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The purpose of this study is to develop a formulation for a once-a-day peroral application with controlled release of nitrendipine. The second aim of the study is to define by the use of modelling and computer simulation those critical points in the development of the formulation, the knowledge and controlling of which brings a rationalisation in the sense of time and material.
A molecular model for the control of plasmid R1 replication has been proposed by Nordström, Molin and Light (Plasmid 12, 71-90, 1984), involving three genes: repA, copA, copB. RepA codes for a polypeptide whose synthesis is required for initiation; replication is controlled by regulating this synthesis. CopA encodes a small, unstable, untranslated RNA molecule that inhibits translation of the repA message whereas copB produces a protein that inhibits transcription from the repA promoter. We have recast this model into precise mathematical terms and tested it by computer simulation of a synchronous culture in steady-state balanced growth, composed of individual Escherichia coli cells harboring the small, unstable derivative, mini-R1. All single-cell steady-state distributions obtained are independent of initial conditions, and the average values of various plasmid-related variables are similar to those measured experimentally. The relationship between the number of replication events per cell and the copy number at birth, as predicted by the model, mitigates against a sensitive correction mechanism for cells born with other than average copy number and is much closer quantitatively to a nonresponse system, although there is a weak dependence on copy number. The effect of the convergent transcription initiated at the repA and copB promoters on the expression of the copA gene is found to contribute little to the stability of mini-R1 replicons under steady-state growth conditions or to their potential for survival following infection. In fact, the role of the entire CopB control loop is shown to be quite minor, both in steady state and after infection. It is pointed out that genetic manipulations are far more easily performed in silico than in vivo but that results of the kind presented here are very often possible only when simulating individual cells.
Research has shown that smoking reduces mood fluctuation in smokers and deprivation of smoking leads to mood change. The purpose of this study was to assess the effects of three hours of deprivation and subsequent smoking on mood in smokers while operating a computer simulation of an air traffic controller's job in a 2 x 2 (Deprived vs. Nondeprived x Nicotine vs. Nicotine Free Cigarettes) factorial design. Subjects operated the simulation for two 20 minute periods, and after each period subjects smoked a nicotine or nicotine-free cigarette. Mood was assessed prior to operating the simulation and before and after each cigarette was smoked. Contrary to predictions, mood generally changed as a function of the procedure and not deprivation status or type of cigarette smoked.
A minimal mechanism is proposed which describes the transcriptional and translational processes for four phage proteins (RNA polymerase, DNase, primase and DNA polymerase) involved in T3/T7 DNA replication. Phage DNA replication is also included. It is shown how lag times may be incorporated into a kinetic mechanism. The distinct three-stage transport of phage DNA into the bacterial host (E. coli) is considered. DNA transport is assumed to be rate-determining for the transcription of class I and II proteins. Transcriptional and translational lag times have been calculated on the basis of available gene mapping of T7 phages. The kinetic behavior of T7 and T3 phage infection is practically identical. The hydrolysis of bacterial DNA by phage DNase (endonculease and exonuclease) as well as the subsequent phosphorylation to the deoxymononucleoside triphosphates are assumed to be rate-determining in phage DNA replication. Good agreement with experiment is obtained in our computer simulations.
A new interpretation of existing data permits us to define a model capable of accounting for agonist-induced Ca2+ oscillations in the cytosol of electrically non-excitable cells. The model only requires one Ca2+ store, which contains Ca2+ channels controlled by inositol 1,4,5-trisphosphate and Ca2+. Computer simulations may generate different experimentally observed patterns of Ca2+ oscillations.
