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PubMed2001

Evolutionary optimization of metabolic pathways. Theoretical reconstruction of the stoichiometry of ATP and NADH producing systems.

The structural design of ATP and NADH producing systems, such as glycolysis and the citric acid cycle (TCA), is analysed using optimization principles. It is assumed that these pathways combined with oxidative phosphorylation have reached, during their evolution, a high efficiency with respect to ATP production rates. On the basis of kinetic and thermodynamic principles, conclusions are derived concerning the optimal stoichiometry of such pathways. Extending previous investigations, both the concentrations of adenine nucleotides as well as nicotinamide adenine dinucleotides are considered variable quantities. This implies the consideration of the interaction of an ATP and NADH producing system, an ATP consuming system, a system coupling NADH consumption with ATP production and a system consuming NADH decoupled from ATP production. It is examined in what respect real metabolic pathways can be considered optimal by studying a large number of alternative pathways. The kinetics of the individual reactions are described by linear or bilinear functions of reactant concentrations. In this manner, the steady-state ATP production rate can be calculated for any possible ATP and NADH producing pathway. It is shown that most of the possible pathways result in a very low ATP production rate and that the very efficient pathways share common structural properties. Optimization with respect to the ATP production rate is performed by an evolutionary algorithm. The following results of our analysis are in close correspondence to the real design of glycolysis and the TCA cycle. (1) In all efficient pathways the ATP consuming reactions are located near the beginning. (2) In all efficient pathways NADH producing reactions as well as ATP producing reactions are located near the end. (3) The number of NADH molecules produced by the consumption of one energy-rich molecule (glucose) amounts to four in all efficient pathways. A distance measure and a measure for the internal ordering of reactions are introduced to study differences and similarities in the stoichiometries of metabolic pathways.

Adenosine Triphosphate↗

PubMed1994

Preclinical studies using immobilized OKT3 to activate human T cells for adoptive immunotherapy: optimal conditions for the proliferation and induction of non-MHC-restricted cytotoxicity.

In order to obtain large numbers of T cells for adoptive immunotherapy after bone marrow transplantation (BMT), we optimized conditions for long-term proliferation of T cells that exhibit non-MHC-restricted cytotoxicity using immobilized anti-CD3 (OKT3) activation and culture in IL-2. Proliferation and cytotoxicity directed at Daudi, K562, and B cell lines were used to determine (1) the optimal concentration of IL-2 and the optimal time of exposure to immobilized OKT3 for maintaining growth and cytotoxicity, (2) the starting populations that can be used, (3) the T cell subsets that mediate cytotoxicity, and (4) the optimal medium and concentration of serum for maintaining growth and cytotoxicity. Peripheral blood lymphocytes (PBL) activated with OKT3 would proliferate and mediate cytotoxicity at IL-2 doses as low as 30 IU/ml. Increasing the IL-2 concentrations beyond 600 IU/ml did not augment the proliferative or cytotoxic responses of PBL. A 24-hr incubation on OKT3 was sufficient to activate PBL. Increasing the incubation time on OKT3 from 24 to 72 hr did not significantly enhance cytotoxicity. Comparisons between PBL and purified T cells (E-rosette) indicated that either cell population could be activated with OKT3 in the presence of IL-2 to proliferate and mediate non-MHC-restricted cytotoxicity. Purified populations of CD4+ or CD8+ T cells demonstrated equivalent proliferation and cytotoxicity when activated using IL-2 and OKT3. With equal concentrations of human or fetal bovine serum, RPMI 1640 and X-Vivo 10 were comparable for supporting proliferation and cytotoxicity. These conditions are being used to activate and expand T cells for clinical trials that involve infusing activated T cells into recipients after autologous BMT.

Blood Physiological Phenomena↗

PubMed1997

A mathematical model to determine the optimal number of fragments for comparison of bacterial chromosomic macrorestriction patterns.

