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PubMed1996

Transport of the anti-cancer drug doxorubicin across cytoplasmic membranes and membranes composed of phospholipids derived from Escherichia coli occurs via a similar mechanism.

An assay was developed to measure and directly compare transport of doxorubicin across right-side-out cytoplasmic membrane vesicles (ROV) and across model membranes (LUVET) composed of pure phospholipids, isolated from the corresponding cells. Escherichia coli was used as a model organism, since mutants are available which differ in phospholipid composition. Both in LUVET and ROV only passive diffusion across the bilayer is involved, because effects of drug concentration, pH, divalent cations, the phospholipid composition, and the active transport inhibitor verapamil were comparable. Permeability coefficients were about 2-3-times higher in ROV compared to LUVET. Furthermore, in LUVET an average activation energy of 87 kJ/mol and in ROV of 50 kJ/mol was observed. These differences are suggested to result from differences in membrane order between LUVET and ROV and differences in the temperature dependence of membrane order in LUVET and ROV, respectively. Because no background carrier-facilitated doxorubicin transport seems to be present, ROV are an excellent model system to study the effect of phospholipid composition on drug transport after expression of a multidrug resistance-conferring protein. Furthermore, data of passive diffusion of doxorubicin obtained with LUVET are representative for more complex, biologically relevant membrane systems.

Antibiotics, Antineoplastic↗
PubMed1996

Molecular diffusion into horse spleen ferritin: a nitroxide radical spin probe study.

Electron paramagnetic resonance spectroscopy and gel permeation chromatography were employed to study the molecular diffusion of a number of small nitroxide spin probes (approximately 7-9 A diameter) into the central cavity of the iron-storage protein ferritin. Charge and polarity of these radicals play a critical role in the diffusion process. The negatively charged radical 4-carboxy-2,2,6,6-tetramethylpiperidine-N-oxyl (4-carboxy-TEMPO) does not penetrate the cavity whereas the positively charged 4-amino-TEMPO and 3-(aminomethyl)-proxyl radical and polar 4-hydroxy-TEMPO radical do. Unlike the others, the apolar TEMPO radical does not enter the cavity but instead binds to ferritin, presumably at a hydrophobic region of the protein. The kinetic data indicate that diffusion is not purely passive, the driving force coming not only from the concentration gradient between the inside and outside of the protein but also from charge interactions between the diffusant and the protein. A model for diffusion is derived that describes the observed kinetics. First-order half-lives for diffusion into the protein of 21-26 min are observed, suggesting that reductant molecules with diameters considerably larger than approximately 9 A would probably enter the protein cavity too slowly to mobilize iron efficiently by direct interaction with the mineral core.

Animals↗
PubMed2003

The influence of environmental variability on silicate exchange rates between sediment and water in a shallow-water coastal ecosystem, the Seto Inland Sea, Japan.

Silicate regeneration was determined in a shallow-water coastal ecosystem (Shido Bay, the Seto Inland Sea, Japan) during 1999-2000. The present study was carried out directly by core incubation and by determining gradients of dissolved silicate (DSi) in the pore water. Incubated fluxes ranged from 25.5 to 132.6 mgSim(-2)d(-1), and were 1.6-21.6 times greater than diffusive fluxes (5.4-43.3 mgSim(-2)d(-1)). The disparity between fluxes measured by core incubation and modeling pore water indicated that other physical, chemical or biological processes, in addition to diffusion of DSi from below, contribute to DSi fluxes measured during the incubation of undisturbed cores. A regression analysis revealed that water temperature and salinity explained 24% and 23%, respectively, of season to season variability in incubated fluxes. Microphytobenthos was responsible for 37% of the variability in measured rate of DSi fluxes, with greatly reducing DSi release rates due to their own DSi demand. Moreover, the inverse relationship between the DSi fluxes and biogenic silica (Bio-Si) concentrations in the surface sediment, suggested that about 41% of the variability in the DSi fluxes were explained by Bio-Si concentrations in the surface sediment. As a result, Shido Bay showed silicate regeneration of incubated cores to be a consequence of Bio-Si dissolution depending on microphytobenthos, temperature and salinity, while diffusive fluxes appeared to be limited by DSi in the pore water. An annual average of DSi flux (68.7+/-32.9 mgSim(-2)d(-1)) from the sediments to the water column corresponds to 38% of DSi, required for primary production by phytoplankton in Shido Bay.

Ecosystem↗
PubMed1991

The pathogenesis of canalicular laceration.