A series of computer simulations of gel patterns assuming non-cooperative binding of a protein to two targets on the same DNA fragment was performed and applied to interprete gel mobility shift experiments of Tet repressor-tet operator binding. While a high binding affinity leads to the expected distribution of free DNA, DNA bound by one repressor dimer and DNA bound by two repressor dimers, a lower affinity or an increased electrophoresis time results in the loss of the band corresponding to the singly occupied complex. The doubly occupied complex remains stable under these conditions. This phenomenon is typical for protein binding to DNA fragments with two identical sites. It results from statistical disproportionation of the singly occupied complex in the gel. The lack of the singly occupied complex is commonly taken to indicate cooperative binding, however, our analysis shows clearly, that cooperativity is not needed to interprete these results. Tet repressor proteins and small DNA fragments with two tet operator sites have been prepared from four classes of tetracycline resistance determinants. The results of gel mobility shift analyses of various complexes of these compounds confirm the predictions. Furthermore, calculated gel patterns assuming different gel mobilities of the two singly occupied complexes show discrete bands only if the electrophoresis time is shorter than the inverse of the microscopic dissociation rate constant. Simulations assuming increasing dissociation rates predict that the two bands first merge into one, which then disappears. This behavior was verified by gel mobility analyses of Tet repressor-tet operator titrations at increased salt concentrations as well as by direct footprinting of the complexes in the gel. It is concluded that comparison of the intensities of the single and the double occupation bands allow a rough estimation of the dissociation rate constant. On this basis the sixteen possible Tet repressor-tet operator combinations can be ordered with decreasing binding affinities by a simple gel shift experiment. The implications of these results for gel mobility analyses of other protein-DNA complexes are discussed.
Computer simulation models have been developed to investigate the effect of intravenous infusions of nutritive amino acid solutions metal equilibria in plasma. The distribution of Ca(II), Mg(II), Zn(II), Cu(II), and Mn(II) among the ligands in the nutritive fluid is calculated and used to estimate the amounts of each metal that should be included in future preparations.
Any investigation of the total number of neurons in a given brain region must first address the following questions. What is the best method for estimating the total number of neurons? What are the validity and the expected precision of the obtained data? What precision must the estimates attain with respect to the scientific question? In the present study, these questions were addressed using a computer simulation. Virtual brain regions with various spatial distributions of virtual neurons were modeled. The total numbers of virtual neurons in the modeled brain regions were repeatedly estimated by simulation of modern design-based stereology, either by using the 'fractionator' method or by the established method based on the product of estimated neuron density and estimated volume of the reference space. We show that estimates of total numbers of neurons obtained using the fractionator are from a statistical and economical standpoint more efficient than corresponding estimates obtained using the density/volume procedure. Furthermore, the use of two simple prediction methods (one for homogeneous and the other for clustered neuron distributions) permits satisfactory predictions about the variation of presumably any estimates of total numbers of neurons obtained using the fractionator. Finally, we show that assessing the reliability of estimates of mean total neuronal numbers using the ratio between the mean of the squared coefficients of error of the estimates and the squared coefficient of variation of the estimated total neuronal numbers, a frequently employed method in stereological studies, is neither useful nor informative. The present results may constitute a new set of recommendations for the rigorous usage of design-based stereology. In particular, we strongly recommend counting considerably more neurons than is currently done in the literature when estimating total neuronal numbers using design-based stereology.
To investigate the particle migration effects and fluid-particle interaction occurring in the flow of highly concentrated fluid-particle suspensions, a numerical method has been developed for effective computer simulation in arbitrary axisymmetric geometries. In the mathematical flow model the suspension is treated as a generalized Newtonian fluid where the effective flow properties of the suspension (density and viscosity) are determined by the local volume fraction of the particles. The description of the particle motion is governed by a modified transport equation with diffusion coefficients accounting for the effects of shear-induced particle migrations. The strongly coupled system of flow and transport equations is solved by applying the Galerkin finite element method and a velocity-pressure projection scheme. The numerical results in tube flow demonstrate strong particle migration towards the center of the tube and an increasing blunting of the velocity profiles which is in good agreement with an available analytical solution. In the case of flow through a stenosed tube model, particle concentration is lowest at the site of maximum constriction whereas a strong accumulation of particles can be seen in the recirculation zone downstream of the stenosis.
Essential hypertension is probably caused by combinations of small quantitative changes in the expression of many genes together with environmental factors. In this article, strategies for studying hypertension using animal models are summarized with emphasis on the combined use of mouse models and computer simulations. We have chosen the rennin-angiotensin system as our main example. Future directions of hypertension research using gene targeting are also discussed.