To our knowledge, although comparison of chromosomic macrorestriction patterns has become one of the most feasible molecular tools of the current microbial taxonomy, a mathematical approach to optimize the choice of a restriction enzyme among the endonucleases tested for such comparison has not been previously described. The coincidence of restriction patterns for two tested bacterial strains with this chosen endonuclease will ensure a high genetic relatedness between them. We report a mathematical model to determine the probability of hazardously obtaining a particular chromosomic macrorestriction pattern by PFGE and to calculate the optimal number of fragments for its comparison. The model presented allows us to determine the optimal number of fragments in order to compare chromosomic restriction patterns. The model calculates this values as a function of the chromosome size and the restriction site length. The model is not useful for choosing a restriction enzyme previous to experimental steps, but as a tool for the choice of the restriction enzyme that yields the lowest probability of hazardously obtaining coincidences of chromosomic patterns. The applicability of this model has been exemplified by determining the optimal number of fragments for some well-characterized bacteria and by comparing these values with those that have been experimentally used.

Bacteria↗

PubMed1997

Anatomical variability and functional ability of vascular trees modeled by constrained constructive optimization.

The aim of this study was to investigate the extent that functional capability of vascular trees is related to anatomical variability. To these ends we used the method of Constrained Constructive Optimization (CCO) to generate optimized computer models of coronary arterial trees. All these model trees were optimized according to the same principle under equal boundary conditions of pressures and flows. However, by stochastically casting the locations of the terminal segments, different tree structures were generated, each of which conformed to the same boundary conditions. The structural variability of these models was interpreted as the correlate of the anatomical variability found in real arterial trees. The advantage that computer model trees are known in numerical detail was exploited to perform comprehensive and exact classifications of all segments into bifurcation levels, STRAHLER orders and composite vessels, and to compute the area expansion ratio. The unexpected result was that, despite striking visual differences in anatomical structure, the model trees were almost identical with regard to functional performance. We conclude that models optimized on the computer for a given perfusion task show little differences in their morphometric parameters even if they differ considerably regarding the course of the large vessels.

Computer Simulation↗

PubMed2000

Fast, optimal alignment of three sequences using linear gap costs.

Alignment algorithms can be used to infer a relationship between sequences when the true relationship is unknown. Simple alignment algorithms use a cost function that gives a fixed cost to each possible point mutation-mismatch, deletion, insertion. These algorithms tend to find optimal alignments that have many small gaps. It is more biologically plausible to have fewer longer gaps rather than many small gaps in an alignment. To address this issue, linear gap cost algorithms are in common use for aligning biological sequence data. More reliable inferences are obtained by aligning more than two sequences at a time. The obvious dynamic programming algorithm for optimally aligning k sequences of length n runs in O(n(k)) time. This is impractical if k>/=3 and n is of any reasonable length. Thus, for this problem there are many heuristics for aligning k sequences, however, they are not guaranteed to find an optimal alignment. In this paper, we present a new algorithm guaranteed to find the optimal alignment for three sequences using linear gap costs. This gives the same results as the dynamic programming algorithm for three sequences, but typically does so much more quickly. It is particularly fast when the (three-way) edit distance is small. Our algorithm uses a speed-up technique based on Ukkonen's greedy algorithm (Ukkonen, 1983) which he presented for two sequences and simple costs.

Algorithms↗

PubMed2003

Heterogeneous perfusion is a consequence of uniform shear stress in optimized arterial tree models.

Using optimized computer models of arterial trees we demonstrate that flow heterogeneity is a necessary consequence of a uniform shear stress distribution. Model trees are generated and optimized under different modes of boundary conditions. In one mode flow is delivered to the tissue as homogeneously as possible. Although this primary goal can be achieved, resulting shear stresses between blood and the vessel walls show very large spread. In a second mode, models are optimized under the condition of uniform shear stress in all segments which in turn renders flow distribution heterogeneous. Both homogeneous perfusion and uniform shear stress are desirable goals in real arterial trees but each of these goals can only be approached at the expense of the other. While the present paper refers only to optimized models, we assume that this dual relation between the heterogeneities in flow and shear stress may represent a more general principle of vascular systems.

Arteries↗

PubMed1995

Requirements for optimal expression of secreted and nonsecreted recombinant proteins in vaccinia virus systems.

