages was investigated. It was shown that inhibition of actin polymerization by latrunculin B had a biphasic time-dependent effect on Ca2+ entry, showing an initial potentiation followed by inhibition of Ca2+ entry. Moreover, addition of latrunculin B after induction of store-dependent Ca2+ entry inhibited the Ca2+ influx. Jasplakinolide, which reorganizes actin filaments into a tight cortical layer adjacent to the plasma membrane, prevented activation of store-dependent Ca2+ entry but did not modify this process after its activation. Vesicular transport inhibitor brefeldin A, which inactivates arfproteins, inhibited activation of store-dependent Ca2+ entry but did not alter this mechanism once being initiated. These data are compatible with the sectretion-like coupling model for store-dependent Ca2+ entry in macrophages based on a reversible trafficking and coupling of Ca2+ store with the plasma membrane.

Animals↗

PubMed1997

Simple apparatus for serial blood sampling in rodents permitting simultaneous measurement of locomotor activity as illustrated with cocaine.

A simple device has been developed for serial venous blood sampling which permits the simultaneous measurement of locomotor activity in the freely moving rat. The device can be easily constructed from routine laboratory material and it does not interfere with the light beams used to measure locomotor activity. The device, in conjunction with an activity cage, has been applied to the combined pharmacokinetic and pharmacodynamic modeling of cocaine. The relationship between the locomotor activity following a single short iv infusion of cocaine (5 mg/kg) and cocaine plasma concentrations can be adequately described by the Sigmoid-E(max) model. Further, the relationship between activity and time can be described by the same model coupled with an effect compartment. These results suggest the applicability of the device in facilitating pharmacokinetic/pharmacodynamic modeling of drugs that affect locomotor activity.

Animals↗

PubMed2005

Using a surface complexation model to predict the nature and stability of nanoparticles.

Nanoparticles are discrete nanometer-scale assemblies of atoms and have dimensions between those characteristic of ions and those of macroscopic materials. These minerals commonly possess extremely large specific surface areas and surface adsorption capacities for foreign ions. Due to the large specific surface area and large fraction of surface atoms, the natures of nanoparticles are expected to be modified by the adsorption (surface complexation) process. In this paper,we discuss theoretically the stability of nanoparticles that make the surface complex with foreign ions. The principal theoretical assumption is that the surface complexation occurs at the bulk of the nanoparticles, as in a solid solution. The surface complexation affects two aspects of the intrinsic stability of the nanoparticles simultaneously: one is the composition of the nanoparticles; the other is the free energy of formation of nanoparticles. The solubility of hydrous ferric oxide (HFO) was estimated by using surface complexation modeling coupled with published data of the free energy of formation of the relevant components. The solubility modeling of surface-charged (H+ or OH- sorbed) HFO mechanistically and quantitatively explained the observed nonintegral behavior of the solubility of HFO. Moreover, solubility modeling of anion (SO4(2-), PO4(3-), and As(V)) sorption by HFO showed that the sorption process strongly influences the stability of the nanoparticles. This result implies that geochemical modeling leads to the erroneous prediction of a natural system if the effect of the sorption process is not taken into account.

Adsorption↗

PubMed1999

Air pollution exposure monitoring and estimation. Part VI. Ambient exposure of adults in an industrialised region.

This paper presents methodology and results of a dynamic individual air pollution exposure model (DINEX) that calculates the hourly exposure for each adult in a panel study. Each of over 260 participants, through the use of a diary, provided information used in the model to calculate his/her personal, individualised exposure. The participants filled out the diary daily, hour by hour, over two, two month periods. The exposure assessment model coupled the diary information and results of an indoor/outdoor measurement program, with the results of dispersion modelling on an hourly basis for an industrial area in Norway. The estimated air pollution concentrations from the dispersion model, based on continuous meteorological measurements, were calibrated with air pollutant concentrations measured continuously.

Adult↗

PubMed1994

Noise and signal decoupling in maximum-likelihood reconstructions and Metz filters for PET brain images.

Images reconstructed with the maximum-likelihood-by-expectation-maximization (ML) algorithm have lower noise in some regions, particularly low count areas, compared with images reconstructed with filtered backprojection (FBP). The use of statistically correct noise model coupled with the positivity constraint in the ML algorithm provides this noise improvement, but whether this model confers a general advantage for ML over FBP with no noise model and any reconstruction filter, is unclear. We have studied the quantitative impact of the correct noise model in the ML algorithm applied to simulated and real PET fluoro-deoxyglucose (FDG) brain images, given a simplified but accurate reconstruction model with spatially invariant resolution. For FBP reconstruction, several Metz filters were chosen and images with different resolution were obtained depending on the order (1-400) of the Metz filters. Comparisons were made based on the mean Fourier spectra of the projection amplitudes, the noise-power spectra, and the mean region-of-interest signal and noise behaviour in the images. For images with resolution recovery beyond the intrinsic detector resolution, the noise increased significantly for FBP compared with ML. This indicates that in the process of signal recovery using ML, the noise is decoupled from the signal. Such noise decoupling is not possible for FBP. However, for image resolution equivalent to or less than the intrinsic detector resolution, FBP with Metz filters of various orders can achieve a performance similar to ML. The significance of the noise decoupling advantage in ML is dependent on the reconstructed image resolution required for specific imaging tasks.

Algorithms↗

PubMed2006

Biomechanical modeling and design optimization of cartilage myringoplasty using finite element analysis.

