ALBERT

Notes: Abstract Analysis is made to show that the mitotic index is simply proportional to the ratio of the duration of mitosis (T) to the intermitotic time only under special conditions. In the case of exponential growth of cell population the simple proportionality hold if the product ofT and the growth constant is small. For power law (t n ) growth of cell population the simple proportionality holds only when a steady state of growth has existed for at least ten intermitotic periods. The simple proportionality does not apply in conditions of transient growth.

Notes: Abstract Food and metabolic waste products, insofar as they act upon the hereditary substrate of cells, are the most important factors governing tissue growth. Equations describing the growth of tissues are derived in consideration of this fact. A quantity is found in these equations which, if slightly changed, results in very great changes in the growth rate of the tissue, where such very great changes are interpretable as neoplastic growth. The relationship between our equations and similar equations which others have proposed is discussed.

Notes: Abstract The formation of neuronal networks requires axonal growth towards target neutons. A simple set of grammar rules is introduced to describe axonal growth towards target cells situated both at short and long distances from the growing neuron. Growth for short distances is descrbed by growth following the highest gradient of a chemical compound (which is spread by diffusion from the targets). This approach fails to describe long-distance growth, which is addressed by adopting a graph grammar theory for growing trees. With these rules a flexible tool to draw network of neurons by computer can be developed.

Notes: Abstract A pair of growth control triads are used to describe coincident tumor growth and liver regeneration after partial hepatectomy. The models are extensions of previous growth control models which describe tumor growth in an unperturbed host (Michelson and Leith, 1991,Bull. math. Biol. 53, 639–656; idem, 1992, Proceedings of the Third International Conference on Communications and Control, Vol. 2, pp. 481–490; idem, 1992,Bull. math. Biol. 55, 993–1011; idem,J. theor. Biol. 169, 327–338). The linkage between the two triads depends upon systemic signals carried by soluble factors, and mathematical descriptors based upon biological first principals are proposed. The sources of the growth factors, their targets and the processing of their signals are investigated. Analyses of equilibrium in the constant coefficients case and simulated growth curves for the dynamic system are presented, and the effects of growth factor-induced mitogenesis and angiogenesis are discussed in particular. A case is made for early and late responses in the coupled control system. The biology of the signal processing paradigm is placed within a new theoretical context and discussed with regard to tumor adaptation, liver differentiation and the development of a tumor hypoxic fraction.

Notes: Abstract We consider the problem of optimal stabilization and control of populations which follow the Leslie model dynamics, within state space and control systems theory and methodology. Various types of culling strategies are formulated and introduced into the Leslie model as control inputs, and their effect on global asymptotic stability is investigated. Our new approach provides answers to several unexplored problems. We show that in general it is possible to achieve a desired stable equilibrium population level, through the design of a class ofshifted-proportional stabilizing culling policies. Further, we formulate general non-linear constrained opitmization problems, for obtaining the cost-optimal policy among this generally infinite class of such stabilizing policies. The theoretical findings are illustrated through the solution of the problem over an infinite planning horizon for a numerical example. A comparative study of the costs and dynamic effects of various culling strategies also supports the mathematical results.

Notes: Abstract A new approach for data assimilation, which is based on the adjoint method, but allows the computer code for the adjoint to be constructed directly from the model computer code, is described. This technique is straightforward and reduces the chance of introducing errors in the construction of the adjoint code. Implementation of the technique is illustrated by applying it to a simple predator-prey model in a model fitting mode. A series of identical twin numerical experiments are used to show that this data assimilation approach can successfully recover model parameters as well as initial conditions. However, the ease with which these values are recovered is dependent on the form of the model equations as well as on the type and amount of data that are available. Additional numerical experiments show that sufficient coefficient and parameter recoveries are possible even when the assimilated data contain significant random noise. Thus, for biological systems that can be described by ecosystem models, the adjoint method represents a powerful approach for estimating values for little-known biological parameters, such as initial conditions, growth rates, and mortality rates.

Notes: Abstract The effect of group size on behavioral parameters of the Oriental hornet,Vespa orientalis, was assessed experimentally under laboratory conditions. Hornet groups of various sizes (ranging from 1 to 100 individuals per group) comprised of young individuals (0–24 hr of age) devoid of a queen were placed in artificial breeding boxes (ABBs). The following three quantitative parameters were evaluated: the amount and rate of building as a function of the number of hornets in the group, the rate of oviposition as, related to group size and the longevity of hornets as a function of their group size. The probability for the occurrence of these events was similarly considered and additional behavioral parameters were only assessed qualitatively. Results of this investigation revealed a relation between the three mentioned quantitative behavioral parameters and the number of hornets per group. The number of hornets per group was positively related to the extent of building, the number of cells built by a group is $$2\pi \sqrt {group size} $$ , but negatively related to the rate of building. As for the delay of building, a non-monotone relation was found. The relation between number of hornets per group and the oviposition delay was found to be non-monotone; the number of hornets per group and their longevity were found to be inversely related. Discrepanices were recorded on the very small (1–2 individuals) or very large (100 individuals) hornet groups.

Notes: Abstract A new method for reconstructing evolutionary relationship among bacteria by use of rRNA sequence data is proposed. The method is based on the concept of fuzzy classification of probabilitiesp(i), p(i/j) andp(i/j*) (i=A,G,C,U) of each sequence. The resulting partition tree shares common features of previous works but has some new peculiarities.

Notes: Abstract We describe the behaviour of motile microorganisms (e.g. flagellates) attracted by “gyrotaxis” to a sinking, non-motile particle (e.g. an algal cell). The model is based on the application of Stokes' solution for the flow field around the settling cell. The volume within which the flagellate is attracted to the sinking particle is determined from the trajectories of the flagellate. The model of gyrotaxis has several applications; these include the colonization of sinking marine snow particles with motile microoganisms and suspension feeding by protozoa.

Notes: Abstract The effect of varying habitat dimensionality on the dynamics of a model predator-prey system is examined using an individual-based simulation. The general results are that in one dimension fluctuations in abundance of prey and predators occur over a large range of spatial scales (extinctions occur over many spatial scales). In two dimensions (and low mobilities of prey and predators) the dynamics become more predictably periodic at local scales and constant at larger scales due to statistical stabilization. In three dimensions, the model can become “phase-locked” with prey and predators displaying oscillations in abundance over large spatial scales.

Notes: Abstract A rather complete model of the gluconeogenic pathway was used, with the known separate pools of mitochondrial and cytosolic oxalacetate, malate and aspartate. The fumarase, malate dehydrogenase and glutamate oxalacetate transaminase reactions were assumed to be isotopically actively reversible, but none at isotopic equilibrium. Malate was assumed to exchange actively between the mitochondrial and cytosol, while aspartate exchange was more limited, in agreement with the known electrogenic nature of aspartate export from the mitochondria. This model was fit to14C data obtained in hepatocyte studies, and to the whole rat14C data obtained by Heath and Rose (Biochem J. 227, 851–876, 1985). The latter data were easily fit to our model, when a single mitochondrial oxalacetate pool was assumed. However, invoking two mitochondrial oxalacetate pools, as proposed by Heath and Rose, with the oxalacetate formed via pyruvate carboxylase preferentially channelled to gluconeogenesis, could not be fit with the known differences in scrambling in glucose and glutamate produced from L[3-14C]lactate.

Notes: Abstract Oscillatory secretion of insulin has been observed in many different experimental preparations ranging from pancreatic islets to the whole pancreas. Here we examine the mathematical features underlying a possible model for oscillatory secretion from the perifused, insulin-secreting cell line, HIT-15. The model includes the kinetics of uptake of glucose by GLUT transporters, the rate of glucose metabolism within the cell, and the effect of glucose on the rate of insulin secretion. Putative feedback by insulin on the rate of glucose transport into the cells is treated phenomenologically and leads to insulin oscillations similar to those observed experimentally in HIT cells. The resulting set of ordinary differential equations is simplified by time-scale analysis to a two-variable set of ordinary differential equations. Because of this simplification we can explore, in great detail, the characteristics of the oscillations and their sensitivity to parameter variation using phase plane analysis.

Notes: Abstract The fluid dynamics of sperm motility near both rigid and elastic walls is studied using the immersed boundary method. Simulations of both single and interacting organisms are presented. In particular, we find that nearby organisms originally undulating with a 90° phase shift may adjust their relative swimming velocities and phase-lock. Comparisons with previous analytical results are also discussed. The tendency of a near-wall to attract organisms is demonstrated.

