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At least 307 records · Page 17Linked to original sources

Design of a novel hydrogel-based intelligent system for controlled drug release.

The present work focused on the design of an assembled drug delivery system (DDS) to provide multifunctions, such as drug protection, self-regulated oscillatory release, and targeted uni-directional delivery by a bilayered self-folding gate and simple surface mucoadhesion. In this device, a pH-sensitive hydrogel together with a poly(hydroxyethyl methacrylate) (HEMA) barrier was used as a gate to control drug release. In addition, poly(HEMA) coated with poly(ethylene oxide)/poly(propylene oxide)/poly(ethylene oxide) (PEO-PPO-PEO) surfactant was utilized to enhance mucoadhesion on the device surface. The release profiles of two model drugs, acid orange 8 (AO8) and bovine serum albumin (BSA) were studied in this assembled system, which compared with the conventional drug-entrapped carriers and enteric-coating systems. Furthermore, targeted uni-directional release was demonstrated in a side-by-side diffusion cell. In conclusion, for such an assembled device, the poly(HEMA) layer not only affects the folding direction but also serves as a barrier to protect the model drugs. The release time can be controlled by the thickness of the bilayered gate and the drug reservoir. Due to the reversible swelling behavior of poly(methyacrylic acid-g-ethylene glycol) (p(MAA-g-EG)) gels, the bilayered gate can sense the environmental pH change and achieve an oscillatory release pattern. Moreover, the local targeting and uni-directional release have been successfully demonstrated in vitro.

Coloring Agents↗

Experimental evaluation of an anisotropic scattering model of a slab geometry.

A model has been developed based on random walk theory that allows the diffusion of light along a principal axis to differ from that in orthogonal directions. We present expressions that describe the time-resolved intensity measured across a slab and on the surface of a semi-infinite medium for a principal axis oriented parallel or perpendicular to the surface. The model of time-resolved transmittance is compared with experimental data acquired by use of a phantom consisting of wax fibers arranged within a solid cube of resin. It is shown that a single set of optical parameters is sufficient to model the experimental measurements acquired across all three orientations of the cube.

Algorithms↗

Biofilm development in a membrane-aerated biofilm reactor: effect of flow velocity on performance.

The effect of liquid flow velocity on biofilm development in a membrane-aerated biofilm reactor was investigated both by mathematical modeling and by experiment, using Vibrio natriegens as a test organism and acetate as carbon substrate. It was shown that velocity influenced mass transfer in the diffusion boundary layer, the biomass detachment rate from the biofilm, and the maximum biofilm thickness attained. Values of the overall mass transfer coefficient of a tracer through the diffusion boundary layer, the biofilm, and the membrane were shown to be identical during different experiments at the maximum biofilm thickness. Comparison of the results with published values of this parameter in membrane attached biofilms showed a similar trend. Therefore, it was postulated that this result might indicate the mechanism that determines the maximum biofilm thickness in membrane attached biofilms. In a series of experiments, where conditions were set so that the active layer of the membrane attached biofilm was located close to the membrane biofilm interface, it was shown that the most critical effect on process performance was the effect of velocity on biofilm structure. Biofilm thickness and effective diffusivity influenced reaction and diffusion in a complex manner such that the yield of biomass on acetate was highly variable. Consideration of endogenous respiration in the mathematical model was validated by direct experimental measurements of yield coefficients. Good agreement between experimental measurements of acetate and oxygen uptake rates and their prediction by the mathematical model was achieved.

Biofilms↗

New modeling and experimental framework to characterize hindered and restricted water diffusion in brain white matter.

To characterize anisotropic water diffusion in brain white matter, a theoretical framework is proposed that combines hindered and restricted models of water diffusion (CHARMED) and an experimental methodology that embodies features of diffusion tensor and q-space MRI. This model contains a hindered extra-axonal compartment, whose diffusion properties are characterized by an effective diffusion tensor, and an intra-axonal compartment, whose diffusion properties are characterized by a restricted model of diffusion within cylinders. The hindered model primarily explains the Gaussian signal attenuation observed at low b values; the restricted non-Gaussian model does so at high b. Both high and low b data obtained along different directions are required to estimate various microstructural parameters of the composite model, such as the nerve fiber orientation(s), the T2-weighted extra- and intra-axonal volume fractions, and principal diffusivities. The proposed model provides a description of restricted diffusion in 3D given by a 3D probability distribution (average propagator), which is obtained by 3D Fourier transformation of the estimated signal attenuation profile. The new model is tested using synthetic phantoms and validated on excised spinal cord tissue. This framework shows promise in determining the orientations of two or more fiber compartments more precisely and accurately than with diffusion tensor imaging.