Selection of an optimal promoter is necessary for efficient expression of foreign genes with vaccinia virus. Since a variety of powerful (homologous) vaccinia virus promoters and foreign (heterologous) promoter systems have been described for use in vaccinia, we have addressed the question of whether a general rule exists that allows the prediction of the optimal promoter/gene combination. We have compared the expression properties of four secreted proteins, the human blood clotting factor IX (FIX), the human blood glycoprotein Protein S (ProtS), the human von Willebrand factor (vWF), and the Hepatitis B virus (HBV) middle surface glycoprotein preS2, with proteins that were reported not to be secreted, the HBV large surface glycoprotein preS1 and the murine leukemia virus (MuLV) BM-5 Eco gag protein. In addition, we have included in our study an internal control protein, the vaccinia virus p11 protein, to monitor possible side effects of the promoter system used. Genes encoding the foreign proteins were placed either under control of a synthetic vaccinia virus early/late promoter (selP) or under control of the bacteriophage T7 promoter (T7/emc system). The secreted proteins were more efficiently expressed when fused to the homologous promoter. Direct comparison of the two promoters indicated that the expression level ranged between 1.4 (ProtS) and 3.9 (FIX)-fold higher with the selP than with the T7 promoter. In contrast, the cell-associated HBV preS1 was more efficiently expressed under the T7 promoter and the MuLV BM-5 Eco gag polypeptide was expressed equally well from both promoters. These data indicate that a careful prediction of optimal promoter/foreign gene combinations for the vaccinia virus expression system is possible. The choice of the optimal promoter/expression system is based on a simple classification scheme, discriminating secreted and nonsecreted proteins.

Animals↗

PubMed2001

Systematic optimization of expression and refolding of the Plasmodium falciparum cysteine protease falcipain-2.

The Plasmodium falciparum cysteine protease falcipain-2 is a potential new target for antimalarial chemotherapy. In order to obtain large quantities of active falcipain-2 for biochemical and structural analysis, a systematic assessment of optimal parameters for the expression and refolding of the protease was carried out. High-yield expression was achieved using M15(pREP4) Escherichia coli transformed with the pQE-30 plasmid containing a truncated profalcipain-2 construct. Recombinant falcipain-2 was expressed as inclusion bodies, solubilized, and purified by nickel affinity chromatography. A systematic approach was then used to optimize refolding parameters. This approach utilized 100-fold dilutions of reduced and denatured falcipain-2 into 203 different buffers in a microtiter plate format. Refolding efficiency varied markedly. Optimal refolding was obtained in an alkaline buffer containing glycerol or sucrose and equal concentrations of reduced and oxidized glutathione. After optimization of the expression and refolding protocols and additional purification with anion-exchange chromatography, 12 mg of falcipain-2 was obtained from 5 liters of E. coli, and crystals of the protease were grown. The systematic approach described here allowed the rapid evaluation of a large number of expression and refolding conditions and provided milligram quantities of recombinant falcipain-2.

Animals↗

PubMedDate not supplied

An optimal strategy for recovering the deuterium (2H) quadrupolar interaction under magic-angle spinning NMR.

By exploiting the homology in the form of the truncated high-field homonuclear dipole-dipole and quadrupole coupling Hamiltonians, we have previously demonstrated that a simple adaptation of a rotor-synchronized pulse sequence (DRAMA) used for the recovery of dipole-dipole couplings can also be used to resurrect quadrupole couplings (QUADRAMA). In the canonical implementation of these recovery pulse sequences, the couplings are not significantly scaled down from their static sample values. While such minimal scaling is of course desirable in the recovery of typical homonuclear dipolar couplings (< or =2 kHz) and small quadrupole couplings, it is clearly not ideal for the recovery of the much larger quadrupole couplings (20-200 kHz) often encountered in solid-state 2H NMR. In such a case, some prior knowledge of the order of magnitude of the coupling is required to optimize the experimental conditions for QUADRAMA. In order to overcome this drawback, in this study, we have developed a general and optimized strategy for implementing the QUADRAMA technique which does not require any knowledge of the size of the coupling vQ. Experimental tests of the optimized protocol demonstrate that by judicious choices of a combination of scaling factors and recoupling times, 2H quadrupole couplings ranging over an order of magnitude from 3 to 42 kHz can be measured. Since this optimized protocol can reliably be used to recover couplings over a broad range, it expands the range of systems accessible to study by 2H NMR into a realm where static sample NMR and simple MAS NMR may fail.

