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At least 235 records · Page 13Linked to original sources
PubMed2003

Quantitative model demonstrating that recombinant adeno-associated virus and green fluorescent protein are non-toxic to the rat retina.

BACKGROUND: Recombinant adeno-associated virus (rAAV) is one of the most promising recombinant viral vectors for delivering therapeutic agents to the retina. The present study aims to quantify any effect that an rAAV construct may have on the retina. To be able to use rAAV for therapeutic purposes, the potentially toxic effect of the vector and an associated green fluorescent protein (gfp) marker has to be investigated. METHODS: By combining histological analysis with computer scanning techniques, the local toxicity of rAAV and gfp can be measured. This will have obvious implications for its role as a carrier in the rapidly developing world of gene therapy. RESULTS: It is shown that a construct consisting of rAAV and gfp, delivered subretinally to rat eyes, causes no more histological damage than injection with saline alone. Furthermore, via fluorescent fundus photography and computer scanning techniques it is seen that the area exposed to the rAAV-gfp construct is significantly greater than the area of histological change. CONCLUSIONS: It is thus concluded that the rAAV-gfp construct has no significant toxic effect, at an anatomical level, on the retina 12 months after injection.

Animals↗
PubMed2001

A quantitative model for membrane fusion based on low-energy intermediates.

The energetics of a fusion pathway is considered, starting from the contact site where two apposed membranes each locally protrude (as "nipples") toward each other. The equilibrium distance between the tips of the two nipples is determined by a balance of physical forces: repulsion caused by hydration and attraction generated by fusion proteins. The energy to create the initial stalk, caused by bending of cis monolayer leaflets, is much less when the stalk forms between nipples rather than parallel flat membranes. The stalk cannot, however, expand by bending deformations alone, because this would necessitate the creation of a hydrophobic void of prohibitively high energy. But small movements of the lipids out of the plane of their monolayers allow transformation of the stalk into a modified stalk. This intermediate, not previously considered, is a low-energy structure that can reconfigure into a fusion pore via an additional intermediate, the prepore. The lipids of this latter structure are oriented as in a fusion pore, but the bilayer is locally compressed. All membrane rearrangements occur in a discrete local region without creation of an extended hemifusion diaphragm. Importantly, all steps of the proposed pathway are energetically feasible.

Membrane Fusion↗
PubMedDate not supplied

Mineral particles in bronchoalveolar lavage fluid (BALF): an attempt at designing a quantitative model.

The author examined by morphology, chemical composition, and crystalline structure, approximately 2 500 mineral particles from bronchoalveolar lavage fluids obtained from 25 residents of Rome. In addition, the author obtained the same structural data for approximately 3000 inhalable particles present in the atmosphere in Rome. The author constructed a model of the concentration and granulometry of the different types of mineral particles in bronchoalveolar lavage fluids, by estimating the clearance times of the different particle classes. The author based the model on the following: (a) data relative to the inhalable particulate to which involved subjects were exposed, (b) updated knowledge about the processes of deposition and retention of the mineral particulate in the human respiratory tract, and (c) the hypothesis that the mineral particle pattern in bronchoalveolar lavage fluid reflects the pattern of particulate in lung parenchyma. Finally, the author compared the model with the particulate pattern observed in the bronchoalveolar lavage fluid samples. Despite some drastic approximations, the model satisfactorily fits the data obtained from the experimental research on mineral particulate in bronchoalveolar lavage fluid.

Adult↗
PubMed1988

A quantitative model of traffic between plasma membrane and secondary lysosomes: evaluation of inflow, lateral diffusion, and degradation.

We present here a mathematical model that accounts for the various proportions of plasma membrane constituents occurring in the lysosomal membrane of rat fibroblasts (Draye, J.-P., J. Quintart, P. J. Courtoy, and P. Baudhuin. 1987. Eur. J. Biochem. 170: 395-403; Draye, J.-P., P. J. Courtoy, J. Quintart, and P. Baudhuin. 1987. Eur. J. Biochem. 170:405-411). It is based on contents of plasma membrane markers in purified lysosomal preparations, evaluations of their half-life in lysosomes and measurements of areas of lysosomal and plasma membranes by morphometry. In rat fibroblasts, structures labeled by a 2-h uptake of horseradish peroxidase followed by a 16-h chase (i.e., lysosomes) occupy 3% of the cellular volume and their total membrane area corresponds to 30% of the pericellular membrane area. Based on the latter values, the model predicts the rate of inflow and outflow of plasma membrane constituents into lysosomal membrane, provided their rate of degradation is known. Of the bulk of polypeptides iodinated at the cell surface, only 4% reach the lysosomes every hour, where the major part (integral of 83%) is degraded with a half-life in lysosomes of integral to 0.8 h. For specific plasma membrane constituents, this model can further account for differences in the association to the lysosomal membrane by variations in the rate either of lysosomal degradation, of inflow along the pathway from the pericellular membrane to the lysosomes, or of lateral diffusion.

5'-Nucleotidase↗
PubMed1986

A quantitative model for nonrandom generalized transduction, applied to the phage P22-Salmonella typhimurium system.

