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On spreading speeds and traveling waves for growth and migration models in a periodic habitat.

It is shown that the methods previously used by the author [Wei82] and by R. Lui [Lui89] to obtain asymptotic spreading results and sometimes the existence of traveling waves for a discrete-time recursion with a translation invariant order preserving operator can be extended to a recursion with a periodic order preserving operator. The operator can be taken to be the time-one map of a continuous time reaction-diffusion model, or it can be a more general model of time evolution in population genetics or population ecology in a periodic habitat. Methods of estimating the speeds of spreading in various directions will also be presented.

Animals↗

Caged probes: a novel tool in studying symplasmic transport in plant tissues.

Caged probes offer a novel approach to study plant cell-to-cell communication. Instead of introducing fluorescent molecules into cells by microinjection, their caged counterparts can be preloaded into the tissue by diffusion. Following spatially controlled photoactivation, movement of the uncaged fluorochrome can be followed in time and direction by confocal laser scanning microscopy. In the onion bulb scale epidermis used as a model system, symplasmic transport of the tracer out of a target cell was followed. Transport via the symplasmic pathway was challenged by plasmolysing the tissue. The experiments confirmed the symplasmic nature of tracer transport.

Biological Transport↗

The evaluation of some pharmaceutically acceptable excipients as permeation enhancers for amoxicillin.

The aim of the present study was to evaluate different pharmaceutically acceptable excipients as permeation enhancers for a low permeability drug, amoxicillin. As a model for the intestinal epithelium excised rat jejunum, mounted in side-by-side diffusion cells, was used. Amoxicillin was actively transported across the intestine in the serosal-to-mucosal direction, but only if glucose was present at the mucosal side. This effect of glucose was abolished by a multridrug resistance associated protein (MRP) inhibitor benzbromarone (0.04 mM), but not by verapamil (0.2 mM). Among the tested pharmaceutically acceptable excipients only sodium lauryl sulfate (0.2 mg/ml) increased the permeability of amoxicillin in the mucosal-to-serosal direction, which was accompanying with the abolishment of the secretory oriented transport of amoxicillin. Other excipients (0.07 2mg/ml Pluronic F68, 0.2 mg/ml Lutrol F127, 0.2 mg/ml Cremophor EL or 0.2 mg/ml Carbopol 934) have no influence on the permeability of amoxicillin. The effect of sodium lauryl sulfate on the active secretion of amoxicillin was mainly attributed to the reversible cellular ATP depletion. We concluded that sodium lauryl sulfate can be considered as a relatively safe permeation enhancer for amoxicillin in drug delivery systems intended to improve oral bioavailability of this drug.

Amoxicillin↗

A kinetic model for predicting the release rate of sparingly-water-soluble drugs from a hydrogel-coated polymeric matrix.

Medical devices used for on-target drug delivery are often coated with a hydrogel coating for friction-reduction purpose. Thus, the delivery of a sparingly-water-soluble drug by such a device must diffuse through a nonerodable hydrogel layer. An empirical rate equation has been derived for such a kinetic model and predicts that the rate of drug release from such a device is directly proportional to the loading of the drug in the polymeric matrix. The validity of this kinetic model was examined by measuring the rate of release of 2,4,4'-trichloro-2'-hydroxydiphenyl ether from different hydrogel-coated (ethylene-vinyl acetate) copolymer stents containing a wide range of the drug. The experimentally determined release rates are in reasonably good agreement with those calculated from the empirical rate equation. Bioefficacy test results based on zone-of-inhibition test against Escherichia coli are also in good agreement with the release rate and drug-loading data predicted according to the empirical rate equation.

Forecasting↗

Scroll waves in isotropic excitable media: linear instabilities, bifurcations, and restabilized states.

Scroll waves are three-dimensional analogs of spiral waves. The linear stability spectrum of untwisted and twisted scroll waves is computed for a two-variable reaction-diffusion model of an excitable medium. Different bands of modes are seen to be unstable in different regions of parameter space. The corresponding bifurcations and bifurcated states are characterized by performing direct numerical simulations. In addition, computations of the adjoint linear stability operator eigenmodes are also performed and serve to obtain a number of matrix elements characterizing the long-wavelength deformations of scroll waves.

Animals↗

Finite thermal conductivity in 1D lattices

We discuss the thermal conductivity of a chain of coupled rotators, showing that it is the first example of a 1D nonlinear lattice exhibiting normal transport properties in the absence of an on-site potential. Numerical estimates obtained by simulating a chain in contact with two thermal baths at different temperatures are found to be consistent with those based on linear response theory. The dynamics of the Fourier modes provides direct evidence of energy diffusion. The finiteness of the conductivity is traced back to the occurrence of phase jumps. Our conclusions are confirmed by the analysis of two variants of this model.