Notes: Abstract The secondary immune response is one of the most important features of immune systems. During the secondary immune response, the immune system can eliminate the antigen, which has been encountered by the individual during the primary invasion, more rapidly and efficiently. Both T and B memory cells contribute to the secondary response. In this paper, we only concentrate on the functions of memory B cells. We explore a model describing the memory contributed by the specific long-lived clone which is maintained by continued stimulation with a small amount of antigens sequestered on the surfaces of the follicular dendritic cells (FDC). The behavior of the secondary response provided by the model can be compared with experimental observations. The model shows that memory B cells indeed play an important role in the secondary response. It is found that a single memory cell in a long-lived clone may not be long-lived. In the present note, the influences of relevant parameters on the secondary response are also explored.

Notes: Abstract A biological system consisting of a population of cells suspended in a liquid substrate is considered. The general problem addressed in the paper is the derivation of the kinetic pattern of population growth as a statistical effect of a very large number of elementary interactions between a single cell and the molecules of nutrient in substrate. Solution of the problem is obtained in the form of equation expressing the population growth ratec as a function of substrate concentration,C s. The analytical expression derived is applied to a real bacterial population (Escherichi coli) and kinetic patterns are theoretically computed. The major findings, expressed roughly, without nuances, are: (i) the concentration of nutrient at the cell membrane,C c, can only be equal to either 0 (for theC s below some threshold valueC *) orC s (forC s〉C *); (ii) the Michaelis-Menten-Monod kinetics observed in experiments is an artifact: the pure (not contaminated by foreign factors) dependence ofc onC s is actually such that the functionc=c(C s) has practically linear increase whenC s〈C *, and is constant,c=c(C *)=const, whenC s〉C *; (iii) the Liebig principle is strictly fulfilled: up to a feasible accuracy of observation, under no circumstances can population growth be limited (controlled) by more than one substrate component—replacement of a limiting component for another one is an instant event rather than a gradual process.

Notes: Abstract We study the equilibrium properties of idiotypically interacting B cell clones in the case where only the differentiation of B cells is affected by idiotypic interactions. Furthermore, we assume that clones may recognize and be stimulated by self antigen in the same fashion as by antiantibodies. For idiotypically interacting pairs of non-autoreactive clones we observe three qualitatively different dynamical regimes. In the first regime, at small antibody production an antibody-free fixed point, the virgin state, is the only attractor of the system. For intermediate antibody production, a symmetric activated state replaces the virgin state as the only attractor of the system. For large antibody production, finally, the symmetric activated state gives way to two asymmetric activated states where one clone suppresses the other clone. If one or both clones in the pair are autoreactive there is no virgin state. However, we still observe the switch from an almost symmetric activated state to two asymmetric activated states. The two asymmetric activated states at high antibody production have profoundly different implications for a self antigen which is recognized by one of the clones of the pair. In the attractor characterized by high autoantibody concentration the self antigen is attacked vigorously by the immune system while in the opposite steady state the tiny amount of autoantibody hardly affects the self antigen. Accordingly, we call the first state the autoimmune state and the second the tolerant state. In the tolerant state the autoreactive clone is down-regulated by its anti-idiotype providing an efficient mechanism to prevent an autoimmune reaction. However, the antibody production required to achieve this anti-idiotypic control of autoantibodies is rather large.

Notes: Abstract It is widely believed, following the work of Connor and Stevens (1971,J. Physiol. Lond. 214, 31–53) that the ability to fire action potentials over a wide frequency range, especially down to very low rates, is due to the transient, potassium A-current (I A). Using a reduction of the classical Hodgkin-Huxley model, we study the effects ofI A on steady firing rate, especially in the near-threshold regime for the onset of firing. A minimum firing rate of zero corresponds to a homoclinic bifurcation of periodic solutions at a critical level of stimulating current. It requires that the membrane's steady-state current-voltage relation be N-shaped rather than monotonic. For experimentally based genericI A parameters, the model does not fire at arbitrarily low rates, although it can for the more atypicalI A parameters given by Connor and Stevens for the crab axon. When theI A inactivation rate is slow, we find that the transient potassium current can mediate more complex firing patterns, such as periodic bursting in some parameter regimes. The number of spikes per burst increases asg A decreases and as inactivation rate decreases. We also study howI A affects properties of transient voltage responses, such as threshold and firing latency for anodal break excitation. We provide mathematical explanations for several of these dynamic behaviors using bifurcation theory and averaging methods.

Notes: Abstract A global kinetic analysis of a model consisting of an autocatalytic zymogen-activation process, in which an irreversible inhibitor competes with the zymogen for the active site of the proteinase, and a monitoring coupled reaction, in which the enzyme acts upon one of its substrates, is presented. This analysis is based on the progress curves of any of the two products released in the monitoring reaction. The general solution is applied to an important particular case in which rapid equilibrium conditions prevail. Finally, we suggest a procedure to predict whether the inhibition or activation route dominates in the steady state of the system. These results generalize our previous analysis of simpler mechanisms.

Notes: Abstract In this work, treating the artery as a thick-walled cylindrical shell made of an incompressible, isotropic and elastic solid, utilizing the large deformation theory and the stress-strain relation proposed by Demiray (1976b,Trans. ASME Ser. E, J. Appl. Mech.,98, 194–197), an explicit expression for the pulse speed is obtained and the effect of lumen pressure and the axial stretch on wave speed is discussed. Numerical results indicate that the wave speed increases with lumen pressure but decreases with the axial stretch. The results of the present model are compared with our previous work (Demiray, 1988,J. Biomech. 21, 55–58) on the same subject.

Notes: Abstract For a one-locus selection model, Svirezhev introduced an integral variational principle by defining a Lagrangian which remained stationary on the trajectory followed by the population undergoing selection. It is shown here (i) that this principle can be extended to multiple loci in some simple cases and (ii) that the Lagrangian is defined by a straightforward generalization of the one-locus case, but (iii) that in two-locus or more general models there is no straightforward extension of this principle if linkage and epistasis are present. The population trajectories can be constructed as trajectories of steepest ascent in a Riemannian metric space. A general method is formulated to find the metric tensor and the surface in the metric space on which the trajectories, which characterize the variations in the gene structure of the population, lie. The local optimality principle holds good in such a space. In the special case when all possible linkage disequilibria are zero, the phase point of then-locus genetic system moves on the surface of the product space ofn higher dimensional unit spheres in a certain Riemannian metric space of gene frequencies so that the rate of change of mean fitness is maximum along the trajectory. In the two-locus case the corresponding surface is a hyper-torus.

Notes: Abstract Most recent models of the immune network are based upon a phenomenological log bell-shaped interaction function. This function depends on a single parameter, the “field”, which is the sum of all ligand concentrations weighted by their respective affinities. The typical behavior of these models is dominated by percolation, a phenomenon in which a local stimulus spreads globally throughout the network. The usual reason for employing a log bell-shaped interaction function is that B cells are activated by cross-linking of their surface immunoglobulin receptors. Here we formally derive a new phenomenological log bell-shaped function from the chemistry of receptor cross-linking by bivalent ligand. Specifying how this new function depends on the ligand concentrations requires two fields: a binding field and a cross-linking field. When we compare the activation functions for ligand-receptor pairs with different affinities, the one-field and the two-field functions differ markedly. In the case of the one-field activation function, its graph is shifted to increasingly higher concentration as the affinity decreases but keeps its width and height. In the case of the two-field activation function, the graph of a low-affinity interaction is nested within the graphs of all higher-affinity interactions. We show that this difference in the relations among activation functions for different affinities radically changes the network behavior. In models that described B cell proliferation using the one-field activation function, network behavior was dominated by low-affinity interactions. Conversely, in our new model, the high-affinity interactions are the most significant. As a consequence, percolation is no longer the only typical network behavior.

Notes: Abstract The dynamics of a microbial community consisting of a eucaryotic ciliateTetrahymena pyriformis and procaryoticEscherichia coli in a batch culture is explored by employing an individual-based approach. In this portion of the article, Part I, population models are presented. Because both models are individual-based, models of individual organisms are developed prior to construction of the population models. The individual models use an energy budget method in which growth depends on energy gain from feeding and energy sinks such as maintenance and reproduction. These models are not limited by simplifying assumptions about constant yield, constant energy sinks and Monod growth kinetics as are traditional models of microbal organisms. Population models are generated from individual models by creating distinct individual types and assigning to each type the number of real individuals they represent. A population is a compilation of individual types that vary in a phase of cell cycle and physiological parameters such as filtering rate for ciliates and maximum anabolic rate for bacteria. An advantage of the developed models is that they realistically describe the growth of the individual cells feeding on resource which varies in density and composition. Part II, the core of the project, integrates models into a dynamic microbial community and provides model analysis based upon available data.