Canalicular lacerations are seen commonly in ophthalmic practice, but the pathogenesis of canalicular lacerations has not been explored. The authors retrospectively reviewed 25 cases of canalicular laceration seen at their institutions. Only 4 patients (16%) had injuries attributable to direct trauma; the remaining 21 patients (84%) had diffuse trauma or trauma to the eyelid remote from the canaliculus. The authors postulate that, in many of their cases, canalicular "lacerations" resulted from indirect trauma, where the eyelid was ruptured when it was stretched acutely to the point of avulsion. Two experimental models were derived to test this hypothesis. The results suggest that the canalicular portion of the eyelid is a particularly vulnerable location, and that injuries morphologically similar to canalicular "lacerations" occur predictably if the eyelid is traumatized indirectly or diffusely to the point of rupture.

Adolescent↗
PubMed2001

Biexponential apparent diffusion coefficient parametrization in adult vs newborn brain.

The decay of brain water signal with b-factor in adult and newborn brains has been measured over an extended b-factor range. Measurements of the apparent diffusion coefficient (ADC) decay curves were made at 16 b-factors from 100 to 5000 s/mm(2) along three orthogonal directions using a line scan diffusion imaging (LSDI) sequence to acquire data from 0.09 ml voxels in a mid-brain axial slice. Regions-of-interest (ROIs) in cortical gray (CG) and white matter in the internal capsule (IC) were selected for ADC decay curve analyses using a biexponential fitting model over this extended b-factor range. Measures of the fast and slow ADC component amplitudes and the traces of the fast and slow diffusion coefficients were obtained from CG and IC ROIs in both adults and newborns. The ADC decay curves from the newborn brain regions were found to have a significantly higher fraction of the fast diffusion ADC component than corresponding regions in the adult brain. The results demonstrate that post-natal brain development has a profound affect on the biexponential parameters which characterize the decay of water signal over an extended b-factor range in both gray and white matter.

Adult↗
PubMed1982

Kinetics of transfer of Escherichia coli single strand deoxyribonucleic acid binding protein between single-stranded deoxyribonucleic acid molecules.

The binding of homogeneous Escherichia coli K12 single strand DNA binding protein to a 3H-labeled 375-nucleotide single-stranded DNA of known sequence was detected with a filter-binding assay. The binding of protein is sufficiently cooperative that an all-or-nothing mechanism governs and DNA is either free of or saturated with protein. The stoichiometry of filter binding agrees with this model. Also, the first-order kinetics of transfer of protein from donor DNA-protein complexes to recipient DNA of the same size is the same whether 3H-labeled donor or recipient DNA is used. The rate of transfer of protein from donor to recipient is found to be weakly temperature dependent, independent of salt concentration over a defined range, and inversely proportional to solvent viscosity. These results are consistent with a diffusion-controlled reaction mechanism. When much larger recipient DNA is used, the rate of transfer of protein is greatly reduced. The magnitude of and the length dependence of the rate constants for protein transfer are incompatible with a mechanism involving uptake of free protein from solution. A model is proposed involving direct transfer of cooperative units of protein from donor to recipient strands. Electron micrographs consistent with this model are presented.

Bacterial Proteins↗
PubMed1999

Net secretion of furosemide is subject to indomethacin inhibition, as observed in Caco-2 monolayers and excised rat jejunum.

PURPOSE: To determine if intestinal secretion occurs for the poorly bioavailable diuretic, furosemide. METHODS: Jejunal segments of male Sprague-Dawley rats were mounted on diffusion chambers, and the permeation of furosemide was measured across the excised tissue in both directions. Studies were repeated using cultured epithelia from adenocarcinoma cells (Caco-2) grown on filter inserts mounted in 6-well plates. Temperature-dependence and chemical inhibition by indomethacin was also tested using the cell culture model. RESULTS: Net secretion from rat intestine of over 3-fold was observed for 20 microM furosemide. Net secretion of furosemide by Caco-2 cells was over 300% greater than for intestinal segments (10-fold vs. 3-fold). For both models, a decrease in furosemide transport in the direction of secretion was observed in the presence of indomethacin (100 microM), although only results using the Caco-2 cells showed in increase in the absorptive transport. Furosemide secretion from Caco-2 cells decreased with decrease in temperature from 37 degrees C to 4 degrees C, suggesting a carrier-mediated process. CONCLUSIONS: Furosemide appears to be secreted in the small intestine. These preliminary results indicate that furosemide bioavailability may be limited by an intestinal transporter.