/ Evaluating the environmental and economic impacts of agricultural policies is not a simple task. A systematic approach to evaluation would include the effect of policy-dependent factors (such as tillage practices, crop rotations, and chemical use) as well as the effect of policy-independent covariates (such as weather, topography, and soil attributes) on response variables (such as amount of soil eroded or chemical leached into the groundwater). For comparison purposes, the effects of these input combinations on the response variable would have to be assessed under competing policy scenarios. Because the number of input combinations is high in most problems, and because policies to be evaluated are often not in use at the time of the study, practitioners have resorted to simulation experiments to generate data. However, generating data from simulation models is often costly and time consuming; thus, the number of input combinations in a study may be limiting even in simulation experiments. In this paper, we discuss the problem of designing computer simulation experiments that require generating data for just a fraction of the possible input combinations. We propose an approach that is based on subsampling the 1992 National Resources Inventory (NRI) points. We illustrate the procedure by assessing soil erosion in a situation where there are "observed" data [reported by the Natural Resources Conservation Service (NRCS)] for comparison. Estimates for soil erosion obtained using the procedure we propose are in good agreement with NRCS reported values.KEY WORDS: Metamodel; National Resources Inventory; Nonpoint source pollution
Intermediary metabolism in rat hearts perfused with 11 mM glucose plus 1 mM palmitate was simulated by a computer model. Several enzyme submodels in a previous version of the isolated rat heart computer model were improved, and a new fatty acid oxidation pathway model was added. Compartmentation of metabolites in a pseudo-stationary state was calculated, and its implications are discussed, e.g., citrate level may not regulate glycolysis because it is mostly mitochondrial. Citrate synthetase, controlled largely by its inhibitors, is of key importance in regulating fatty acid metabolism. The response of aconitase to the mitochondrial Mg2+ level is of major importance in setting both the mitochondrial citrate and isocitrate levels. Pyruvate dehydrogenase is about 96% in the inactive phosphorylated form, and the active form is also 15% inhibited by products, severely limiting pyruvate oxidation and causing preferential utilization of palmitate as the metabolic fuel. The simulation is consistent with a creatine phosphate shuttle which delivers high energy phosphate to the site of its utilization for mechanical work.
According to a classical, antigen-driven view of the immune system, autoimmunity is due to the presence of self-reactive lymphocyte clones which have not been eliminated. However, computer simulations of the immune network show that the greater the degree of connectivity of a clone, the greater its degree of tolerance to chronic antigenic stimulation. This tolerance does not correspond to an absence of response on the part of the system as a whole. On the contrary, stimulation by a 'tolerogenic antigen' results in widespread modification and overall activation of the whole network. This suggests that on an autopoietic network view of the immune system, autoimmunity arises not because of the presence of self-reactive clones, which is completely normal, but because such clones are inadequately connected to the network. This amounts to a complete reversal in perspective, whose significance for the clinical treatment of autoimmunity and the future of immunology is discussed.
It is known that macroscopic properties of colloidal suspensions are often determined by the microstructure of the particles in the suspensions, depending on the interparticle, Brownian, and hydrodynamic (if any) forces. We take electrorheological (ER) fluids as an example. By using a computer simulation and an experimental approach, we investigate the structure of ER fluids subjected to both an electric field and a shear flow. The microstructure evolution from random structure, to chains, and then to stable lamellar patterns, observed in the experiments, agrees very well with that obtained in the simulations. It is shown that the formation of such lamellar patterns originates from the difference between the dipole moment induced in the particles suspended in the ER fluids without shear and the one with shear. The results on the relaxation process of structural formation and the internal structure of layers are also presented. Thus, it seems possible to achieve various structures and hence desired macroscopic properties of colloidal suspensions by adjusting external fields and, simultaneously, a shear flow.