Notes: Abstract Mathematical models are developed for the chemotherapy of AIDS. The models are systems of differential equations describing the interaction of the HIV infected immune system with AZT chemotherapy. The models produce the three types of qualitative clinical behavior: anuninfected steady state, aninfected steady state (latency) and aprogression to AIDS state. The effect of treatment is to perturb the system from progression to AIDS back to latency. Simulation of treatment schedules is provided for the consideration of treatment regimes. The following issues of chemotherapy are addressed: (i) daily frequency of treatment, (ii) early versus late initiation of treatment and (iii) intermittent treatment with intervals of no treatment. The simulations suggest the following properties of AZT chemotherapy: (i) the daily period of treatment does not affect the outcome of the treatment, (ii) treatment should not begin until after the final decline of T cells begins (not until the T cell population falls below approximately 300 mm−3) and then, it should be administered immediately and (iii) a possible strategy for treatment which may cope with side effects and/or resistance, is to treat intermittently with chemotherapy followed by interruptions in the treatment during which either a different drug or no treatment is administered. These properties are revealed in the simulations, as the model equations incorporate AZT chemotherapy as a weakly effective treatment process. We incorporate into the model the fact that AZT treatment does not eliminate HIV, but only restrains its progress. The mathematical model, although greatly simplified as a description of an extremely complex process, offers a means to pose hypotheses concerning treatment protocols, simulate alternative strategies and guide the qualitative understanding of AIDS chemotherapy.

Notes: Abstract A stochastic cellular automata model for the population dynamics of the army antEciton burchelli on Barro Colorado Island in Panama is set up. It is simulated on the computer and shown to give good agreement with biological data. It is analysed using two approximations akin to the mean field approximation in statistical mechanics, and good agreement with the simulations is obtained. Finally, the role of distance between successive statary phase bivouacs is discussed with regard to the rate of colony growth. There are two aspects of the biological system studied here that make it of general importance. First, the population is structured, since the size of each colony of army ants is crucial. Second, the spatial behaviour of the population, as in many others, is not diffusion-like, although it is random. This has implications for the kind of model that is chosen.

Notes: Abstract An analytical model for thermal damage of retinal tissue due to absorption of laser energy by finite-sized melanin granules is developed. Since melanin is the primary absorber of visible and near-IR light in the skin and in the retina, bulk heating of tissue can be determined by superposition of individual melanin granule effects. Granules are modeled as absorbing spheres surrounded by an infinite medium of water. Analytical solutions to the heat equation result in computations that are quick and accurate. Moreover, the model does not rely on symmetric beam profiles, and so arbitrary images can be studied. The important contribution of this model is to provide a more accurate biological description of submillisecond pulse exposures than previous retinal models, while achieving agreement for longer pulses. This model can also be naturally extended into the sub-microsecond domain by including vaporization as a damage mechanism. It therefore represents the beginning of a model which can be applied across the entire pulse duration domain.

Notes: Abstract Most of the elastic tubes found in the mammalian body will collapse from a distended circular cross section and when collapsed may undergo flow-induced oscillations. A mathematical model describing fluid flow in a collapsible tube is analysed using the software package AUTO-86. AUTO-86 is used for continuation and bifurcation problems in systems of non-linear ordinary differential equations. The model is a third-order lumped-parameter type and is based on the classical “Starling resistor”; it describes the unsteady flow behaviour and, in particular, the experimentally observed self-excited oscillations, in a way which is simple enough to give physical understanding, yet still firmly based on fluid mechanical principles. Some of the bifurcation types found in this model bear close resemblance to the types suggested by experimental observations of self-excited oscillations in collapsible tubes; they thus shed some light on the various topological changes which occur in practice, particularly in view of the fact that some of the points found numerically are diffcult to achieve experimentally, while the existence of others can only be inferred indirectly and uncertainly from experiment.

Notes: Abstract A solution algorithm yielding the pressure and flow-rate distributions for steady flow in an arbitrary, tree-like network is provided. Given the tree topology, the conductance of each segment and the pressure distribution at the boundary nodes, the solution is obtained from a simple recursion based on perfect Gauss elimination. An iterative solution method using this algorithm is suggested to solve for the pressure and flow-rate distributions in an arbitrary diverging-converging (arterial-venous) network consisting of two tree-like networks which are connected to each other at the capillary nodes. A number of special solutions for tree-like networks are obtained for which the general algorithm is either simplified or can be replaced by closed form solutions of the pressure and flow-rate distributions. These special solutions can also be obtained for each tree of diverging-converging networks having particular topologies and conductance distributions. Sample numerical results are provided.

Notes: Abstract Previous game-theoretic models of reciprocity have assumed that populations are large and organisms effectively sessile. This paper analyzes an iterated prisoner's dilemma among non-sessile organisms in a finite population, on the assumption that an individual's chance of remaining in one place is not influenced by a partner's behavior. This mode of interaction is suitable for analyzing potentially cooperative behaviors that are secondary to the advantage of group formation, e.g. allogrooming among social mammals. The analysis yields necessary conditions for stable reciprocity in terms of three parameters, namely, a benefit/cost ratio, the probability of further interaction and the probability of partner retention. The results suggest that, in highly mobile organisms such as fish, birds and mammals, reciprocity may be stable only if the population is small and the relative benefit and future interaction probability are both large.

Notes: Abstract We consider the kinetics of an autocatalytic reaction network in which replication and catalytic actions are separated by a translation step. We find that the behaviour of such a system is closely related to second-order replicator equations, which describe the kinetics of autocatalytic reaction networks in which the replicators act also as catalysts. In fact, the qualitative dynamics seems to be described almost entirely be the second-order reaction rates of the replication step. For two species we recover the qualitative dynamics of the replicator equations. Larger networks show some deviations, however. A hypercyclic system consisting of three interacting species can converge toward a stable limit cycle in contrast to the replicator equation case. A singular perturbation analysis shows that the replication-translation system reduces to a second-order replicator equation if translation is fast. The influence of mutations on replication-translation networks is also very similar to the behavior of selection-mutation equations.

Notes: Abstract In this work, we studied the propagation of non-linear waves in a pre-stressed thin elastic tube filled with an inviscid fluid. In the analysis, analogous to the physiological conditions of the arteries, the tube is assumed to be subject to a uniform pressureP 0 and a constant axial stretch ratio λz. In the course of blood flow it is assumed that a large dynamic displacement is superimposed on this static field. Furthermore, assuming that the displacement gradient in the axial direction is small, the non-linear equation of motion of the tube is obtained. Using the reductive perturbation technique, the propagation of weakly non-linear waves in the long-wave approximation is investigated. It is shown that the governing equations reduce to the Korteweg-deVries equation which admits a solitary wave solution. The result is discussed for some elastic materials existing in the literature.

Notes: Abstract The present paper deals with the bifurcation analysis of a simple food chain model consisting of components like detritus, nutrients, microorganisms, phytoplankton and zooplankton in an aquatic environment. The food chain model is described by a system of differential equations. If the length of the food chain (LFCH) is equal to 3 or 4, then an asymptotically stable equilibrium exists. For LFCH=5 or 6 the non-trivial equilibrium is unstable and the food-chain model has periodic orbits.

Notes: Abstract We develop a macroscopic model for delivering drug to brain tumors. The model accounts for bulk convective and diffusive transport across the blood-brain barrier and through the interstitial space. Through mathematical analysis and simulations, we assess the effects of changing parameters (within physiological bounds) on drug delivery. We find that there is an optimal treatment for convective drug delivery to the center of the tumor. We interpret this phenomenon in terms of traffic flow. The implications of our analyses on existing chemotherapeutic protocols are discussed.

Notes: Abstract The concept of shape space proposed by Perelson and Oster (1979,J. Theor. Biol. 81, 645–670) has been a useful tool for theoretical immunologists, who have invoked it to model idiotypic binding, which plays a significant role in mathematical models of immune networks. The actual construction of such a space from its definition requires specialized experimental information, which is not completely available. In this article, we discuss, with illustrative examples, how graphical representations similar to the idea of shape space can be derived by analyzing real affinity matrices, and the relative merits of such representations to approximations that might be obtained by the approach of Perelson and Oster. We also give directions for future research with a view toward applications.

Notes: Abstract A novel intact circular dsDNA supercoil is proposed as an alternative to the conventional DNA supercoil, so that the two complementary strands of ssDNA circles are separable without any covalent bond breakage. This new structure can be visualized by using two tubings: one black and one clear. Twist the black tubing a number of times and connect its two ends. Do the same for the clear tubing. Then wrap the two tubings together. This forms the separable or novel supercoil. On the other hand, the conventional supercoil can be modeled by twisting the black and clear tubings together and then connect their respective ends, so that the two tubings are not separable unless one of them is cut. Experimentally, in the absence of any enzyme, many intact plasmid dsDNA circles give two bands on agarose gel electrophoresis under a certain given condition, while the same plasmid molecules after cutting once by a restriction enzyme give only one band under the same, condition. In the case of intact pUC19 plasmids, these two bands can then be, recovered and sequenced separately, using two primers in opposite directions. Each band gives mostly one sequence which is complementary to that of the other band. The combination of the above theoretical model and experimental results strongly suggests that there is an alternative structure of DNA which does not have the usual difficulty of unwinding, rewinding and requiring numerous covalent bond breakages and ligations during semiconservative replication.