Journal Article↗

PubMed1996

Optimal Level of Chemical Defense Decreasing with Leaf Age

A recent study on a biennial plant demonstrated that pyrrolizidine alkaloids decrease with the age of leaves due to reallocation from old leaves to new leaves. Here we study the optimal age-specific pattern of defense chemical concentration in leaves that achieves the maximum growth rate of the plant. We consider a plant growing exponentially in a constant environment. Assumptions are the following: (1) The loss of leaves due to herbivory decreases with defense chemical concentration (2) The daily net photosynthesis of a leaf decreases with its age. (3) Using photosynthetic products, the plant produces new leaves that may contain defense chemicals. (4) Although there is a cost to producing new defense chemicals, such chemicals can be reallocated without cost. In the optimal schedule calculated using Pontryagin's maximum principle, the chemical defense level decreases with leaf age. The optimal level of chemical defense increases with the cost of leaf production and herbivory intensity but decreases with the cost of defense chemical production, effectiveness of the defense chemical, net productivity, and growth rate of the plant. If both generalist and specialist herbivores attack the same plant, the optimal defense level is dependent only on the generalists' abundance and sensitivity, but is independent of the specialists that are unaffected by the defense chemical.

Journal Article↗

PubMed1995

Optimization of dose distribution for LINAC based radiosurgery using elliptical collimators.

The use of non-circular collimators is considered on all or some of the arcs used for radiosurgery on a linear accelerator in order to obtain conformal dose distribution for non-spherical lesions using a single isocenter. An extension of software to allow for use of non-circular collimators and a mathematical optimization based on prescribed doses on the lesion surface and on points in normal tissue (critical structures) are presented. Tests of the optimization method on simulated cases indicate that several boosts from selected positions along the arcs, superimposed on an optimized arc configuration allows one to obtain a highly conformal dose distribution with simple elliptical inserts. The optimization method can be applied to any type of collimation and is particularly effective with variable dose-rate machines.

Brain Neoplasms↗

PubMed1995

The atom assignment problem in automated de novo drug design. 3. Algorithms for optimization of fragment placement onto 3D molecular graphs.

Atom assignment onto 3D molecular graphs is a combinatoric problem in discrete space. If atoms are to be placed efficiently on molecular graphs produced in drug binding sites, the assignment must be optimized. An algorithm, based on simulated annealing, is presented for efficient optimization of fragment placement. Extensive tests of the method have been performed on five ligands taken from the Protein Data Bank. The algorithm is presented with the ligand graph and the electrostatic potential as input. Self placement of molecular fragments was monitored as an objective test. A hydrogen-bond option was also included, to enable the user to highlight specific needs. The algorithm performed well in the optimization, with successful replications. In some cases, a modification was necessary to reduce the tendency to give multiple halogenated structures. This optimization procedure should prove useful for automated de novo drug design.

Adenosine Monophosphate↗

PubMed1991

Optimal pension funding with demographic instability and endogenous returns on investment.

"This paper tries to explore some optimal funding policies for pension systems in a general equilibrium setting where funding affects returns on investment and wages through its impact on capital formation. This is done in the context of irregular demographic evolutions such as those expected in developed countries for the next century. Particular attention is given to the intergenerational welfare criterion which is used for designing optimal policies.... We will first present the model for the pension system and the economy and discuss a general one-parameter form for the intergenerational utility function. We will then present the simulated optimal paths for different numerical specifications of the model and the utility function. The last section will show by how much a simpler policy with fixed transfers and purely individual funding can depart from optimal paths...."

Developed Countries↗

PubMed1986

Optimal harvesting of a logistic population in an environment with stochastic jumps.

Dynamic programming is employed to examine the effects of large, sudden changes in population size on the optimal harvest strategy of an exploited resource population. These changes are either adverse or favorable and are assumed to occur at times of events of a Poisson process. The amplitude of these jumps is assumed to be density independent. In between the jumps the population is assumed to grow logistically. The Bellman equation for the optimal discounted present value is solved numerically and the optimal feedback control computed for the random jump model. The results are compared to the corresponding results for the quasi-deterministic approximation. In addition, the sensitivity of the results to the discount rate, the total jump rate and the quadratic cost factor is investigated. The optimal results are most strongly sensitive to the rate of stochastic jumps and to the quadratic cost factor to a lesser extent when the deterministic bioeconomic parameters are taken from aggregate antarctic pelagic whaling data.