The speciation and distribution of Zn(II) and the effect of Gd(III) on Zn(II) speciation in human blood plasma were studied by computer simulation. The results show that, in normal blood plasma, the most predominant species of Zn(II) are [Zn(HSA)] (58.2%), [Zn(IgG)](20.1%), [Zn(Tf)] (10.4%), ternary complexes of [Zn(Cit)(Cys)] (6.6%) and of [Zn(Cys)(His)H] (1.6%), and the binary complex of [Zn(Cys)2H] (1.2%). When zinc is deficient, the distribution of Zn(II) species is similar to that in normal blood plasma. Then, the distribution changes with increasing zinc(II) total concentration. Overloading Zn(II) is initially mainly bound to human serum albumin (HSA). As the available amount of HSA is exceeded, phosphate metal and carbonate metal species are established. Gd(III) entering human blood plasma predominantly competes for phosphate and carbonate to form precipitate species. However, Zn(II) complexes with phosphate and carbonate are negligible in normal blood plasma, so Gd(III) only have a little effect on zinc(II) species in human blood plasma at a concentration above 1.0 x 10(-4) M.
In some angiographic methods for measurement of mean coronary flow in ml/min, a threshold is applied to 'concentration-distance' curves obtained from a constant rate injection by computing the intravascular contrast medium concentration along the main coronary branches. If the shape of the velocity profile would remain parabolic throughout the cardiac cycle, the correct threshold value would be '50% of the concentration at the injection site'. But, coronary flow being strongly pulsatile, the shape of the velocity profile must be expected to vary appreciably within the cardiac phase. In order to investigate if a single, appropriate threshold value nevertheless exists for a great variety of coronary flow pulses and velocity profiles, the spreading of contrast medium injected continuously in a tube perfused by a time varying flow Q(t) was studied by computer simulation. While the particular time courses of flow and velocity profile appear to be of secondary importance, the ratio 'injection rate to peak coronary flow' has a major impact. If it is equal to or greater than 1, a threshold value of 47% is the best choice. If the ratio is markedly less than 1, no appropriate threshold exists and use of the 47% threshold will result in considerable flow underestimations. This was fully confirmed by measurements of absolute coronary flow performed in patients.
Parallel investigations were done using the reticular formation of the lower brainstem of dogs and computer simulated neuronal networks with properties of reticular neurones. By the aid of the simulations, understanding of the functional organisation of the common brainstem system, reticular formation and the experiments performed were optimized. The fact that discharge sequences of model neurones are very similar to those of reticular neurones was proved by interval histograms and covariance histograms. Discharges of neighbouring reticular neurones tend to be strongly coupled. In the model the discharges of the neurones could be coupled by common afferent inflows. Physiologically, neighbouring reticular neurones receive common afferents from peripheral somato-sensory systems. Neighbouring neurones with strongly coupled discharging are organized in subpopulations. The configurations of the subpopulations are determined by number and type of afferents actively influencing neurones and by the level of intrinsic activity of the network. Signal processing and transfer by neuronal subpopulations depend on the level of activity and on the degree of coupled discharging, i.e. the local organisation of the neurones.
OBJECTIVE: To compare the cost effectiveness of two possible modifications to the current UK screening programme: shortening the screening interval from three to two years and extending the age of invitation to a final screen from 64 to 69. DESIGN: Computer simulation model which first simulates life histories for women in the absence of a screening programme for breast cancer and then assesses how these life histories would be changed by introducing different screening policies. The model was informed by screening and cost data from the NHS breast screening programme. SETTING: North West region of England. MAIN OUTCOME MEASURES: Numbers of deaths prevented, life years gained, and costs. RESULTS: Compared with the current breast screening programme both modifications would increase the number of deaths prevented and the number of life years saved. The current screening policy costs 2522 pounds per life year gained; extending the age range of the programme would cost 2612 pounds and shortening the interval 2709 pounds per life year gained. The marginal cost per life year gained of extending the age range of the screening programme is 2990 pounds and of shortening the screening interval is 3545 pounds. CONCLUSIONS: If the budget for the NHS breast screening programme were to allow for two more invitations per woman, substantial mortality reductions would follow from extending the age range screened or reducing the screening interval. The difference between the two policies is so small that either could be chosen.