Notes: Abstract In a lysophospholipid binary mixture, there are three ways of association between the mixture components of single-chain amphiphiles: (a) between two identical molecules each of the first and second component (self-association process) and (b) between two different molecules (cross-association process). Association probabilities for three binary mixtures were analysed as functions depending on the electric dipole moments of the polar head groups. A 3-D view representation is most suitable for this analysis. The most important finding is that for certain values of the electric dipole moments there are molecular couples which have a maximum stability to the changes in the external electrolytic medium. This fact confirms the formation of clusters and their stability, which is equivalent to the existence of micro-heterogeneities within the lipid bilayers. On the other hand, there are unstable molecular associations, and this fact influences the appearance of some phase transitions. Generally, the increase of the electric dipole moment or the increase of the acyl-chain length of one component from a binary lipid mixture decreases the self-association probability between its own molecules, but it increases the self-association probability of the other mixture components. Furthermore, the cross-association probability has high values for any binary lipid mixture of single-chain amphiphiles.

Notes: Abstract The processes by which certain classes of toxic compounds or their metabolites may react with DNA to alter the genetic information contained in subsequent generations of cells or organisms are a major component of hazard associated with exposure to chemicals in the environment. Many classes of chemicals may form DNA adducts and there may or may not be a defined mechanism to remove a particular adduct from DNA independent of replication. Many compounds and metabolites that bind DNA also readily bind existing proteins; some classes of toxins and DNA adducts have the capacity to inactivate a repair enzyme and divert the repair process competitively. This paper formulates anintracellular dynamic model for one aspect of the action of toxins that form DNA adducts, recognizing a capacity for removal of those adducts by a repair enzyme combined with reaction of the toxin and/or the DNA adduct to inactivate the repair enzyme. This particular model illustrates the possible saturation of repair enzyme capacity by the toxin dosage and shows that bistable behavior can occur, with the potential to induce abrupt shifts away from steady-state equilibria. The model suggests that bistable behavior, dose and variation between individuals or tissues may combine under certain conditions to amplify the biological effect of dose observed as DNA aduction and its consequences as mutation. A model recognizing stochastic phenomena also indicates that variation in within-cell toxin concentration may promote jumps between stable equilibria.

Notes: Abstract Integrodifference models of growth and dispersal are analyzed on finite domains to investigate the effects of emigration, local growth dynamics and habitat heterogeneity on population persistence. We derive the bifurcation structure for a range of population dynamics and present an approximation that allows straighforward calculation of the equilibrium populations in terms of local growth dynamics and dispersal success rates. We show how population persistence in a heterogeneous environment depends on the scale of the heterogeneity relative to the organism's characteristic dispersal distance. When organisms tend to disperse only a short distance, population persistence is dominated by local conditions in high quality patches, but when dispersal distance is relatively large, poor quality habitat exerts a greater influence.

Notes: Abstract In vivo tumor growth data from experiments performed in our laboratory suggest that basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) are angiogenic signals emerging from an up-regulated genetic message in the proliferating rim of a solid tumor in response to tumor-wide hypoxia. If these signals are generated in response to unfavorable environmental conditions, i.e. a decrease in oxygen tension, then the tumor may play an active role in manipulating its own environment. We have idealized this type of adaptive behavior in our mathematical model via a parameter which represents the carrying capacity of the host for the tumor. If that model parameter is held constant, then environmental control is limited to tumor shape and mitogenic signal processing. However, if we assume that the response of the local stroma to these signals is an increase in the host's ability to support an ever larger tumor, then our models describe a positive feedback control system. In this paper, we generalize our previous results to a model including a carrying capacity which depends on the size of the proliferating compartment in the tumor. Specific functional forms for the carrying capacity are discussed. Stability criteria of the system and steady state conditions for these candidate functions are analyzed. The dynamics needed to generate stable tumor growth, including countervailing negative feedback signals, are discussed in detail with respect to both their mathematical and biological properties.

Notes: Abstract Community effects are believed to play an important role in the patterning of many tissues during development. They involve an interaction between neighbouring equivalent cells that is necessary for them to proceed to their fully differentiated state. However, the mechanisms underlying these effects remain unclear. In this paper, diffusion-based mathematical models are constructed and analysed in order to study possible mechanisms for the community effect inXenopus muscle differentiation. These models differ from each other in the assumptions that are made about the nature of an inhibitory effect that ectodermal tissue has been observed to have on muscle differentiation. It is possible to construct consistent models based on all the forms of inhibition considered. However, each model requires the diffusible factors on which it is based to have different properties. The current data from tissues reaggregate experiments are insufficient to determine the mechanisms underlying the community effect; the work presented here suggests that quantitative analysis of a further series of reaggregate experiments will make it possible to distinguish between the proposed mechanisms.

Notes: Abstract We propose two methods to control spatial chaos in an ecological metapopulation model with long-range dispersal. The metapopulation model consists of local populations living in a patchily distributed habitat. The habitat patches are arranged in a one-dimensional array. In each generation, density-dependent reproduction occurs first in each patch. Then individuals disperse according to a Gaussian distribution. The model corresponds to a chain of coupled oscillators with long-range interactions. It exhibits chaos for a broad range of parameters. The proposed control methods are based on the method described by Güémez and Matías for single difference equations. The methods work by adjusting the local population sizes in a selected subset of all patches. In the first method (pulse control), the adjustments are made periodically at regular time intervals, and consist of always removing (or adding) a fixed proportion of the local populations. In the second method (wave control), the adjustments are made in every generation, but the proportion of the local population that is affected by the control changes sinusoidally. As long as dispersal distances are not too low, these perturbations can drive chaotic metapopulations to cyclic orbits whose period is a multiple of the control period. we discuss the influence of the magnitude of the pulses and wave amplitudes, and of the number and the distribution of controlled patches on the effectiveness of control. When the controls start to break down, interesting dynamic phenomena such as intermittent chaos can be observed.

Notes: Abstract Ensembles of mutually coupled ultradian cellular oscillators have been proposed by a number of authors to explain the generation of circadian rhythms in mammals. Most mathematical models using many coupled oscillators predict that the output period should vary as the square root of the number of participating units, thus being inconsistent with the well-established experimental result that ablation of substantial parts of the suprachiasmatic nuclei (SCN), the main circadian pacemaker in mammals, does not eliminate the overt circadian functions, which show no changes in the phases or periods of the rhythms. From these observations, we have developed a theoretical model that exhibits the robustness of the circadian clock to changes in the number of cells in the SCN, and that is readily adaptable to include the successful features of other known models of circadian regulation, such as the phase response curves and light resetting of the phase.

Notes: Abstract This paper develops a method to estimate a minimal amount of flurothyl necessary to induce the seizures (the seizure threshold). A simple mathematical model is proposed which permits one to determine the drug absorption rate from the amount which has been administered and from the measured latency to onset of seizure. Experimental animal (rats) were exposed to a continuous intake of flurothyl in two different situations: either being alone in the airtight chamber or sharing it in a pair. In the latter case, we assume that the two rats uniformly share the infused drug. Our calculations estimate that approximately 20 μl of flurothyl is necessary to induced twitches, whereas 25 μl of flurothyl is the dose required for the induction of clonic seizures. The model can be used to estimate the threshold amounts of any drug producing obvious behavioral changes irrespective of the route of administration.

Notes: Abstract We study a multispecies community of autotrophic microorganisms which grow in a batch culture regime with several perfectly complementary resources. A basic hypothesis is that a stationary phase of the polyculture corresponds to a maximum diversity under the constraints having the meaning of matter conservation laws. The corresponding conditional extremum problem is studied in detail. It is shown that a unique solution to this problem—a “species structure formula”—adequately describes the experimental data. We prove a number of strict statements concerning the domain of definition and maxima of the obtained solutions. These statements find an adequate interpretation as limitation principles in ecology and in the problems of community structure control.

Notes: Abstract The paper presents a mathematical analysis of the criteria for gene therapy of T helper cells to have a clinical effect on HIV infection. The analysis indicates that for such a therapy to be successful, it must protect the transduced cells against HIV-induced death. The transduced cells will not survive as a population if the gene therapy only blocks the spread of virus from transduced cells that become infected. The analysis also suggests that the degree of protection against disease-related cell death provided by the gene therapy is more important than the fraction of cells that is initially transduced. If only a small fraction of the cells can be transduced, transduction of T helper cells and transduction of haematopoietic progenitor cells will result in the same steady-state level of transduced T helper cells. For gene therapy to be efficient against HIV infection, our analysis suggests that a 100% protection against viral escape must be obtained. The study also suggests that a gene therapy against HIV infection should be designed to give the transduced cells a partial but not necessarily total protection against HIV-induced cell death, and to avoid the production of viral mutants insensitive to the gene therapy.