Animals↗
PubMed2004

Two-dimensional chemotherapy simulations demonstrate fundamental transport and tumor response limitations involving nanoparticles.

Zheng et al. (2004) developed a multiscale, two-dimensional tumor simulator with the capability of showing tumoral lesion progression through the stages of diffusion-limited dormancy, neo-vascularization (angiogenesis) and consequent rapid growth and tissue invasion. In this paper we extend their simulator to describe delivery of chemotherapeutic drugs to a highly perfused tumoral lesion and the tumor cells' response to the therapy. We perform 2-D simulations based on a self-consistent parameter estimation that demonstrate fundamental convective and diffusive transport limitations in delivering anticancer drug into tumors, whether this delivery is via free drug administration (e.g., intravenous drip), or via 100 nm nanoparticles injected into the bloodstream, extravasating and releasing the drug that then diffuses into the tumoral tissue, or via smaller 1-10 nm nanoparticles that are capable of diffusing directly and targeting the individual tumor cell. Even in a best-case scenario involving: constant ("smart") drug release from the nanoparticles; a homogenous tumor of one cell type, which is drug-sensitive and does not develop resistance; targeted nanoparticle delivery, with resulting low host tissue toxicity; and for model parameters calibrated to ensure sufficient drug or nanoparticle blood concentration to rapidly kill all cells in vitro ; our analysis shows that fundamental transport limitations are severe and that drug levels inside the tumor are far less than in vitro , leaving large parts of the tumor with inadequate drug concentration. A comparison of cell death rates predicted by our simulations reveals that the in vivo rate of tumor shrinkage is several orders of magnitude less than in vitro for equal chemotherapeutic carrier concentrations in the blood serum and in vitro, and after some shrinkage the tumor may achieve a new mass equilibrium far above detectable levels. We also demonstrate that adjuvant anti-angiogenic therapy "normalizing" the vasculature may ameliorate transport limitations, although leading to unwanted tumor fragmentation. Finally, our results suggest that small nanoparticles equipped with active transport mechanisms (e.g., chemotaxis) would overcome the predicted limitations and result in improved tumor response.

Animals↗
PubMed2006

Phase of molecular ink in nanoscale direct deposition processes.

We report the first observation of a phase transition in a nanoscale direct deposition process. This transition involves the melting of molecular ink layers in dip-pen nanolithography, and it is observed by measuring the temperature dependence of the growth rate of the deposited pattern. The results are interpreted using a diffusion equation approach in conjunction with a "double-molecular-layer" model of the adsorbed molecules on the atomic force microscope tip. The theory provides a qualitative explanation for the dependence of the pattern growth rate on solvent and adsorbed water as well as on temperature.

Adsorption↗
PubMed2001

Pattern formation and traveling waves in myxobacteria: theory and modeling.

Recent experiments have provided new quantitative measurements of the rippling phenomenon in fields of developing myxobacteria cells. These measurements have enabled us to develop a mathematical model for the ripple phenomenon on the basis of the biochemistry of the C-signaling system, whereby individuals signal by direct cell contact. The model quantitatively reproduces all of the experimental observations and illustrates how intracellular dynamics, contact-mediated intercellular communication, and cell motility can coordinate to produce collective behavior. This pattern of waves is qualitatively different from that observed in other social organisms, especially Dictyostelium discoideum, which depend on diffusible morphogens.

Models, Biological↗
PubMed2005

Constrained geometric simulation of diffusive motion in proteins.

We describe a new computational method, FRODA (framework rigidity optimized dynamic algorithm), for exploring the internal mobility of proteins. The rigid regions in the protein are first determined, and then replaced by ghost templates which are used to guide the movements of the atoms in the protein. Using random moves, the available conformational phase space of a 100 residue protein can be well explored in approximately 10-100 min of computer time using a single processor. All of the covalent, hydrophobic and hydrogen bond constraints are maintained, and van der Waals overlaps are avoided, throughout the simulation. We illustrate the results of a FRODA simulation on barnase, and show that good agreement is obtained with nuclear magnetic resonance experiments. We additionally show how FRODA can be used to find a pathway from one conformation to another. This directed dynamics is illustrated with the protein dihydrofolate reductase.

Algorithms↗
PubMed2006

Calculation of total effective dose equivalent and collective dose in the event of a LOCA in Bushehr Nuclear Power Plant.