A mathematical model for nonrandom generalized transduction is proposed and analyzed. The model takes into account the finite number of transducing particle classes for any given marker. The equations for estimation of the distance between markers from contransduction frequency data are derived and standard errors of the estimates are given. The obtained relationships depend significantly on the number of classes of transducing fragments. The model was applied to estimate the number of transducing fragment classes for a given marker in transduction with phage P22 of Salmonella typhimurium. It was found that the literature data on frequencies of contransduction in crosses with mutual substitution of selective and nonselective markers can be rationalized most accurately by assuming that the mean number of classes is equal to 2. An improved method for analysis of cotransduction data is proposed on the basis of our model and the results of calculation. The method relies on solving a set of algebraic equations for cotransduction frequencies of markers located within one phage length. The method allows a relatively precise determination of distances between markers, positions of transducing particle ends and deletion or insertion lengths. The approach is applied to the trp-cysB-pyrF and aroC-hisT-purF-dhuA regions of the Salmonella typhimurium chromosome.

Chromosome Deletion↗
PubMedDate not supplied

The participative method of subject definition as used in the quantitative modelling of hospital laundry services.

The objectives for developing the participative method of subject definition were to gain all the relevant information to a high level of fidelity in the earliest stages of the work and so be able to build a realistic model at reduced labour cost. In order to better integrate the two activities--information acquisition and mathematical modelling--a procedure was devised using the methods of interactive management to facilitate teamwork. This procedure provided the techniques to create suitable working relationships between the two groups, the informants and the modellers, so as to maximize their free and accurate intercommunication, both during the initial definition of the linen service and during the monitoring of the accuracy and reality of the draft models. The objectives of this project were met in that the final model was quickly validated and approved, at a low labour cost.

Computer Simulation↗
PubMed2000

Primacy versus recency in a quantitative model: activity is the critical distinction.

Behavioral and neurobiological evidence shows that primacy and recency are subserved by memory systems for intermediate- and short-term memory, respectively. A widely accepted explanation of recency is that in short-term memory, new learning overwrites old learning. Primacy is not as well understood, but many hypotheses contend that initial items are better encoded into long-term memory because they have had more opportunity to be rehearsed. A simple, biologically motivated neural network model supports an alternative hypothesis of the distinct processing requirements for primacy and recency given single-trial learning without rehearsal. Simulations of the model exhibit either primacy or recency, but not both simultaneously. The incompatibility of primacy and recency clarifies possible reasons for two neurologically distinct systems. Inhibition, and its control of activity, determines those list items that are acquired and retained. Activity levels that are too low do not provide sufficient connections for learning to occur, while higher activity diminishes capacity. High recurrent inhibition, and progressively diminishing activity, allows acquisition and retention of early items, while later items are never acquired. Conversely, low recurrent inhibition, and the resulting high activity, allows continuous acquisition such that acquisition of later items eventually interferes with the retention of early items.

Animals↗
PubMed2003

Quantitative model of price diffusion and market friction based on trading as a mechanistic random process.

We model trading and price formation in a market under the assumption that order arrival and cancellations are Poisson random processes. This model makes testable predictions for the most basic properties of markets, such as the diffusion rate of prices (which is the standard measure of financial risk) and the spread and price impact functions (which are the main determinants of transaction cost). Guided by dimensional analysis, simulation, and mean-field theory, we find scaling relations in terms of order flow rates. We show that even under completely random order flow the need to store supply and demand to facilitate trading induces anomalous diffusion and temporal structure in prices.

Journal Article↗
PubMed1983

Nitrogen Redistribution during Grain Growth in Wheat (Triticum aestivum L.) : IV. Development of a Quantitative Model of the Translocation of Nitrogen to the Grain.

Translocation of nitrogen was measured in wheat (Triticum aestivium L. cv SUN 9E) plants grown without an exogenous supply of nitrogen from the time that the flagleaf began to emerge, and a model of nitrogen translocation was constructed to describe translocation on one day during the linear period of grain growth. Nitrogen for grain development was derived entirely by the redistribution of nitrogen from vegetative organs. Leaves contributed 40%, glumes 23%, stem 23%, and roots 16% of the nitrogen incorporated by the grains on the fifteenth day after anthesis. Less than 50% of the nitrogen exported from leaves was translocated directly to the grain via the phloem, the rest was translocated to the roots and was cycled in the roots and exported to the shoot in the transpiration stream. Nitrogen imported by leaves and glumes via the xylem was not accumulated in these organs but was transferred to the phloem for reexport from the organs. A large proportion (60%) of the nitrogen in the transpiration stream was cycled in the glumes. The glumes were also a major source of nitrogen for grain development. It was considered likely that this organ always plays an important role in nitrogen metabolism in wheat.

Journal Article↗
PubMed1997

Calcium ion current from an extracellular electrolyte toward a channel opening in an insulating membrane: quantitative model with rotational symmetry.