Notes: Abstract It is theoretically analysed whether the structural design of ATP-producing pathways, in particular the design of glycolysis, may be explained by optimization principles. On the basis of kinetic and thermodynamic principles conclusions are derived concerning the stoichiometry of these pathways in states of high ATP production rates. One of the extensions to previous investigations is that the concentrations of the adenine nucleotides are taken into account as variable quantities. This necessitates the consideration of an interaction of the ATP-producing system I with an external ATP-consuming system II. A great variety of pathways is studied which differ in the number and location of ATP-consuming reactions, ATP-producing reactions and reactions involving inorganic phosphate. The corresponding number of possible pathways may be calculated in an explicit manner as a function of the number of those reactions which do not couple to ATP or inorganic phosphate. The kinetics of the individual reactions are described by linear or bilinear functions of reactant concentrations and all rate equations are expressed in terms of equilibrium constants and characteristic times. A thermodynamical analysis of the two coupled systems yields upper and lower limits for the concentration of ATP and an explicit expression for the maximal difference between the number of ATP-producing and ATP-consuming reactions of system I. The following results of the optimization are obtained. (i) The ATP production rate always increases if the ATP-producing reactions as well as those reactions characterized by an uptake of inorganic phosphate are shifted as far as possible towards the end of system I. (ii) Explicit conditions for the optimal location of the ATP-consuming reactions are presented. The results are discussed in the context of characteristic times as well as in terms of enzyme kinetic parameters. (iii) For two sets of characteristic times the resulting stoichiometries and their corresponding steady-state fluxes are investigated in detail. One of these stoichiometries shows a close correspondence to contemporary standard glycolysis. (iv) It is shown that most possible pathways result in a very low steady-state flux, that is, the optimal stoichiometry is characterized by a significant selective advantage. (v) The standard free energy profile of a pathway with an optimal stoichiometry is discussed. It differs significantly from the free energy profiles of nonoptimized pathways.

Notes: Abstract Calcification and eventual integration of orthopedic implants into bone is important to many load-bearing devices, and the influence of load and implant stiffness on this process are assessed in this mathematical modelling study. Three research questions are posed in this study. First, can limiting material models provide useful information on the overall behavior of the tissue adjacent to a loaded orthopedic implant? Second, can the limiting models lead to optimization criteria? Third, can an optimization approach be used to differentiate between the four prospective remodeling rate equations which are proposed? The answers are yes, yes, and no, respectively. A two degree of freedom lumped parameter model for axial loading of an intramedullary implant is considered. Two limiting composite material models are used, and the strain energy density in the calcified and non-calcified phases are assessed as stimuli for calcification. The rate equations posed here assume that the calcified material volume fraction decreases at high strain-energy densities, and increases at small strain-energy densities. In all four cases (both models, both phases) the steady states for these rate equations find equilibrium points of indicator functions which are a weighted sum of total strain energy and the mass of calcified tissue in the layer considered. The weights on strain-energy density and mass differ in each case. This shows that for appropriate choices of parameters, all four models can yield the same results, and it also shows that an optimization approach does not uniquely determine the appropriate rate equation in these cases. The rate equations showed complicated dynamic behavior and a phase-plane analysis was used which led to upper bounds on load, which depended on implant stiffness and distal support. The predictions of the four cases studied are compared.

Notes: Abstract Atritrophic food-chain chemostat model composed of a prey with Monod-type nutrient uptake, a Holling Type II predator and a Holling Type II exploited superpredator is considered in this paper. The bifurcations of the model show that dynamic complexity first increases and then decreases with the nutrient supplied to the bottom of the food chain. Extensive simulations prove that the same holds for food yield, i.e., there exists an optimum nutrient supply which maximizes mean food yield. Finally, a comparative analysis of the results points out that the optimum nutrient supply practically coincides with the nutrient supply separating chaotic dynamics from high-frequency cyclic dynamics. This reinforces the idea, already known for simpler models, that food yield maximization requires that the system behaves on the edge of chaos.

Notes: Abstract We developed a non-stochastic methodology to deal with the uncertainty in models of population dynamics. This approach assumed that noise is bounded; it led to models based on differential inclusions rather than stochastic processes, and avoided stochastic calculus. Examples of estimations of extinction times for exponential and logistic population growth with environmental and demographic noise are presented.

Notes: Abstract We present a method for generating alternative biochemical pathways between specified compounds. We systematically generated diverse alternatives to the nonoxidative stage of the pentose phosphate pathway, by first finding pathways between 5-carbon and 6-carbon skeletons. Each solution of the equations for the stoichiometric coefficients of skeleton-changing reactions defines a set of networks. Within each set we selected networks with modules; a module is a coupled set of reactions that occurs more than one in a network. The networks can be classified into at least 53 families in at least seven superfamilies, according to the number, the input-output relations, and the internal structure of their modules. We then assigned classes of enzymes to mediate transformations of carbon skeletons and modifications of functional groups. The ensemble of candidate networks was too large to allow complete determination of the optimal network. However, among the networks we studied the real pathway is especially favorable in several respects. It has few steps, uses no reducing or oxidizing compounds, requires only one ATP in one direction of flux, and does not depend on recurrent inputs.

Notes: Abstract Intratrophic predation is a phenomenon not usually considered in mathematical models of biological populations, and yet it may occur in any model where many species are considered as a single model variable. This paper demonstrates how intratrophic predation can be rationally included in a general predator-prey model, and shows that the resulting model has some desirable and intuitively plausible features. A simple asymptotic method is developed in order to investigate how intratrophic predation can affect both the position and stability of the equilibria of a model. The methods can be applied to wide classes of population models, and the conclusions drawn are of practical importance.

Notes: Abstract This paper addresses the problem of modelling heterogeneous individual characteristics in a population. A flexible unified approach for stochastic parametrization dynamics of the distribution in population data is proposed. To approximate data with multiple observations per individual, models based on Markov processes are constructed. The method can be applied to scalar or multivariate characteristics, and its application to growth and allometry data is considered. Different stochastic versions of known growth and allometry functions are developed, which enable wide applicability. Simple informative growth indices are calculated as the moments of distribution. The three-parameter Gompertz growth model for size-at-age data was reparametrized to a size-increment data model with two parameters.

Notes: Abstract A rigorous Bayesian analysis is presented that unifies protein sequence-structure alignment and recognition. Given a sequence, explicit formulae are derived to select (1) its globally most probable core structure from a structure library; (2) its globally most probable alignment to a given core structure; (3) its most probable joint core structure and alignment chosen globally across the entire library; and (4) its most probable individual segments, secondary structure, and super-secondary structures across the entire library. The computations involved are NP-hard in the general case (3D-3D). Fast exact recursions for the restricted sequence singleton-only (1D-3D) case are given. Conclusions include: (a) the most probable joint core structure and alignment is not necessarily the most probable alignment of the most probable core structure, but rather maximizes the product of core and alignment probabilities; (b) use of a sequence-independent linear or affine gap penalty may result in the highest-probability threading not having the lowest score; (c) selecting the most probable core structure from the library (core structure selection or fold recognition only) involves comparing probabilities summed over all possible alignments of the sequence to the core, and not comparing individual optimal (or near-optimal) sequence-structure alignments; and (d) assuming uninformative priors, core structure selection is equivalent to comparing the ratio of two global means.

Notes: Abstract The theory of autocatalytic binary ligation is reviewed within the context of a consistently applied Michaelis-Menten quasi-steady-state approximation to obtain explicit analytical results describing time-course data from experiments. A detailed protocol for the step-wise elucidation of a minimal set of experimental parameters is outlined. The kinetic equations are then generalized to cases of self-and cross-catalysis among an arbitrary number of different templates and applied to experiments involving just two templates. Depending on the values of various kinetic parameters such systems can display exclusionary Darwinian selection corresponding to an exponential growth law, selective coexistence or coexistence of all species characteristic of a parabolic growth law; the intermediate behaviour arises as a property of the full mechanism analysed here. Our results are applicable to the classical case of self-replicating nucleic acids and their analogues as well as to newly discovered self-replicating peptides.

Notes: Abstract Theoretical results show that the measles ‘pulse’ vaccination strategy can be distinguished from the conventional strategies in leading to disease eradication at relatively low values of vaccination. Using the SIR epidemic model we showed that under a planned pulse vaccination regime the system converges to a stable solution with the number of infectious individuals equal to zero. We showed that pulse vaccination leads to epidemics eradication if certain conditions regarding the magnitude of vaccination proportion and on the period of the pulses are adhered to. Our theoretical results are confirmed by numerical simulations. The introduction of seasonal variation into the basic SIR model leads to periodic and chaotic dynamics of epidemics. We showed that under seasonal variation, in spite of the complex dynamics of the system, pulse vaccination still leads to epidemic eradication. We derived the conditions for epidemic eradication under various constraints and showed their dependence on the parameters of the epidemic. We compared effectiveness and cost of constant, pulse and mixed vaccination policies.