In this research, total effective dose equivalent (TEDE) and collective dose (CD) are calculated for the most adverse potential accident in Bushehr Nuclear Power Plant from the viewpoint of radionuclides release to the environment. Calculations are performed using a Gaussian diffusion model and a slightly modified version of AIREM computer code to adopt for conditions in Bushehr. The results are comparable with the final safety analysis report which used DOZAM code. Results of our calculations show no excessive dose in populated regions. Maximum TEDE is determined to be in the WSW direction. CD in the area around the nuclear power plant by a distance of 30 km (138 man Sv) is far below the accepted limits. Thyroid equivalent dose is also calculated for the WSW direction (maximum 25.6 mSv) and is below the limits at various distances from the reactor stack.

Air Pollutants, Radioactive↗
PubMed2003

Intradermal delivery of antisense oligonucleotides by the pulse depolarization iontophoretic system.

The intradermal delivery of an antisense oligonucleotide was examined by iontophoresis. In this experiment, the antisense sequence of [(32)P]-labeled phosphodiester oligonucleotide ([(32)P]D-oligo, 18-mer) hybridizing to mouse interleukin 10 (IL-10) mRNA was used as a model D-oligo. In in vitro iontophoretic experiments, isolated hairless mouse skin was used with a horizontal diffusion cell. The enhancing effect of pulse depolarization (PDP) iontophoresis on the [(32)P]D-oligo permeation through the skin was better, and the skin irritation was less, than those of constant direct current (CDC) iontophoresis. The apparent fluxes of [(32)P]D-oligo were enhanced with the increasing current densities and [(32)P]D-oligo concentrations in the donor solution, whereas the enhanced flux decreased with the increasing NaCl concentrations in the donor solution. An optimum electric current was observed for the intradermal delivery of [(32)P]D-oligo, and intact [(32)P]D-oligo was detected within the skin after iontophoresis for 6 h. These results suggest that PDP iontophoresis may be useful for the intradermal delivery of antisense oligonucleotides.

Animals↗
PubMed1992

Transport of salicylic acid through monolayers of a kidney epithelial cell line (LLC-PK1).

LLC-PK1 cells were used as a model of renal proximal epithelium to study the nonionic diffusion of salicylic acid (SAL). The apparent [14C]SAL transcellular permeability (PSal) and intracellular content were estimated at 20-21 degrees C from fluxes measured across cell monolayers grown on filters, in both apical-to-basolateral and basolateral-to-apical directions. The medium pH of the cis-side was varied from 6.0 to 7.4, and the medium pH of the trans-side was kept at 7.4. In the apical-to-basolateral direction, PSal increased linearly with the calculated concentration of nonionized SAL, indicating that SAL permeability was essentially the result of nonionic diffusion. In the basolateral-to-apical direction, PSal was about 2.5-fold higher than in the apical-to-basolateral direction and was not linearly related to the concentration of nonionized SAL molecules (0-4.5 nM), suggesting that besides nonionic diffusion, SAL was transported in its ionized form by a facilitated mechanism still active at 21 degrees C. This was confirmed by measuring basolateral-to-apical fluxes at 37 degrees C and observing that probenecid, an inhibitor of organic anion secretion, and cold SAL decreased PSal. Interestingly, at 37 degrees C, PSal in the apical-to-basolateral direction was also decreased by probenecid and cold SAL, suggesting the existence of a facilitated transport in this direction. These data demonstrated that the secretory transport of SAL is present in LLC-PK1 cells. The facilitated transport observed in the apical-to-basolateral direction suggests that in proximal tubule, SAL reabsorption might occur by facilitated mechanism and nonionic diffusion.

Biological Transport↗
PubMed1999

Theoretical examination of electroosmosis control with external radial electric field in capillary electrophoresis.

The influence of an external radial electric field (E(R)) on electroosmosis in capillary electrophoresis was studied theoretically. Based on a Stern-like model, three basic equations were deduced, with only two unknown parameters of delta and psi(d) where delta is the distance between the flowing shear interface and the tube wall, while psi(d) is the potential at the starting point of diffuse layer. The new equations reveal that, to effectively regulate the electroosmosis at E(R) <3 x 10(8) V/m, buffer pH should be kept below 5. In a common case of E(R) <10(8) V/m, the buffer pH should be below 4, otherwise the flow direction of the electroosmosis cannot be reversed. A way to increase the working pH range lies in the use of chemically coated rather than bare tubes. As expected, small capillaries and low ionic strength are preferred.

Electrochemistry↗
PubMed1995

Influence of microvascular architecture on oxygen exchange in skeletal muscle.

