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Computationally efficient algorithms for convection-permeation-diffusion models for blood-tissue exchange.

Analysis of data on tissue depositions obtained by positron tomographic or NMR imaging, or of multiple tracer outflow dilution curves, requires fitting data with models composed of aggregates of capillary-tissue units. These units account for heterogeneities of flows and multisolute exchanges between longitudinally distributed regions across capillary and cell barriers within an organ. Because the analytic solutions to the partial differential equations require convolution integration, solutions are obtained relatively efficiently by a fast numerical method. Our approach centers on the use of a sliding fluid element algorithm for capillary convection, with the time step set equal to the length step divided by the fluid velocity. Radial fluxes by permeation between plasma, interstitial fluid, and cells and axial diffusion exchanges within each time step are calculated analytically. The method enforces mass conservation unless there is regional consumption. Solution for a 2-barrier, 3-region model, accurate to within 0.5%, are 100 to 1000 times faster than the corresponding, purely analytic solution, and over 10,000 times for a 4-region model. Applications include multiple indicator dilution studies of kinetics of transcapillary exchange and positron emission tomographic studies of the mechanisms of substrate transport into cells of organs in vivo.

Algorithms

Mechanisms for intracellular distribution of mRNA: in situ hybridization studies in muscle.

The intracellular distribution of mRNA in striated muscle fibers is highly ordered, as is the structural organization of the fibers' contractile apparatus. Results from in situ hybridization of muscle mRNA are reviewed in an attempt to discern the mechanisms involved in mRNA distribution and to determine its relationship to developmental, growth, and repair processes in muscle. Nonradioactively labeled complementary RNA probes allow anatomic localization of mRNA at the light and electron microscopic level. Myosin mRNA in striated muscle is concentrated around transcriptionally active nuclei, myosin mRNA is excluded by the myofibrillar mass, myosin mRNA distribution correlates with that of cytoskeletal elements, and myosin mRNA is concentrated in regions of rapid growth and repair. The even distribution of myosin mRNA along the length of myofibrils gives no indication of specific association with either the thick or thin filaments. Of the possible mechanisms directing mRNA distribution, results from in situ hybridization and other analyses support a restricted diffusion model. Diffusion of mRNA (and polysomes) is severely limited by the myofibrillar lattice. It is possible that myosin mRNA is also associated with a cytoskeletal element, which may direct the mRNA to specific intracellular locations and affect translational activity.

Animals

Multilayer model of photon diffusion in skin.

A diffusion model describing the propagation of photon flux in the epidermal, dermal, and subcutaneous tissue layers of the skin is presented. Assuming that the skin is illuminated by a collimated, finite-aperture source, we develop expressions relating photon flux density within the skin and intensities re-emitted from the skin surface to the optical properties of the individual layers. Model simulations show that the rate at which re-emitted intensities diminish with radial distance away from the source can provide information about absorption and scattering in underlying tissues. Re-emitted intensities measured from homogeneous and two-layer tissue phantoms compare favorably with model predictions. We demonstrate potential applications of the model by estimating the absorption (sigma a) and transport-corrected scattering (sigma's) coefficients of dermis and subcutis from intensities measured from intact skin and by predicting the magnitude of the optical-density variations measured by a photoplethysmograph.

Diffusion

Analysis of drug penetration through the skin by the two-layer skin model.

A diffusion model for the skin penetration of drug in the finite-dose system was developed considering the skin to be composed of two layers, the outermost layer (stratum corneum) and the lower layer (viable epidermis and dermis). Based on this skin model, the Laplace transforms of the equations for the drug amounts in the receptor, the vehicle, and the skin were derived. The penetration profiles of 6-mercaptopurine (6-MP) through the intact and stripped guinea pig skin were obtained from in vitro diffusion experiments. The computer fitting of those profiles to the Laplace-transformed equations by a nonlinear least-squares program based on a fast inverse Laplace transform algorithm [MULTI-(FILT)] gave parameters such as diffusion coefficients of 6-MP and thicknesses of both layers. The mean transit time (MTT) for each diffusion process was defined based on statistical moment concept and calculated using the obtained parameters. Under the present condition, the process to move from the vehicle to the stratum corneum is demonstrated to have the longest mean time in overall processes of 6-MP penetration.

Animals

Diffusion approximations of the two-locus Wright-Fisher model.