Animals↗

PubMed1983

Optimal control of antagonistic muscles.

Recently, a model for a pair of antagonistic muscles has been studied (Oğuztöreli and Stein, 1982). In the present paper we formulate and investigate the minimization of the costs associated with the time to complete the movement, the oscillation about the endpoint, the energy costs to the muscles to complete the movement, the cost to the nervous system to supply the inputs, and the cost of reliability in the face of perturbing forces. To solve these optimization problems the maximum principle of Pontryagin is employed. In all of these optimization problems, except the energy optimal problem, the optimal controls (active states or nervous inputs) are of the bang-bang type.

Animals↗

PubMed1996

Optimization of use of UEA-1 magnetic beads for endothelial cell isolation.

Most endothelial cells (EC) in the body belong to the microvasculature. Isolation and subsequent culture of these microvessel EC contributes greatly to our understanding of the heterogeneity and vascular specificity that exist between one organ site and another. However, a major obstacle is the overgrowth of contaminating cells (fibroblasts, pericytes, smooth-muscle cells) in cultures. Since 1990 the use of magnetic beads in combination with either a lectin, Ulex europaeus agglutinin-1 (UEA-1), or a monoclonal antibody has represented a powerful tool for the isolation/purification of microvessel EC. In the former case, operative conditions remain to be optimized to obtain pure cultures of EC. We have performed studies to optimize conditions of use for magnetic beads coated with UEA-1. Incubating beads with cells, the influences are studied of time, temperature, cell concentration, and number of beads per target cell for two cell types, human umbilical vein EC (HUVEC) and skin fibroblasts (HSF), either isolated or mixed. The effect of the last parameter was also checked on the behavior of cells undergoing proliferation after isolation. Results, expressed as isolation efficiency (from 40% to 90%) allowed us to select a 15-min incubation time at 4 degrees C with rotary agitation, an optimal concentration of 4 x 10(5) cells/ml, and an optimal cell:bead ratio of 1:3. From a mixed cell population and in these conditions, even very low HUVEC:HSF proportions of 2.5:97.5 allowed us to obtain a pure HUVEC population in subsequent culture.

Culture Techniques↗

PubMed1996

Left ventricular radial tagging acquisition using gradient-recalled-echo techniques: sequence optimization.

Myocardial tagging with magnetic resonance (MR) imaging offers unique possibilities for noninvasive left ventricular (LV) strain analysis. True three-dimensional strain analysis can be achieved with tags implemented in cardiac short axis and long axis images. Spin-echo (SE) techniques have been used for these studies. However, this approach is time-consuming: images at different phases of the cardiac cycle have to be obtained in successive measurements and hence the total number of measurements equals the number of time frames. Moreover, the images are often degraded by flow and motion artifacts. The purpose of this study was to optimize a faster and more robust MR tagging sequence for use on a clinical whole-body 1 T MR system with optimal persistence of the tags during the entire cardiac cycle. The tagging pulses were implemented in gradient-recalled-echo (GRE) sequences and compared to SE-based acquisitions. The effects of the use of flow-compensating gradients, the excitation angles, and the angles of the saturation pulses have been studied with MR signal simulations and in comparative measurements in volunteers. GRE acquisitions with flow-compensating gradients are robust techniques for myocardial tagging acquisitions. Use of optimized flip angles and saturation pulses can significantly improve delineation of the tag and can be used up to at least 700 ms after the R-wave. Therefore, LV tagging with GRE acquisitions using optimized MR parameters is a robust and promising technique.

Heart↗

PubMed1981

Sensitivity analysis and optimization for a head movement model.

A sixth order nonlinear model for horizontal head rotations in humans is analyzed using an extended parameter sensitivity analysis and a global optimization algorithm. The sensitivity analysis is used in both the direct sense, as a model fitting tool, and in the indirect sense, as a guide to experimental design. Resolution is defined in terms of the sensitivity table, and is used to interpret the sensitivity results. Using sensitivity analyses, the head and eye movement systems are compared and contrasted. Controller signal parameters are the most influential. Their variations and effects on head movement trajectories and accelerations are investigated, and the conclusions are compared with clinical neurological findings. The global optimization algorithm, in addition to automating the fitting of various types of data, is combined with time optimality theory to give theoretical time-optimal inputs to the model.

Computers↗