The normal function of skeletal muscle requires that a continuous supply of oxygen be provided by the cardiovascular system. This article reviews the development of our understanding of the role of microvascular architecture on the oxygen transport system, with emphasis on direct microcirculatory observations and mathematical modeling dating from the work of August Krogh to present studies. The contributions of the various elements of the vascular network (i.e., arterioles, capillaries, and venules) and microvascular hemodynamics to oxygen exchange are discussed. Oxygen moves through the microvascular network by convection, almost all of it being reversibly bound to the hemoglobin within red blood cells. Thus, the flow properties and distribution of the red cells within the network can play a significant role in oxygen transport. Because the walls of all the vessels in the microcirculation appear to be permeable to oxygen, it continuously diffuses between the blood and the interstitium, the direction depending on the oxygen partial pressure difference. Because of the high permeability of the vascular wall to oxygen, the complex spatial relationships among the various microvessels lead to correspondingly complex diffusive interactions among them. The proximity of capillaries, arterioles, and venules, along with the anastomotic connections and tortuosity of capillaries, provides the "complex spatial relationships" that lead to diffusive interactions between neighboring capillaries, between capillaries and nearby arterioles and venules, and between paired arterioles and venules. Although there are a number of outstanding problems regarding our understanding of oxygen transport at the microcirculatory level, the most interesting and significant of these has to do with the adjustments that are made in the transition from the resting state to that of sustained aerobic exercise.

Animals↗
PubMed2003

On the analysis of protein self-association by sedimentation velocity analytical ultracentrifugation.

Analytical ultracentrifugation is one of the classical techniques for the study of protein interactions and protein self-association. Recent instrumental and computational developments have significantly enhanced this methodology. In this paper, new tools for the analysis of protein self-association by sedimentation velocity are developed, their statistical properties are examined, and considerations for optimal experimental design are discussed. A traditional strategy is the analysis of the isotherm of weight-average sedimentation coefficients s(w) as a function of protein concentration. From theoretical considerations, it is shown that integration of any differential sedimentation coefficient distribution c(s), ls-g(*)(s), or g(s(*)) can give a thermodynamically well-defined isotherm, as long as it provides a good model for the sedimentation profiles. To test this condition for the g(s(*)) distribution, a back-transform into the original data space is proposed. Deconvoluting diffusion in the sedimentation coefficient distribution c(s) can be advantageous to identify species that do not participate in the association. Because of the large number of scans that can be analyzed in the c(s) approach, its s(w) values are very precise and allow extension of the isotherm to very low concentrations. For all differential sedimentation coefficients, corrections are derived for the slowing of the sedimentation boundaries caused by radial dilution. As an alternative to the interpretation of the isotherm of the weight-average s value, direct global modeling of several sedimentation experiments with Lamm equation solutions was studied. For this purpose, a new software SEDPHAT is introduced, allowing the global analysis of several sedimentation velocity and equilibrium experiments. In this approach, information from the shape of the sedimentation profiles is exploited, which permits the identification of the association scheme and requires fewer experiments to precisely characterize the association. Further, under suitable conditions, fractions of incompetent material that are not part of the reversible equilibrium can be detected.

Algorithms↗
PubMed1993

Diffusion patterns on domains representing developing Xenopus retina.

The retinotectal map of mature Xenopus frogs has linear metrics. The regions of the Xenopus retina were modeled during embryonic and early larval development with a set of standard geometrical shapes. A disk was used to model the entire early retina, rings of various thickness were used to model the ciliary margin (the growth zone of the larval retina), and portions of a sphere were used to model the entire late embryonic and larval retina. Gradients produced by several reaction-diffusion pattern-generating configurations were considered: Gierer-Meinhardt and Kauffman-type activator-inhibitor systems; an ideal Turing-like two morphogen system; a point source with diffuse sinks; and variously placed point source-point sink combinations. A few special arrangements produced linear metrics: a point source-point sink system produced linear angular metrics on a thin ring; and ideal Turing system produced linear cartesian metrics on a thin ring; and carefully configured multiple sources and sinks produced linear metrics on a disk. These cases could lead to linear map metrics, but are biologically implausible. Thus linear map metrics are probably not a direct consequence of linear positional values, and more generally, most embryonic tissues probably use non-linear gradients of positional information. Formation of linear map metrics may be functionally important for Xenopus frogs, accounting in part for the evolutionary preservation of mechanisms for interactions among neighboring retinal fibers.

Animals↗