Diffusion approximations are established for the multiallelic, two-locus Wright-Fisher model for mutation, selection, and random genetic drift in a finite, panmictic, monoecious, diploid population. All four combinations of weak or strong selection and tight or loose linkage are treated, though the proof in the case of strong selection and loose linkage is incomplete. Under certain conditions, explicit formulas are obtained for the stationary distributions of the two diffusions with loose linkage.

Genetic Linkage

A diffusion theory model of spatially resolved, steady-state diffuse reflectance for the noninvasive determination of tissue optical properties in vivo.

A model based upon steady-state diffusion theory which describes the radial dependence of diffuse reflectance of light from tissues is developed. This model incorporates a photon dipole source in order to satisfy the tissue boundary conditions and is suitable for either refractive index matched or mismatched surfaces. The predictions of the model were compared with Monte Carlo simulations as well as experimental measurements made with tissue simulating phantoms. The model describes the reflectance data accurately to radial distances as small as 0.5 mm when compared to Monte Carlo simulations and agrees with experimental measurements to distances as small as 1 mm. A nonlinear least-squares fitting procedure has been used to determine the tissue optical properties from the radial reflectance data in both phantoms and tissues in vivo. The optical properties derived for the phantoms are within 5%-10% of those determined by other established techniques. The in vivo values are also consistent with those reported by other investigators.

Diffusion

Role of geometry and anisotropic diffusion for modelling PO2 profiles in working red muscle.

A 3-dimensional analytical model of O2 diffusion in heavily working muscle is proposed which considers anisotropic, myoglobin (Mb)-facilitated O2 diffusion inside the muscle fiber and a carrier-free layer separating erythrocytes and fiber. The model is used to study the effects of some commonly applied simplifying assumptions (reduced dimensionality, neglected anisotropy) on the resulting PO2 distributions: (1) In order not to underestimate PO2 drops near erythrocytes, modelling O2 transport in 3 dimensions is important. (2) For a capillary-to-fiber ratio of 1, the results from the 2-dimensional version of the present model and from a Krogh-type model which incorporates a carrier-free layer agree well. (3) This is not true if the capillary-to-fiber ratio is 2. (4) In neither case, a Hill-type model furnishes a good description of the PO2 distributions. (5) Anisotropic diffusion may become important under critical O2 supply conditions. For a capillary-to-fiber ratio of 1, a Krogh-type model in which the O2 fluxes within the carrier-free layer are adapted according to Hellums (Microvasc. Res. 13: 131, 1977) yields almost identical PO2 distributions as the present 3-dimensional model.

Animals

A new model of diffuse interstitial pulmonary fibrosis in the rat.

We have produced experimental diffuse interstitial pulmonary fibrosis in rats with a combination of low and repeated doses of paraquat plus continuous exposure to normobaric 74% O2 in the breathing air for several weeks. Pulmonary fibrosis was evaluated histologically and biochemically, through the determination of total collagen content in the lung. Our procedure is characterized by low initial mortality, the development of extensive distortion of the pulmonary architecture, and the presence of severe and diffuse interstitial fibrosis. The model was compared with bleomycin-induced pulmonary fibrosis in the same rat strain, in which the process is focal and leaves most of the lung unaffected. We conclude that lung damage produced by the combination of low doses of paraquat plus normobaric 74% O2 concentration in the breathing air is an adequate experimental model of diffuse interstitial pulmonary fibrosis as it occurs in many of the human cases of this condition.

Animals

Non-reciprocal coevolution in a fungus-gardening ant.

Symbioses are often characterized by nonrandom associations between hosts and symbionts. Hosts may obtain symbionts horizontally from the environment or vertically from a parent or sometimes use both methods. Macroevolutionary examinations of fungus-gardening ants and their fungi have shown either a 1:1 coevolution model or a 'diffuse' model between ant host and fungal symbionts. However, some of these conclusions may have been based on using relatively conservative molecular markers, which could obscure cryptic variation. The use of whole genome approaches potentially offer more power in elucidating coevolutionary history. In this study, we examined patterns of coevolution in a single species (Trachymyrmex septentrionalis) using genomic and experimental approaches. We tested whether ant-fungal specificity patterns reflected either 1:1 or diffuse models of coevolution. While we report significant co-phylogenetic signal among intraspecific ant host and fungal symbiont lineages, we found evidence of 1:1 coevolution in some lineages and diffuse in others. These conclusions were supported by the results of experiments where newly mated T. septentrionalis queens were forced to grow novel fungi that suggested that not all fungi are equivalent symbionts and would require specialized hosts. Thus, within a single ant species, there is a mixed support for both models.