Notes: Abstract The self-complementary subset $$\mathcal{T}_0 = \mathcal{X}_0 $$ ∪{AAA,TTT} with $$\mathcal{X}_0 $$ = {AAC, AAT, ACC, ATC, ATT, CAG, CTC, CTG, GAA, GAC, GAG, GAT, GCC, GGC, GGT, GTA, GTC, GTT, TAC, TTC} of 22 trinucleotides has a preferential occurrence in the frame 0 (reading frame established by the ATG start trinucleotide) of protein (coding) genes of both prokaryotes and eukaryotes. The subsets $$\mathcal{T}_1 = \mathcal{X}_1 $$ ∪{CCC} and $$\mathcal{T}_2 = \mathcal{X}_2 $$ ∪{GGG} of 21 trinucleotides have a preferential occurrence in the shifted frames 1 and 2 respectively (frame 0 shifted by one and two nucleotides respectively in the 5′-3′ direction). $$\mathcal{T}_1 $$ and $$\mathcal{T}_2 $$ are complementary to each other. The subset $$\mathcal{T}_0 $$ contains the subset $$\mathcal{X}_0 $$ which has the rarity property (6 × 10−8) to be a complementary maximal circular code with two permutated maximal circular codes $$\mathcal{X}_1 $$ and $$\mathcal{X}_2 $$ in the frames 1 and 2 respectively. $$\mathcal{X}_0 $$ is called a C3 code. A quantitative study of these three subsets $$\mathcal{T}_0 ,\mathcal{T}_1 ,\mathcal{T}_2 $$ in the three frames 0, 1, 2 of protein genes, and the 5′ and 3′ regions of eukaryotes, shows that their occurrence frequencies are constant functions of the trinucleotide positions in the sequences. The frequencies of $$\mathcal{T}_0 ,\mathcal{T}_1 ,\mathcal{T}_2 $$ in the frame 0 of protein genes are 49, 28.5 and 22.5% respectively. In contrast, the frequencies of $$\mathcal{T}_0 ,\mathcal{T}_1 ,\mathcal{T}_2 $$ in the 5′ and 3′ regions of eukaryotes, are independent of the frame. Indeed, the frequency of $$\mathcal{T}_0 $$ in the three frames of 5′ (respectively 3′) regions is equal to 35.5% (respectively 38%) and is greater than the frequencies $$\mathcal{T}_1 $$ and $$\mathcal{T}_2 $$ , both equal to 32.25% (respectively 31%) in the three frames. Several frequency asymmetries unexpectedly observed (e.g. the frequency difference between $$\mathcal{T}_1 $$ and $$\mathcal{T}_2 $$ in the frame 0), are related to a new property of the subset $$\mathcal{T}_0 $$ involving substitutions. An evolutionary analytical model at three parameters (p, q, t) based on an independent mixing of the 22 codons (trinucleotides in frame 0) of $$\mathcal{T}_0 $$ with equiprobability (1/22) followed by t ≈ 4 substitutions per codon according to the proportions p ≈ 0.1; q ≈ 0.1 and r = 1 − p − q ≈ 0.8 in the three codon sites respectively, retrieves the frequencies of $$\mathcal{T}_0 ,\mathcal{T}_1 ,\mathcal{T}_2 $$ observed in the three frames of protein genes and explains these asymmetries. Furthermore, the same model (0.1, 0.1, t) after t ≈ 22 substitutions per codon, retrieves the statistical properties observed in the three frames of the 5′ and 3′ regions. The complex behaviour of these analytical curves is totally unexpected and a priori difficult to imagine.

Notes: Abstract A simple mathematical model for the dynamics of network-bundle transitions in actin filaments has been previously proposed and some of its mathematical properties have been described. Other models in this class have since been considered and investigated mathematically. In this paper, we have made the first steps in connecting parameters in the model with biologically measurable quantities such as published values of rate constants for filament-crosslinker association. We describe how this connection was made, and give some preliminary numerical simulation results for the behavior of the model under biologically realistic parameter regimes. A key result is that filament length influences the bundle-network transition.

Notes: Abstract This paper concerns the minimal speed of traveling wave fronts for a two-species diffusion-competition model of the Lotka-Volterra type. An earlier paper used this model to discuss the speed of invasion of the gray squirrel by estimating the model parameters from field data, and predicted its speed by the use of a heuristic analytical argument. We discuss the conditions which assure the validity of their argument and show numerically the existence of the realistic range of parameter values for which their heuristic argument does not hold. Especially for the case of the strong interaction of two competing species compared with the intraspecific competition, we show that all parameters appearing in the system affect the minimal speed of invasion.

Notes: Abstract We describe a method of implementing efficient computer simulations of immune systems that have a large number of unique B-and/or T-cell clones. The method uses an implementation technique called lazy evaluation to create the illusion that all clones are being simulated, while only actually simulating a much smaller number of clones that can respond to the antigens in the simulation. The method is effective because only 0.001–0.01% of clones can typically be stimulated by an antigen, and because many simulations involve only a small number of distinct antigens. A lazy simulation of a realistic number of clones and 10 distinct antigens is 1000 times faster and 10 000 times smaller than a conventional simulation—making simulations of immune systems with realistic-size repertoires computationally tractable.

Notes: Abstract We introduce a simple mathematical model of regulation of division of labor in insect societies based on fixed-response thresholds. Individuals with different thresholds respond differently to task-associated stimuli. Low-threshold individuals become involved at a lower level of stimulus than high-threshold individuals. We show that this simple model can account for experimental observations of Wilson (1984), extend the model to more complicated situations, explore its properties, and study under what conditions it can account for temporal polyethism.

Notes: Abstract Patterning events in development often depend on the transmission over a range of several cell diameters of signals emanating from a localized source. Experimental studies of such long-range signalling by members of the TGF-β family of growth factors suggests that a cell-relay mechanism in which cells signal only with their immediate neighbours (i.e., juxtacrine signalling) may be operating in some tissues. Here, this possibility is investigated through the analysis of a model of juxtacrine signalling. Depending on the strength of the signal relay between cells, a localized signal source can generate either stable gradients or travelling fronts of cell activation. Both of these behaviors could in principle be involved in the long-range transmission of signals and patterning of cell fates by cell relays. There are significant and surprising differences between the gradients generated by the mechanism studied here, and those generated by the diffusion of a morphogen. In particular, there is an upper limit on the distance over which any given level of cell activation can be attained in a relay-mediated gradient, irrespective of the strength of signal source.

Notes: Abstract We present the analysis of a phase-shift sequence obtained from random transitions between periodic solutions of a biochemical dynamical model, formed by a system of three differential equations and which represent an instability-generating multienzymatic mechanism. The phase-shift series was studied in terms of Hurst’s rescaled range analysis. We found that the data were characterized by a Hurst exponent H = 0.69, which was clearly indicative of long-term trends. This result had a high significance level, as was confirmed through Monte Carlo simulations in which the data were scrambled in the series, destroying its original ordering. For these series we obtained a Hurst exponent which was consistent with the expectation of H = 0.5 for a random independent process. This clearly showed that, although the transitions between the periodic solutions were provoked randomly, the stochastic process obtained exhibited long-term persistence. The fractal dimension was also estimated and found to be consistent with the value of the Hurst exponent.

Notes: Abstract Angiogenesis, the formation of blood vessels from a pre-existing vasculature, is a process whereby capillary sprouts are formed in response to externally supplied chemical stimuli. The sprouts then grow and develop, driven initially by endothelial-cell migration, and organize themselves into a dendritic structure. Subsequent cell proliferation near the sprout tip permits further extension of the capillary and ultimately completes the process. Angiogenesis occurs during embryogenesis, wound healing, arthritis and during the growth of solid tumors. In this paper we present both continuous and discrete mathematical models which describe the formation of the capillary sprout network in response to chemical stimuli (tumor angiogenic factors, TAF) supplied by a solid tumor. The models also take into account essential endothelial cell-extracellular matrix interactions via the inclusion of the matrix macromolecule fibronectin. The continuous model consists of a system of nonlinear partial differential equations describing the initial migratory response of endothelial cells to the TAF and the fibronectin. Numerical simulations of the system, using parameter values based on experimental data, are presented and compared qualitatively with in vivo experiments. We then use a discretized form of the partial differential equations to develop a biased random-walk model which enables us to track individual endothelial cells at the sprout tips and incorporate anastomosis, mitosis and branching explicitly into the model. The theoretical capillary networks generated by computer simulations of the discrete model are compared with the morphology of capillary networks observed in in vivo experiments.