Journal Article↗

Measurement and 3D simulation of self-organized filaments in a barrier discharge.

We report on pattern formation phenomena in the filamentary dielectric barrier discharge between plane glass electrodes. It is for the first time that a three-dimensional (3D) self-organized glow pattern was both observed in an actual experiment and directly calculated in a full 3D discharge simulation in a quantitative manner. Specifically, we investigate the genesis of periodic patterns during the first breakdowns. Despite our simple drift-diffusion discharge model, the correspondence of experimental and numerical findings is surprisingly good.

Electrodes↗

In vitro assessment of gastric mucosal transfer of anti-Helicobacter therapeutic agents.

A novel animal model for studying antibiotic transfer across gastric mucosa was developed by using adult rats. Gastric corpus mucosa was mounted in an Ussing chamber system and bathed in oxygenated Krebs solution. Metronidazole flux from serosa to mucosa (J(S-->M)) was measured over 60 min under basal conditions and compared with mucosa-to-serosa flux (J(M-->S)). The effects of varying the chamber cross-sectional diameter and of stimulation by histamine and carbachol were assessed. Metronidazole J(M-->S) was measured with the mucosal pH at 2.2, 2.7, 3.2, and 7.4. Amoxicillin J(S-->M) under basal conditions was also measured and compared with metronidazole J(S-->M). Metronidazole J(S-->M) was proportional to serosal concentration (P < 0.001) under basal conditions, being 3.98 nmol x h(-1) x cm(-2) with a serosal concentration of 0.2 mmol/liter. Amoxicillin J(S-->M) was significantly lower under similar conditions at 0.50 nmol x h(-1) x cm(-2) (P < 0.01). Metronidazole J(S-->M) was not significantly different from J(M-->S), between chambers of different sizes, or following stimulation. When the mucosal pH was changed, J(M-->S) was proportional to the un-ionized concentration on the mucosal side (P < 0.001). Therefore, this model shows properties analogous to those of human gastric mucosa in vivo, with partitioning of metronidazole on the mucosal side according to pH, diffusion of metronidazole across the mucosa in both directions, and selectivity for different antibiotics, and it will be useful for the study of other therapeutic agents in the treatment of Helicobacter pylori.

Amoxicillin↗

GABAA receptor kinetics in the cerebellar nuclei: evidence for detection of transmitter from distant release sites.

Neurons of the cerebellar nuclei receive GABAergic input from Purkinje cells. Purkinje boutons have several closely spaced presynaptic densities without GABA transporters, raising the possibility that neurotransmitter released by one presynaptic site diffuses to multiple postsynaptic sites. To test whether such local spillover may contribute to transmission, we studied gating of GABA(A) receptors at 31-33 degrees C in cerebellar nuclear neurons acutely dissociated from mice. Currents were evoked by rapid application of long steps, brief pulses, and high-frequency trains of GABA to outside-out patches. Receptors desensitized and deactivated rapidly, and dose-response measurements estimated an EC(50) of approximately 30 microM. From these data, a kinetic scheme was developed that replicated the recorded currents. Next, we simulated diffusion of GABA in the synaptic cleft, constrained by previous electron microscopic data, and drove the kinetic GABA(A) receptor model with modeled concentration transients. Simulations predicted receptor occupancies of approximately 100% directly opposite the release site and approximately 50% at distant postsynaptic densities, such that receptors up to 700 nm from a release site opened on the timescale of the inhibitory postsynaptic currents before desensitizing. Further simulations of probabilistic release from multiple-site boutons suggested that local spillover-mediated transmission slows the onset and limits the extent of depression during high-frequency signaling.

Action Potentials↗

Dynamics of glycine receptor insertion in the neuronal plasma membrane.

The exocytosis site of newly synthesized glycine receptor was defined by means of a morphological assay to characterize its export from the trans-Golgi Network to the plasma membrane. This was achieved by expressing in transfected neurons an alpha1 subunit bearing an N-terminal tag selectively cleavable from outside the cell by thrombin. This was combined with a transient temperature-induced block of exocytic transport that creates a synchronized exocytic wave. Immunofluorescence microscopy analysis of the cell surface appearance of newly synthesized receptor revealed that exocytosis mainly occurred at nonsynaptic sites in the cell body and the initial portion of dendrites. At the time of cell surface insertion, the receptors existed as discrete clusters. Quantitative analysis showed that glycine receptor clusters are stable in size and subsequently appeared in more distal dendritic regions. This localization resulted from diffusion in the plasma membrane and not from exocytosis of transport vesicles directed to dendrites. Kinetic analysis established a direct substrate-product relationship between pools of somatic and dendritic receptors. This indicated that clusters represent intermediates between newly synthesized and synaptic receptors. These results support a diffusion-retention model for the formation of receptor-enriched postsynaptic domains and not that of a vectorial intracellular targeting to synapses.