Animals

[A diffusion kinetics model of the growth of a cancerous tumor].

Diffusion kinetics model of development of solid tumor has been proposed. This model allows qualitative description of a number of experimental effects, e.g. formation of necrosis zones, change of exponential growth to linear one. Critical parameters for transfer from tumor stabilization mode to its growth have been obtained. Methods of calculation have been elaborated and model calculations have been carried out.

Animals

Mathematical models of the spatial distribution of retinal oxygen tension and consumption, including changes upon illumination.

To better understand oxygen utilization by the retina, a mathematical model of oxygen diffusion and consumption in the cat outer, avascular retina was developed by analyzing previously recorded profiles of oxygen tension (PO2) as a function of retinal depth. Simple diffusion modelling of the oxygen distribution through the outer retina is possible because the PO2 depends only on diffusion from the choroidal and retinal circulations and on consumption within the tissue. Several different models were evaluated in order to determine the best one from the standpoints of their ability to represent the data and to agree with physiological reality. For the steady state one-dimensional diffusion model adopted (the special three-layer diffusion model), oxygen consumption was constant through the middle layer and zero in the layers near the choroid and near the inner retina. On the average, the oxygen consuming layer, as found by nonlinear regression for each profile, extended from about 75% to 85% of the retinal depth from the vitreous. This is a narrow band through the mid-region of the photoreceptors. Oxygen consumption of the entire avascular retina, determined from fitting eight PO2 profiles measured in light-adapted retinas, averaged 2.7 ml O2(STP)/(100 g tissue.min), while the value determined from fitting thirty-two PO2 profiles measured in dark-adapted retinas averaged 4.4 ml O2(STP)/(100 g tissue.min). Consumption in the light was thus only 60% of that in the dark. This suggests that the outer retina is at greater risk of hypoxic injury in the dark than in the light, a finding of considerable clinical significance.

Animals

Quantitative aspects of a unified model of diffusion mediated receptor--cyclase coupling.

A quantitative model is presented of diffusion mediated coupling of adenylate cyclase to multivalent plasma membrane receptors which accounts for a wide range of phenomena including non linear occupation-activation plots with either positive or negative second derivatives, spare receptors, silent receptors, and negative and positive binding cooperativity. A non linear least square fit of the predicted equation for cyclase activation to available data predicts translational diffusion coefficients in the range of (10(-10) - 10(-11))cm2/s.

Adenylyl Cyclases

The role of diffusion in the photoresponse of an extraretinal photoreceptor of Aplysia.

1. Membrane currents produced by flashes and steps of light (photo-current) were recorded from the ventral photoresponsive neurone of Aplysia californica. The effects of background illumination and changes in temperature were also examined. 2. The falling phase of the response wave form may be separated into two components with time constants of 10--12 sec and 50 sec. 3. Background illumination reduced the response amplitude to light impulses without appreciably altering the response wave form. 4. Lowering the temperature greatly reduced the amplitude of the photo-current with a Q10 of 2.91 (25--15 degrees C) and greatly prolonged the duration of the response. 5. Because of the relatively large distance between the plasma membrane and the pigmented cytoplasmic lipochondria where light is absorbed, a diffusion-based model with Ca as the internal-transmitter (Andresen & Brown, 1979) was developed. 6. In this model diffusion of Ca2+ released from the lipochondria upon photon absorption is slowed by the reversible uptake of Ca2+ at cytoplasmic binding sites. Ca2+ interacts with sites at the plasma membrane to increase GK and Ca2+ levels are subsequently restored by irreversible uptake processes. Ca2+ release and its adsorption and desorption from the more numerous plasma membrane binding sites were assumed to be instantaneous with respect to the duration of the light-evoked response. 7. The linearized model equations adequately predict the experimental response wave forms, the effects of temperature, and saturation of the steady-state amplitude--stimulus relationship. Aside from amplitude scaling, no curve-fitting was used. 8. The model also gives realistic values for the cytoplasmic diffusion coefficient of Ca and the net rate of Ca efflux required to restore dark Ca activity.

Animals