Notes: Abstract There appear to be two different kinds of theoretical results about stochastic patch-occupancy metapopulation models: those recently proposed by Gyllenberg and Silvestrov about metapopulations including a very stable patch, and those by Darroch and Seneta about more general metapopulations. Based on the spectral theory of linear operators, it is shown that the results by Gyllenberg and Silvestrov are a limiting case of those by Darroch and Seneta. Taking the examples proposed by Gyllenberg and Silvestrov as a case study, the application and relevance of these results are discussed, with a particular stress to their bearing on real metapopulations.

Notes: Abstract In this paper a mathematical model is developed to describe the migration of labelled particles within a multicell spheroid. In the model, spatial variations in cell proliferation and death create an internal velocity field which leads to redistribution of the labelled and unlabelled cells. By applying a range of numerical and analytical techniques to the model equations, it is possible to show that, whilst the speed with which the labelled cells migrate through the tumour is independent of the type of cells that are labelled, their limiting distribution depends crucially on whether inert polystyrene microspheres or live tumour cells are labelled. These predictions are shown to be in good qualitative agreement with independent experimental results.

Notes: Abstract Human T-cell lymphotropic virus type I (HTLV-I) infection in humans causes a chronic infection of CD4+ T cells, and is associated with various disease outcomes, among them with the development of adult T-cell leukemia (ATL). The T-cell dynamics after HTLV-I infection can be described in a mathematical model with coupled differential equations. The infection process is modeled assuming cell-to-cell infection of CD4+ T cells. The model allows for CD4+ T cell subsets of susceptible, latently infected and actively infected cells as well as for leukemia cells. Latently infected T cells may harbor the virus for several years until they become activated and able to infect susceptible T cells. Uncontrolled proliferation of CD4+ T cells with monoclonal DNA-integration of HTLV-I results in the development of ATL. The model describes basic features that characterize HTLV-I infection; the chronic infection of CD4+ T cells, the increasing number of abnormal cells and the possible progression to ATL.

Notes: Abstract A neighbourhood-based competition model for plant individuals is studied to evaluate how a hierarchical structure related to size may emerge in plant communities. It is shown by numerical simulations and linear stability analysis that many stable states exist in the hierarchical structure when both the total number of individuals and the degree of asymmetry of competition are high. When the hierarchical structures are self-organized by the dynamic instability of the homogeneous state due to non-linearity of competition, it is proved that these states are always locally stable. The relevance of the results to size structures in real plant communities (boreal forests vs tropical and temperate forests) is discussed. This is suggested to be the mechanism responsible for the coexistence of species in plant communities.

Notes: Abstract Phenomenological models represent a simplified approach to the study of complex systems such as host-parasitoid interactions. In this paper we compare the dynamics of three phenomenological models for host-parasitoid interactions developed by May (1978), May and Hassell (1981) and May et al. (1981). The essence of the paper by May and Hassell (1981) was to define a minimum number of parameters that would describe the interactions, avoiding the technical difficulties encountered when using models that involve many parameters, yet yielding a system of equations that could capture the essence of real world interactions in patchy environments. Those studies dealt primarily with equilibrium and coexistence phenomena. Here we study the dynamics through bifurcation analysis and phase portraits in a much wider range of parameter values, carrying the models beyond equilibrium states. We show that the dynamics can be either stable or chaotic depending on the location of a damping term in the equations. In the case of the stable system, when host density dependence acts first, a stable point is reached, followed by a closed invariant curve in phase space that first increases then decreases, finally returning to an asymptotically stable point. Chaos is not seen. On the other hand, when parasitoid attack occurs before host density dependence, chaos is inevitably apparent. We show, as did May et al. (1981) and stated earlier byWang and Gutierrez (1980), that the sequence of events in host-parasitoid interactions is crucial in determining their stability. In a chaotic state the size of the host (e.g., insect pests) population becomes unpredictable, frequently becoming quite large, a biologically undesirable outcome. From a mathematical point of view the system is of interest because it reveals how a strategically placed damping term can dramatically alter the outcome. Our study, reaching beyond equilibrium states, suggests a strategy for biological control different from that of May et al. (1981).

Notes: Abstract In this paper we study the uniform persistence (UP) of an association of two competing host species sharing a directly transmitted macroparasite. Like predators, parasites can regulate UP while the hosts are either coexisting or in a dominance relationship without any infections, but cannot regulate UP in case the hosts are in bistability. The regulatory mechanism depends on the relationships between the parameters, such as host intrinsic growth rate, host carrying capacity, susceptibility, parasite pathogenicity and the magnitude of parasite aggregation. In the case of coexistence the parametric space for UP is more than that for global stability of the host-parasite equilibrium, but is less than that for UP in the case of dominance. In the case of dominance, the parasites can alter the competitive outcome locally or can enhance the local exclusion of the inferior competitor and thus, unlike the predation, parasitism has an beneficial effect over competition. We derive explicitly the range of the values of ratios of the rates of reproduction and survivorship of the hosts, and also of the values of the degree of aggregations, with which macroparasites are not effective in maintaining its beneficial effect over competition. Finally our results support the body-size hypothesis of Price et al. (1988), with possible explanations of certain exceptional examples of the hypothesis.

Notes: Abstract The representation of the shape of a biconcave erythrocyte by a set of three parametric equations was achieved by using the expressions that transform the curvilinear coordinates from the disc-cyclide coordinate system [denoted J2R; Moon and Spencer (1988), Field Theory Handbook, Springer-Verlag, Berlin] to Cartesian coordinates. The equations are products of elliptic functions, so the challenge was to relate the three major ’shape-defining’ measurements of the human erythrocyte in Cartesian coordinates to three parameters in the new curvilinear coordinates, to give a realistic representation of the shape of the membrane-surface. The relationships between the coefficients of the Cartesian degree-4 surface that describes the discocyte and the coordinate transformation equations were derived with the aid of Mathematica; and the membrane-surface of the cell was drawn using the ParametricPlot3D function in this ‘package’. By having the erythrocyte shape expressed in its new form it is readily amenable to further transformations that might be used to model those changes in shape that are seen when the cells are immersed in media of various osmolalities, or when they change metabolic ’states’. On the other hand, the relationship between the coefficients of the Cartesian expression for the disc-cyclide surface is relevant to image analysis of erythrocytes, as determined by physical methods that rely on Cartesian imaging ’slices’. These methods include confocal microscopy and various nuclear magnetic resonance microimaging procedures.

Notes: Abstract A coupled model is presented for simulating physical and biological dynamics in fresh water lakes. The physical model rests upon the assumption that the turbulent kinetic energy in a water column of the lake is fully contained in a mixed layer of variable depth. Below this layer the mechanical energy content is assumed to vanish. Additionally, the horizontal currents are ignored. This one-dimensional two-layered model describes the internal conversion of the mechanical and thermal energy input from the atmosphere into an evolution of the mixed layer depth by entrainment and detrainment mechanisms. It is supposed to form the physical domain in which the simulation of the biological processes takes place. The biological model describes mathematically the typical properties of phyto-and zooplankton, their interactions and their response to the physical environment. This description then allows the study of the behaviour of Lagrangian clusters of virtual plankton that are subjected to such environments. The essence of the model is the dynamical simulation of an arbitrary number of nutrient limited phytoplankton species and one species of zooplankton. The members of the food web above and below affect the model only statically. The model is able to reproduce the typical progression of a predator-prey interaction between phyto-and zooplankton as well as the exploitative competition for nutrients between two phytoplankton species under grazing pressure of Daphnia. It suggests that the influence of the biological system on the physical system results in a weak increase of the surface temperature for coupled simulations, but a considerably higher seasonal thermocline in spring and a lower one in autumn.

Notes: Abstract We investigate the dynamical behaviour of a simple plankton population model, which explicitly simulates the concentrations of nutrient, phytoplankton and zooplankton in the oceanic mixed layer. The model consists of three coupled ordinary differential equations. We use analytical and numerical techniques, focusing on the existence and nature of steady states and unforced oscillations (limit cycles) of the system. The oscillations arise from Hopf bifurcations, which are traced as each parameter in the model is varied across a realistic range. The resulting bifurcation diagrams are compared with those from our previouswork, where zooplankton mortality was simulated by a quadratic function—here we use a linear function, to represent alternative ecological assumptions. Oscillations occur across broader ranges of parameters for the linear mortality function than for the quadratic one, although the two sets of bifurcation diagrams show similar qualitative characteristics. The choice of zooplankton mortality function, or closure term, is an area of current interest in the modelling community, and we relate our results to simulations of other models.