Animals↗

The complex of cGMP-gated channel and Na+/Ca2+, K+ exchanger in rod photoreceptors.

Ca2+ is an important signal ion in photoreceptors for recovery after excitation and light adaptation. It enters the outer segment as a minor fraction of the dark current through cGMP-gated channels and is extruded in the same cell compartment by Na+/Ca2+, K+ exchange. Channel and exchanger are located exclusively in the plasma membrane, but not in the cytoplasmic membrane stack, the discs, which contain the visual pigment rhodopsin. The channel consists presumably of two alpha-subunits and two beta-subunits, whereas the exchanger is a monomeric protein. Recently, considerable evidence has been accumulated indicating that both proteins form a complex which is bound to peripherin/rds, an integral protein of the disc rim. This review focuses on the complex of cGMP-gated channel and Na+/Ca2+, K+ exchanger. The possibility of direct functional interaction between channel and exchanger is discussed. Furthermore, the consequences of different subunit arrangements of the channel for the channel-exchanger complex are considered. Finally, a Ca2+ diffusion model is presented which examines the possibility that Ca2+ currents are locally restricted to the close vicinity of the channel.

Allosteric Site↗

[Calcium homeostasis and exocrine pancreas: physiological ans pathological interrelations].

Calcium homeostasis and exocrine pancreas interact on several levels under both physiologic and pathophysiologic conditions. (1) Calcium ions are important intracellular mediators of cholinergic and hormonal stimulation of the pancreatic acinar cell, and thus play a central role in the stimulus-secretion coupling of ecbolic pancreatic function. (2) The calcium concentration in pancreatic juice is lower than in the interstitial fluid: pancreatic juice calcium is composed of two fractions, one of which is secreted together with enzyme proteins and the other diffuses along paracellular pathways dependent on serum calcium. Disturbed calcium secretion in pancreatic juice can be observed even following slight pancreatic alteration; conversely, disturbed calcium secretion may be of importance in the pathogenesis of chronic calcifying pancreatitis. (3) Hypocalcemia is an important symptom of acute pancreatitis whose pathogenesis has not been fully elucidated. (4) On the other hand, pancreatitis complicates chronic and acute hypercalcemic syndromes though the pathogenic mechanisms is uncertain. Experimental chronic hypercalcemia in animal models causes characteristic pancreatic secretory changes and disturbs the diffusion barrier for calcium. Experimental acute hypercalcemia causes stimulation of pancreatic enzyme secretion and cholecystokinin release. In addition, extracellular calcium has a direct stimulatory effect on pancreatic acinar cells in vitro.

Acute Disease↗

Mathematical modelling of oxygen transport to tissue.

The equations governing oxygen transport from blood to tissue are presented for a cylindrical tissue compartment, with blood flowing along a co-axial cylindrical capillary inside the tissue. These governing equations take account of: (i) the non-linear reactions between oxygen and haemoglobin in blood and between oxygen and myoglobin in tissue; (ii) diffusion of oxygen in both the axial and radial directions; and (iii) convection of haemoglobin and plasma in the capillary. A non-dimensional analysis is carried out to assess some assumptions made in previous studies. It is predicted that: (i) there is a boundary layer for oxygen partial pressure but not for haemoglobin or myoglobin oxygen saturation close to the inflow boundary in the capillary; (ii) axial diffusion may not be neglected everywhere in the model; (iii) the reaction between oxygen and both haemoglobin and myoglobin may be assumed to be instantaneous in nearly all cases; and (iv) the effect of myoglobin is only significant for tissue with a low oxygen partial pressure. These predictions are validated by solving the full equations numerically and are then interpreted physically.

Capillaries↗

Airborne infection in a fully air-conditioned hospital. II. Transport of gaseous and airborne particulate material along ventilated passageways.

A mathematical model is described for the transport of gaseous or airborne particulate material between rooms along ventilated passageways. Experimental observations in three hospitals lead to a value of about 0.06 m.2/sec. for the effective diffusion constant in air without any systematic directional flow. The 'constant' appears to increase if there is any directional flow along the passage, reaching about 0.12 m. 2/sec. at a flow velocity of 0.04 m./sec. Together with previously published methods the present formulae make it possible to calculate the expected average amounts of gaseous or particulate material that will be transported from room to room in ventilated buildings in which the ventilation and exchange airflows can be calculated. The actual amounts transported in occupied buildings, however, vary greatly from time to time.