The purpose of this study was to determine the acoustic transfer characteristics of cartilage for optimal cartilage myringoplasty. In order to do so, we developed a cartilage plate/tympanic membrane-coupled model using finite element analysis. Cartilage specimens of the tragus were obtained from fresh human cadavers, and the parameters of the tragus were determined by curve fitting and cross-calibration. A cartilage plate was used to repair an eardrum perforation, and the new coupled tympanic membrane-cartilage complex was loaded into our 3-dimensional biomechanical model of the middle ear for analysis. Our results show that first the beta-damping value of the cartilage plate depends on frequency. The value of beta damping was close to 3 x 10(-4) s at lower frequencies and 5 x 10(-6) s at higher frequencies. Secondly, reducing cartilage thickness leads to an improvement of its acoustic transfer qualities. From an acoustics point of view, the 0.1- to 0.2-mm cartilage plate seems to be most preferable with regard to tympanic membrane vibration. Furthermore, thicknesses of 0.2 mm at lower frequencies and 0.1 mm at higher frequencies were regarded as good compromises between sufficient mechanical stability and low acoustic transfer loss.

Biomechanical Phenomena↗

PubMed2006

Assessment of QT liabilities in drug development.

Since the publication, in 1997, of the CPMP (Committee for Proprietary Medicinal Products) Points to Consider document on "The assessment of potential for QT prolongation by non-cardiovascular medicinal products," both regulatory bodies and the pharmaceutical industry have paid increasing attention to the conduct of careful preclinical studies on the subject. Regulatory attention has focused on the drafting of Safety Pharmacology guidelines through the ICH (International Conference on Harmonization) process, which resulted in approval by the ICH and acceptance by the three main regions (USA, Europe, and Japan) of the ICH S7A guideline. The guideline does not deal only with cardiovascular studies and does not provide guidance on QT investigations. This part has been deferred to a second guideline (ICH S7B). Nevertheless, pharmaceutical companies have implemented screening strategies aimed at selecting compounds that do not present QT liabilities. These strategies can differ according to the pharmaceutical class, while experimental models differ according to the stage of development of the compound. Several in vitro models are employed in discovery (radioligand binding, high-throughput patch clamp, efflux, and fluorescence assays). These models, coupled with in silico methods, allow companies to screen a high number of compounds. Other in vitro models, applied later in the R&D process (action potential duration, APD, in Purkinje fibers or papillary muscle and the isolated heart) are useful in better describing the activity of compounds on cardiac ion channels. The most robust and accepted in vivo test is represented by telemetry studies in conscious non-rodents.

Animals↗

PubMed2003

Modeling diffusion and adsorption in compacted bentonite: a critical review.

The current way of describing diffusive transport through compacted clays is a simple diffusion model coupled to a linear adsorption coefficient (K(d)). To fit the observed results of cation diffusion, this model is usually extended with an adjustable "surface diffusion" coefficient. Description of the negative adsorption of anions calls for a further adjustment through the use of an "effective porosity". The final model thus includes many fitting parameters. This is inconvenient where predictive modeling is called for (e.g., for waste confinement using compacted clay liners). The diffusion/adsorption models in current use have been derived from the common hydrogeological equation of advection/dispersion/adsorption. However, certain simplifications were also borrowed without questioning their applicability to the case of compacted clays. Among these simplifications, the assumption that the volume of the adsorbed phase is negligible should be discussed. We propose a modified diffusion/adsorption model that accounts for the volume of the adsorbed phase. It suggests that diffusion through highly compacted clay takes place through the interlayers (i.e., in the adsorbed phase). Quantitative prediction of the diffusive flux will necessitate more detailed descriptions of surface reactivity and of the mobility of interlayer species.

Adsorption↗

PubMed2002

[Interfaces in rehabilitation: three models].

Interfaces can cause disruptions in the care provision process. They can, however, also signify a differentiated and specialized division of labour of the care providing system. Three models for the description of interfaces are presented and compared: a linear model oriented towards the continuity of the provision of care for individuals, the Principal Agent (PA) Model from contract theory, and a complex systems model. In all three models coupling and information management are identified as essential interface functions. In regard to optimisation possibilities, the linear model leads to the case-management concept, the PA Model to integrated forms of provision and systems theory to context controlling.

Case Management↗

PubMed2006

Voltage sensor conformations in the open and closed states in ROSETTA structural models of K(+) channels.

Voltage-gated ion channels control generation and propagation of action potentials in excitable cells. Significant progress has been made in understanding structure and function of the voltage-gated ion channels, highlighted by the high-resolution open-state structure of the voltage-gated potassium channel, K(v)1.2. However, because the structure of the closed state is unknown, the gating mechanism remains controversial. We adapted the rosetta membrane method to model the structures of the K(v)1.2 and KvAP channels using homology, de novo, and domain assembly methods and selected the most plausible models using a limited number of experimental constraints. Our model of K(v)1.2 in the open state is very similar in overall topology to the x-ray structure of this channel. Modeling of KvAP in the open state suggests that orientation of the voltage-sensing domain relative to the pore-forming domain is considerably different from the orientation in the K(v)1.2 open state and that the magnitude of the vertical movement of S4 is significantly greater. Structural modeling of closed state of K(v)1.2 suggests gating movement that can be viewed as a sum of two previously suggested mechanisms: translation (2-4 A) plus rotation ( approximately 180 degrees ) of the S4 segment as proposed in the original "sliding helix" or "helical screw" models coupled with a rolling motion of the S1-S3 segments around S4, similar to recent "transporter" models of gating. We propose a unified mechanism of voltage-dependent gating for K(v)1.2 and KvAP in which this major conformational change moves the gating charge across the electric field in an analogous way for both channels.

Cell Membrane↗