A mathematical model of three-dimensional (3-D) ion transport is formulated in an approximation assuming rotational symmetry. The model consists of three particle-conservation equations for sodium, calcium, and chlorine ions complemented with the Poisson equation. The numerical method of solution is based on the Gummel-Scharfetter semianalytical approach, the program is written in FORTRAN and the system of discrete equations is solved explicitly in the axial direction and by iterations in the radial direction. The present report deals with calcium flux toward a channel opening in an insulating impermeable membrane, assuming depolarization to zero potential. The initial homogeneous concentrations of sodium, calcium, and chlorine ions are 8.729 x 10(19), 6.02 x 10(17), and 8.849 x 10(19) (cm-3), respectively, corresponding to molar concentrations of 145-mM NaCl and 1-mM of CaCl2; the calcium concentration in the circle representing the channel entry is set at 0.1 microM, corresponding approximately to the concentration of free calcium ions in the cytoplasm. The calculations were carried out up to 3 microseconds. The calcium flux caused a perturbation of quasi-neutrality and the formation of a space charge, which reached the maximum value (i.e., maximum in absolute value) of -0.2 Ccm-3 at the channel entry; the corresponding maximum of the axial component of the electric field was about 1 kV/cm. The maximum value of the calcium current was 0.362 pA, decreasing to 0.283 pA at 3 microseconds. A review of several experimental studies of calcium currents yielded the average current values for higher and lower conductance channels (mainly L- and T-type) 0.76 and 0.42 pA, respectively. This implies that, at Ca++ concentrations of 1 mM or lower the calcium ion current may be limited by the ion influx from an extracellular medium.

Animals↗
PubMed2000

Stereoselectivity of Pseudomonas cepacia lipase toward secondary alcohols: a quantitative model.

The lipase from Pseudomonas cepacia represents a widely applied catalyst for highly enantioselective resolution of chiral secondary alcohols. While its stereopreference is determined predominantly by the substrate structure, stereoselectivity depends on atomic details of interactions between substrate and lipase. Thirty secondary alcohols with published E values using P. cepacia lipase in hydrolysis or esterification reactions were selected, and models of their octanoic acid esters were docked to the open conformation of P. cepacia lipase. The two enantiomers of 27 substrates bound preferentially in either of two binding modes: the fast-reacting enantiomer in a productive mode and the slow-reacting enantiomer in a nonproductive mode. Nonproductive mode of fast-reacting enantiomers was prohibited by repulsive interactions. For the slow-reacting enantiomers in the productive binding mode, the substrate pushes the active site histidine away from its proper orientation, and the distance d(H(N epsilon) - O(alc)) between the histidine side chain and the alcohol oxygen increases, d(H(N epsilon) - O(alc)) was correlated to experimentally observed enantioselectivity: in substrates for which P. cepacia lipase has high enantioselectivity (E > 100), d(H(N epsilon) - O(alc)) is >2.2 A for slow-reacting enantiomers, thus preventing efficient catalysis of this enantiomer. In substrates of low enantioselectivity (E < 20), the distance d(H(N epsilon) - O(alc)) is less than 2.0 A, and slow- and fast-reacting enantiomers are catalyzed at similar rates. For substrates of medium enantioselectivity (20 < E < 100), d(H(N epsilon) - O(alc)) is around 2.1 A. This simple model can be applied to predict enantioselectivity of P. cepacia lipase toward a broad range of secondary alcohols.

Alcohols↗
PubMed1997

Iontophoretic delivery of ALA provides a quantitative model for ALA pharmacokinetics and PpIX phototoxicity in human skin.

Photodynamic therapy (PDT) with topical 5-aminolevulinic acid (ALA) is increasingly employed for skin cancer, yet ALA dosing is crude. Using iontophoresis, we developed a rapid and quantifiable system for topical ALA delivery, with measurement of subsequent PpIX fluorescence and phototoxicity. ALA was iontophoresed from a 2% solution into upper inner arm skin of 13 healthy volunteers. Six doses of ALA were delivered with a series of charges varying from 3-120 milliCoulombs (mC); four additional doses were given with a charge of 60 mC. Five hours post-iontophoresis, sites were irradiated with broad-band yellow-red light, the series of six ALA doses receiving 100 J/cm2, while the four identical doses received 6.25, 12.5, 25, and 50 J/cm2, respectively. Resultant erythema was measured by reflectance spectroscopy. The time course of PpIX fluorescence was ALA-dose-dependent. With charge < or = 24 mC, PpIX fluorescence peaked at 3 h and returned to zero at 9-10 h, whereas charges > 24 mC had a sustained peak at 5-10 h, falling to zero by 24 h. Pre-irradiation, PpIX fluorescence correlated with ALA dose (r = 1.0). PpIX fluorescence fell immediately post-irradiation (p < 0.0001); recovery levels at 3 h correlated with ALA dose (p < 0.0001). Delayed erythema correlated with ALA dose and irradiation dose (p < 0.0001, p < 0.01, respectively). Both PpIX fluorescence intensity pre-irradiation and fall in PpIX fluorescence post-irradiation correlated with erythema (r = 0.98). Hence, PpIX synthesis is ALA-dose-dependent, and phototoxicity can be predicted from ALA dose, irradiation dose, and photobleaching of PpIX. This reproducible system allows accurate dosimetry in topical PDT and facilitates study of ALA metabolism.

Adult↗