Air Conditioning↗

Advances in magnetic resonance imaging methods for the evaluation of bipolar disorder.

This article reviews the current state of magnetic resonance imaging techniques as applied to bipolar disorder. Addressed are conventional methods of structural neuroimaging and recently developed techniques. This latter group comprises volumetric analysis, voxel-based morphometry, the assessment of T2 white matter hyperintensities, shape analysis, cortical surface-based analysis, and diffusion tensor imaging. Structural analysis methods used in magnetic resonance imaging develop exponentially, and now present opportunities to identify disease-specific neuroanatomic alterations. Greater acuity and complementarity in measuring these alterations has led to the generation of further hypotheses regarding the pathophysiology of bipolar disorder. Included in the summary of findings is consideration of a resulting neuroanatomic model. Integrative issues and future directions in this relatively young field, including multi-modal approaches enabling us to produce more comprehensive results, are discussed.

Bipolar Disorder↗

Modeling of phosphorus dynamics in aquatic sediments: I--model development.

A model is developed to study the phosphorus dynamics in aquatic sediments and to conduct dynamic predictions of phosphorus release across a sediment-water interface. The model focuses on the sediment active layer below the sediment-water interface and is based on primary mechanisms regulating phosphorus behavior in sediments, including effective diffusion, bioturbation mixing and burial processes (transport), organic decomposition, sorption kinetic processes and non-linear partitioning (mobilization). The effects of environmental factors such as dissolved oxygen and temperature are taken into account. The model is solved by numerical integration. The primary difference from models in the literature is that the model directly describes the dynamic behavior of dissolved, particulate exchangeable ortho-phosphorus and organic phosphorus in sediments, and incorporates dynamic sorption and non-linear partitioning processes. These improve model mechanisms and allow regulation of phosphorus flux through the sediment reservoir that acts as both a source and sink of phosphorus.

Biological Availability↗

Knowledge diffusion in social work: a new approach to bridging the gap.

The continuing gap between research and practice has long been a problem in social work. A great deal of the empirical practice literature has emphasized practice evaluation (usually in the form of single-case methodologies) at the expense of research dissemination and utilization. An alternative focus for social work researchers can be found in the extensive theoretical and research literature on knowledge diffusion, technology transfer, and social marketing. Knowledge diffusion and social marketing theory is explored in terms of its relevance to social work education and practice, including a consideration of issues of culture and power. The authors present an integrated dissemination model for social work and use a case example to illustrate the practical application of the model. The OPTIONS (OutPatient Treatment In ONtario Services) project is an example of the effective dissemination of two research-based addiction treatment modalities to nearly 1,000 direct practice clinicians in Ontario, Canada.

Diffusion of Innovation↗

Polarization and movement of keratocytes: a multiscale modelling approach.

Eukariotic cell motility is a complex phenomenon, in which the cytoskeleton and its major constituent, actin, play an essential role. Actin forms polymers of long, stiff filaments that are cross-linked into an anisotropic network inside a thin sheet-like cellular protrusion, the lamellipod. At the leading edge of this structure, polymerization of actin filaments creates the force that pushes out the membrane and leads to translocation of a motile cell. Dynamics of the actin network account for changes in cell shape, crawling motion and turning of the cell in response to external cues. Regulating the dynamics of the cytoskeleton, and playing a central role in signal transduction in the cell, are Cdc42, Rac and Rho (GTPases of the rho family, collectively known as the small G-proteins) and the actin nucleating complex, Arp2/3. In this paper, we use a multiscale modelling approach in a 2D model of a motile cell. We describe the mutual interactions of the small G-proteins, and their effects on capping and side-branching of actin filaments. We incorporate the pushing exerted by oriented actin filament ends on the cell edge, and a Rho-dependent contraction force. Combining these biochemical and mechanical aspects, we investigate the dynamics of a model epidermal fish keratocyte through in silico experiments. Our model gives insight into how, in response to some cue, a cell can polarize, form a leading edge, and move; concomitantly it explains how a keratocyte cell can maintain its shape and polarity, even after removal of the initial stimulus, and how it can change direction quickly in response to changes in its environment. We show that establishment of polarity stems from interactions of Cdc42, Rac and Rho, while maintenance and robustness of polarity is due to the rapid cytosolic diffusion of the inactive (GDI-bound) forms of the small G-proteins. Our model produces a cell shape that closely resembles the keratocytes and correct speeds for biologically reasonable parameter values. Movies of the simulations can be obtained from http://theory.bio.uu.nl/stan/keratocyte.

Actins↗