Animals↗

Determination of the membrane permeability coefficient and the reflection coefficient by the two-dimensional laminar flow model for intestinal perfusion experiments.

We performed single perfusion experiments in the small intestine of rats in order to prove that the two-dimensional laminar flow model is suitable to determine the membrane permeability coefficient and the reflection coefficient. We used progesterone as an aqueous-diffusion-limited drug, urea as a membrane transport-limited drug and the tritiated water as an intermediate substance. The membrane permeability coefficient for progesterone was calculated to be 3.6 X 10(-4) cm/s. This value did not change when the thickness of the aqueous diffusion layer was altered by increasing the perfusion rate 10-fold. It was directly demonstrated that the two-dimensional laminar flow model was suitable to analyze the data of intestinal perfusion experiments. Membrane permeability coefficients for urea and tritiated water were determined to be 3.4 X 10(-5) cm/s and 8.9 X 10(-5) cm/s, respectively. In the presence of water absorption with the hypotonic perfusion solution, the reflection coefficient for urea was 0.84. This value is thought to be theoretically reasonable, suggesting the usefullness of the two-dimensional laminar flow model to obtain the reflection coefficient in the intestinal membrane.

Animals↗

Diffusion imaging of experimental allergic encephalomyelitis.

Diffusion-weighted magnetic resonance imaging (MRI) was compared with T2-weighted MRI in longitudinal studies of experimental allergic encephalomyelitis (EAE), an animal model of multiple sclerosis, in five monkeys (Macaca fascicularis). In a region of the brain that had highly directional myelinated fibers (internal capsule) sequential changes were identified on diffusion-weighted images on and before the day these changes were detected on conventional T2-weighted images. Changes were also identified on diffusion-weighted images in brain areas that did not develop T2-weighted abnormalities. This result suggests that diffusion-weighted image intensities are sensitive to pathologic conditions of the brain that can not be seen on T2-weighted images.

Animals↗

The estimation of the diffusion constant and solubility of O(2)in tissue using kinetics.

The diffusion of a gas through a substance in which it is soluble is analogous to the passage of electric current through a circuit with both capacitance and resistance. We model steady-state diffusion employing this analogy, and extend the model to include a description of the kinetics of systems under circumstances of changing partial pressure, applying two physical constants from electrical circuitry to gas diffusion: capacitance (zeta) and resistance (R). We represent the substrate of the diffusion as a capacitor being charged through a resistor after the rapid imposition of a voltage change. Using the insight derived from this model we have devised an experimental system that allows us to approximate both D, the diffusion coefficient, and alpha, solubility, directly from the kinetic data. We do this by recording the exponential change in P(O(2))on one side of a sheet of material both with and without the addition of a purely resistive barrier of known resistivity. The method was used to estimate D and alpha for distilled water at a number of temperatures, olive oil, and the belly skin of Rana catesbeiana.

Animals↗

Evolution of cardiac calcium waves from stochastic calcium sparks.

We present a model that provides a unified framework for studying Ca2+ sparks and Ca2+ waves in cardiac cells. The model is novel in combining 1) use of large currents (approximately 20 pA) through the Ca2+ release units (CRUs) of the sarcoplasmic reticulum (SR); 2) stochastic Ca2+ release (or firing) of CRUs; 3) discrete, asymmetric distribution of CRUs along the longitudinal (separation distance of 2 microm) and transverse (separated by 0.4-0.8 microm) directions of the cell; and 4) anisotropic diffusion of Ca2+ and fluorescent indicator to study the evolution of Ca2+ waves from Ca2+ sparks. The model mimics the important features of Ca2+ sparks and Ca2+ waves in terms of the spontaneous spark rate, the Ca2+ wave velocity, and the pattern of wave propagation. Importantly, these features are reproduced when using experimentally measured values for the CRU Ca2+ sensitivity (approximately 15 microM). Stochastic control of CRU firing is important because it imposes constraints on the Ca2+ sensitivity of the CRU. Even with moderate (approximately 5 microM) Ca2+ sensitivity the very high spontaneous spark rate triggers numerous Ca2+ waves. In contrast, a single Ca2+ wave with arbitrarily large velocity can exist in a deterministic model when the CRU Ca2+ sensitivity is sufficiently high. The combination of low CRU Ca2+ sensitivity (approximately 15 microM), high cytosolic Ca2+ buffering capacity, and the spatial separation of CRUs help control the inherent instability of SR Ca2+ release. This allows Ca2+ waves to form and propagate given a sufficiently large initiation region, but prevents a single spark or a small group of sparks from triggering a wave.

Animals↗

[Modified agar diffusion test for direct testing of the effectiveness of released antibiotics from bone cements].

A modified agar-diffusion method is used to test the bactericidal efficacy of antibacterial substances (model substance: Gentamicin) that have been mixed with Palacos osseous cement. Holes of a diameter slightly larger than the diameter of the cylindric Palacos test block are cut from the agar plate. The remaining space (inner wall of the hole--edge of the test body) is filled with various eluate media. The release of active antibacterial substances from polymethylmetacrylates can thereby be determined under nearly physiologic conditions at varying pHs by direct antibacterial testing.

Agar↗

Lateral diffusion of PDGF beta-receptors in human fibroblasts.

When platelet-derived growth factor (PDGF) binds to its receptors a number of biochemical reactions are elicited in the cell. Several models have been presented for the effects of ligand-induced receptor conformation and aggregation on signal transduction but little is known about the direct effects on receptor diffusion. This study concerns the lateral mobility of PDGF receptors in fibroblasts. It was assessed with fluorescence recovery after photobleaching (FRAP), using rhodaminated receptor antibodies or Fab-fragments of the antibody as ligands. The aims of the investigation were: (a) to compare the lateral mobility of membrane receptors of human fibroblasts labelled with either antibodies against the PDGF receptor or Fab-fragments of the same antibodies, and (b) to study the effects of serum or PDGF on the mobility of the receptors. Human foreskin fibroblasts (AG 1523) were grown on coverslips either under standard or under serum-free conditions yielding "normal" and "starved" cells, respectively. Two parameters of the diffusion were evaluated; the diffusion coefficient (D) and the mobile fraction (R) of the receptors. We found that normal fibroblasts had a smaller diffusion coefficient and a lower mobile fraction compared to starved cells using antibodies for receptor labelling. The addition of PDGF, just before the measurement, increased the D and R for normal cells, while starved cells, showing higher initial values, displayed slightly reduced values of D and R. After the addition of serum, D increased and R remained low for normal cells, whereas for starved cells both D and R increased to upper limits of 11.0 x 10(-10) cm2s-1 and greater than 90% respectively. In general, the D and R values, both in normal and starved cells, were higher for cells labelled with Fab-fragments than for antibody-labelled cells. The results are discussed in relation to the natural complexity of the receptor, and how PDGF, serum, antibodies and Fab-fragments might interfere with receptor structure, aggregation state and membrane diffusion characteristics.

Cell Line↗

Modeling and simulation of illumination effects for evaluation of microvessels of the conjunctiva.

We present the development of a comprehensive model that was undertaken to determine the relationships between the components of an image and the light intensity values present in the image of the microvessels of translucent tissues such as the bulbar conjunctiva. Experiments were conducted during the modeling process by use of a cylindrical microvessel embedded in a diffuse medium (phantom) on a reflecting background to affirm model components and simulations. The three-dimensional model was reduced to a single illumination plane with four regions of interest and modeled as Lambertian radiators and surfaces. The modeling showed that the top of the cylinder and its immediate vicinity are diffuse reflectors of light from the source plus light reflected from the background. The limbus of the cylinder is a diffuse reflector of the source and background illumination and a specular reflector of background reflections that achieve a high grazing angle with the cylinder. The immediate vicinity of the cylinder receives direct illumination from the source, but the light is partially obscured by the cylinder. The region beyond the shadow of the cylinder is a diffuse reflector of the overhead light. The diffuse medium additionally reflects the source and also attenuates the illumination reaching the other compo- rents of the scene. The direct and reflected illumination at each region of the model was calculated by use of specific geometric relationships. To verify those calculations, we analyzed a video simulation for the effects of different illumination conditions and their contributing elements. Intensity values were calculated from the relative reflectivity data determined from the video signals. The illumination values at the points along the line at the meridian of the cylinder were due to its reflectivity and also that of the medium. Similarly, the values of points distant from the shadow of the cylinder were due to the reflectivity of the background and the medium. The excellent agreement between the model and the phantom provides a foundation for the detection and precise measurement of microvessel dimensions within a diffuse medium. The additional ability to compute relative depth, from a single view, also permits discrimination between neighboring microvessels in complex images.

Computer Simulation↗

Anisotropic thermally activated diffusion in percolation systems.

We present a study of static and frequency-dependent diffusion with anisotropic thermally activated transition rates in a two-dimensional bond percolation system. The approach accounts for temperature effects on diffusion coefficients in disordered anisotropic systems. Static diffusion shows an Arrhenius behavior for low temperatures with an activation energy given by the highest energy barrier of the system. From the frequency-dependent diffusion coefficients, we calculate a characteristic frequency omega(c) approximately 1/t(c), related to the time t(c) needed to overcome a characteristic barrier. We find that omega(c) follows an Arrhenius behavior with different activation energies in each direction.

Anisotropy↗

Effect of dentine on release of TEGDMA from resin composite in vitro.

Triethylene glycol dimethacrylate (TEGDMA) is a component of some resin composites which contributes to their cytotoxicity. The presence of dentine between resin composite and test cells reduces the cytotoxicity in vitro. To determine why dentine has this protective effect, the diffusion of TEGDMA from a composite resin through dentine to the pulp space was compared with release directly into aqueous solution in vitro. Both release rate and total cumulative release of TEGDMA for the two groups, at times up to 100 days, were determined using reversed-phase HPLC. Release rate directly into water was highest in the minutes immediately after immersion and declined thereafter. However, in the tooth model, using an equivalent mass and surface area of composite resin, no TEGDMA was detectable in the pulp space until 43 min after restoration placement. The rate of diffusion through dentine from that time until day 1 was less than 1% of the highest (initial) direct release rate. The rate declined thereafter. It is relevant, however, that by day 3 the total cumulative release of TEGDMA through dentine was 60% of the direct release. Dentine therefore appears to exert its protective effect principally by retarding or 'damping' the initial high release of TEGDMA to a substantial degree.

Bisphenol A-Glycidyl Methacrylate↗

Intrinsic scaling complexity in animal dispersion and abundance.

Ecological theory related to animal distribution and abundance is at present incomplete and to some extent naive. We suggest that this may partly be due to a long tradition in the field of model development for choosing mathematical and statistical tools for convenience rather than applicability. Real population dynamics are influenced by nonlinear interactions, nonequilibrium conditions, and scaling complexity from system openness. Thus, a coherent theory for individual-, population-, and community-level processes should rest on mathematical and statistical methods that explicitly confront these issues in a manner that satisfies principles from statistical mechanics for complex systems. Instead, ecological theory is traditionally based on premises from simpler statistical mechanical theory for memory-free, scale-specific, random-walk, and diffusion processes, while animals from many taxa generally express strategic homing, site fidelity, and conspecific attraction in direct violation of primary model assumptions. Thus, the main challenge is to generalize the theory for memory-free physical, many-body systems to include a more realistic memory-influenced framework that better satisfies ecological realism. We describe, simulate, and discuss three testable aspects of a model for multiscaled habitat use at the individual level: (1) scale-free distribution of movement steps under influence of self-reinforcing site fidelity, (2) fractal spatial dispersion of intra-home range relocations, and (3) nonasymptotic expansion of observed intra-home range patch use with increasing set of relocations. Examples of literature data apparently supporting the conjecture that multiscaled, strategic space use is widespread among many animal taxa are also described. We suggest that the present approach, which provides a protocol to test for influence from scale-free, memory-dependent habitat use at the individual level, may also point toward a guideline for development of a generalized theoretical framework for complex population kinetics and spatiotemporal population dynamics.

Animal Migration↗

Crystal structure of the human GGA1 GAT domain.

GGAs are a family of vesicle-coating regulatory proteins that function in intracellular protein transport. A GGA molecule contains four domains, each mediating interaction with other proteins in carrying out intracellular transport. The GAT domain of GGAs has been identified as the structural entity that binds membrane-bound ARF, a molecular switch regulating vesicle-coat assembly. It also directly interacts with rabaptin5, an essential component of endosome fusion. A 2.8 A resolution crystal structure of the human GGA1 GAT domain is reported here. The GAT domain contains four helices and has an elongated shape with the longest dimension exceeding 80 A. Its longest helix is involved in two structural motifs: an N-terminal helix-loop-helix motif and a C-terminal three-helix bundle. The N-terminal motif harbors the most conservative amino acid sequence in the GGA GAT domains. Within this conserved region, a cluster of residues previously implicated in ARF binding forms a hydrophobic surface patch, which is likely to be the ARF-binding site. In addition, a structure-based mutagenesis-biochemical analysis demonstrates that the C-terminal three-helix bundle of this GAT domain is responsible for the rabaptin5 binding. These structural characteristics are consistent with a model supporting multiple functional roles for the GAT domain.

ADP-Ribosylation Factors↗

Large animal models of traumatic injury to the immature brain.

Large animal models have been used much less frequently than rodent models to study traumatic brain injury. However, large animal models offer distinct advantages in replicating specific mechanisms, morphology and maturational stages relevant to age-dependent injury responses. This paper reviews how each of these features is relevant in matching a model to a particular scientific question and discusses various scaling strategies, advantages and disadvantages of large animal models for studying traumatic brain injury in infants and children. Progress to date and future directions are outlined.

Aging↗

Modelling study on the protective role of OH radical scavengers and DNA higher-order structures in induction of single- and double-strand break by gamma-radiation.

PURPOSE: To quantify the protective effects of (non-histonic) OH-radical scavengers and DNA higher-order structures in induction of single- (ssbs) and double-strand breaks (dsbs) by gamma-rays. MATERIALS AND METHODS: Spatial distributions of energy depositions by gamma-rays in liquid water were modelled with the track structure modules of the biophysical simulation code PARTRAC. Such distributions were superimposed on different DNA structure models (e.g. linear DNA, SV40 'minichromosomes' and compact chromatin), and direct energy depositions in the sugar-phosphate were considered as potential (direct) ssbs. The diffusion and interaction of the main chemical species produced in liquid water radiolysis were explicitly simulated, and reactions of *OH with the sugar-phosphate were considered as potential (indirect) ssbs. Two ssb on opposite DNA strands within 10 base pairs were considered as one dsb. Yields of ssb and dsb Gy(-1) Dalton(-1) in different DNA target structures were calculated as a function of the *OH mean lifetime, whose inverse value was taken as representative of the scavenging capacity of the DNA environment. RESULTS AND CONCLUSIONS: A further validation of the models implemented in the PARTRAC code has been provided, thus allowing a better understanding of the mechanisms underlying DNA damage. More specifically, the protection due to *OH scavengers was separately quantified with respect to that due to histones and chromatin folding, which could be 'switched off' in the simulations. As expected, for a given value of the environment scavenging capacity, linear DNA was more susceptible to strand breakage than SV40 minichromosomes, which in turn showed higher damage yields with respect to cellular DNA due to the larger accessibility offered to *OH. Furthermore, by increasing the scavenging capacity, the break yields decreased in all structures and tended to coincide with direct damage yields. Very good agreement was found with available experimental data. Comparisons with data on 'nucleoid' DNA (i.e. unfolded and histone-depleted DNA) also suggested that the experimental procedures used to obtain such structures might lower the environment scavenging capacity owing to the loss of cellular scavengers.

DNA↗

Prothymosin alpha is a nonspecific facilitator of nuclear processes: studies of run-on transcription.

The effect of prothymosin alpha on transcriptional elongation has been examined. The addition of prothymosin alpha to COS-1 and NIH3T3 cell nuclei engaged in run-on transcription stimulated RNA synthesis approximately two- to threefold in a dose-dependent manner. Polyglutamic acid or a random polypeptide composed of glutamic acid, alanine, and tyrosine, did not substitute for prothymosin alpha. Enhanced transcription occurred in the presence of high and low doses of actinomycin D and in the presence of alpha-amanitin, but not in nuclear extracts. The stimulatory effect was dependent on a limiting concentration of one nucleoside triphosphate and was nearly abrogated by saturating levels of precursors. In the presence of Sarkosyl, which itself increases transcription, prothymosin alpha was almost ineffectual. The data are consistent with a model in which prothymosin alpha does not interact directly with polymerases but, instead, nonspecifically decreases the barriers to diffusion of charged molecules in electrostatically charged environments.

3T3 Cells↗