Notes: Abstract The bayesian decomposition of posterior distribution was used to develop a likelihood function to correct bias in the estimates of population parameters from data collected randomly with size-specific selectivity. Positive distributions with time as a parameter were used for parametrization of growth data. Numerical illustrations are provided. The alternative applications of the likelihood to estimate selectivity parameters are discussed.

Notes: Abstract We present a model for the formation of parallel rows of scale cells in the developing adult wing of moths and butterflies. Precursors of scale cells differentiate throughout each epithelial monolayer and migrate into rows that are roughly parallel to the body axis. Grafting experiments have revealed what appears to be a gradient of adhesivity along the wing. What is more, cell adhesivity character is maintained after grafting. Thus we suggest that it is a cell’s location prior to migration that determines its interactions during migration. We use nonlinear bifurcation analysis to show that differential origin-dependent cell adhesion can result in the stabilization of rows over spots.

Notes: Abstract Critical to epithelial cell viability is the homeostasis of cell volume and composition during changes in transcellular transport. In this study, two previously developed mathematical models (principal cell of the collecting duct and proximal tubule cell) are approximated by their linearizations about a reference condition. This yields matrices which estimate cell volume, cell composition, and transcellular fluxes in response to perturbations of bath conditions and membrane transporter activity. These approximations are themselves extended with the inclusion of linear dependence of membrane transport coefficients on cell variables (e.g., volume, solute concentrations, or electrical potential). This provides cell models with variable permeabilities, which may be homeostatic, and which can be examined systematically: sequentially testing each membrane permeability and its controlling cell variable. In the proximal tubule approximation, volume-mediated increases in peritubular K—Cl or Na—3HCO3 cotransport, and volume-mediated decreases in Na,K-ATPase activity are homeostatic; modulation of peritubular K permeability has little impact. In the principal cell model, volume homeostasis is afforded by volume-sensitive peritubular Na/H exchange or Cl− conductance. Predictions from the linear analysis are confirmed in the full models. This approach yields a systematic examination of homeostasis in an epithelial model, and identifies candidate control parameters.

Notes: Abstract This paper deals with the relative growth of three different fruit tissues. Their morphogenetic periods and the mathematical constraints involved are described, and more precisely, the paper shows an allometric relationship (Y=nX m ) between the widths (X, Y) of the main tissues in stone fruits such as cherries, peaches and prunes. The mathematical relationships between the growth of the mesocarp and of the endocarp of somePrunus fruits are described, and it is proved that before the formation of the embryo, growth is allometric, in agreement with conclusions drawn from some experimental data. However, according to another study, the growth of the mesocarp and of the endocarp are ruled by autocatalytic and monomolecular functions, before as well as after the formation of the embryo. In this case, it is proved that if allometry exits in stone fruits, it can only be anantiometry (m=−1). To solve the dilemma, two main alternatives are proposed and discussed. We conclude that, while allometry is established on reasonable grounds before the formation of the embryo, after the formation of the embryo the mesocarp and endocarp evolve independently since a center for the coordination of growth no longer exists, and each tissue can grow according to its own independent rules.

Notes: Abstract In many organisms, a reliable number of segments is produced even though important properties of the region involved, especially its size at the time of pattern formation, are apparently not specified with sufficient precision. We show that this can be readily accomplished if segmentation occurs through a sequence of bifurcations rather than all at once, and we provide evidence from developmental studies that indicates that this is typically what actually occurs. Our results strongly suggest that where patterns are formed reliably, this generally happens in stages rather than by the setting up in advance of a complete prepattern.

Notes: Abstract Adaptive characteristics of circadian rhythm are based on their capacity to be synchronized by external signals, particularly light signals. The effect of both single and periodic light signals on the electroretinogram (ERG) circadian rhythm in crayfish is studied. In a previous work (Lara-Aparicioet al., Bull math. Biol. 55, 97–110, 1993) we developed a mathematical model simulating the emergence of the ERG circadian rhythm during the ontogeny of the crayfish. In the present work we have tested the familiar wave-shift behaviour of an oscillator with a single limit cycle. Two new facts, not present in a simpler model, now appear, which simulate adequately the experimental results, i.e. the presence of a transient stage and the shape of the perturbed wave which changes according to the characteristics of the external light signals.

Notes: Abstract In the field of biological regulation, models dictated by expreimental work are usually complex networks comprising intertwined feedback loops. In this paper the biological roles of individual positive loops (multistationarity, differentiation) and negative loops (homeostasis, with or without oscillations, buffering of gene dosage effect) are discussed. The relationship between feedback loops and steady states is then clarified, and the problem: “How can one conveniently disentangle complex networks?” is then considered. Initiated long ago, logical descriptions have been generalized from various viewpoints; these developments are briefly discussed. The recent concept of the loop-characteristic state, defined as the logical state located at the level of the thresholds involved in the loop, together with its application, are then presented. Biological applications are also discussed.

Notes: Abstract Trees with a coloration of their leaves have an induced “length” which forms the basis of the widely used maximum parsimony method for reconstructing evolutionary trees in biology. Here we describe five unexpected properties of this length function, including refinements of earlier results.

Notes: Abstract A number of bacterial and viral genes take part in the decision between lysis and lysogenization in temperate bacteriophages. In the lambda case, at least five viral genes (cI, cro, cII, N and cIII) and several bacterial genes are involved. Several attempts have been made to model this complex regulatory network. Our approach is based on a logical method described in the first paper of the series which formalizes the interactions between the elements of a regulatory network in terms of discrete variables, functions and parameters. In this paper two models are described and discussed, the first (two-variable model) focused on cI and cro interactions, the second (four-variable model) considering, in addition, genes cII and N. The treatment presented emphasizes the roles of positive and negative feedback loops and their interactions in the development of the phage. The role of the loops between cI and cro, and of cI on itself (which both have to be positive loops) was discovered earlier; this group's contribution to this aspect mainly deals with the possibility of treating these loops as parts of a more extended network. In contrast, the role of the negative loop of cro on itself had apparently remained unexplained. We realized that this loop buffers the expression of genes cro itself, cII, O and P against the inflation due to the rapid replication of the phage. More generally negative auto-control of a gene appears an efficient way to render its expression insensitive (or less sensitive) to gene dosage, whereas a simple negative control would not provide this result.

Notes: Abstract Cannibalism can have a stabilizing effect in a predator-prey system. Contrary to the intuitive expectation cannibalism of the predator leads to an increase of the standing stocks of both, prey and predator.

Notes: Abstract The bifurcations of a periodically forced predator-prey model (the chemostat model), with a prey feeding on a limiting nutrient, are numerically detected with a continuation technique. Eight bifurcation diagrams are produced (one for each parameter in the model) and shown to be topologically equivalent. These diagrams are also equivalent to those of the most commonly used predator-prey model (the Rosenzweig-McArthur model). Thus, all basic modes of behavior of the two main predator-prey models can be explained by means of a single bifurcation diagram.

Notes: Abstract Concomitant resistance is a tumor growth dynamic which results when the growth of a second tumor implant is inhibited by the presence of the first. Recently, we modeled tumor growth in the presence of a regenerating liver after partial hepatectomy (Michelson and Leith,Bull. Math. Biol. 57, 345–366, 1995), with an interlocking pair of growth control triads to account for the accelerated growth observed in both tissues. We also modeled tumor dormancy and recurrence as a dynamic equilibrium achieved between proliferating and quiescent subpopulations. In this paper those studies are extended to initially model the concomitant resistance case. Two interlocking model systems are proposed. In one an interactive competition between the tumor implants is described, while in the other purely proportional growth inhibition is described. The equilibria and dynamics of each system when the coefficients are held constant are presented for three subcases of model parameters. We show that the dynamic called concomitant resistance can be real or apparent, and that if the model coefficients are held constant, the only way to truly achieve concomitant resistance is by forcing one of the tumors into total quiescence. If this is the true state of the inhibited implant, then a non-constant recruitment signal is required to insure regrowth when the inhibitor mass is excised. We compare these theoretical results to a potential explanation of the phenomenon provided by Prehn (Cancer Res. 53, 3266–3269, 1993).

Notes: Abstract Radiation target theory has been extended to complex biochemical systems. Mathematical analyses are presented for multiple forms of biological active proteins, for the presence of large inhibitors or activators, for compounds which regulate rate or affinity and for multipe-step reactions. Several predictions of these models have been verified experimentally.

Notes: Abstract Aggregation of membrane molecules is a crucial phenomenon in developing organisms, a classic example being the aggregation of post-synaptic receptors during synaptogenesis. Our understanding of the molecular events involved is improving, but most models of the aggregation or concentration process do not address binding events on the molecular level. An exception is the study of diffusion limited aggregation, in which the aggregation process is simulated on a molecular level. In this analysis, however, important physical parameters such as molecular size, diffusion constant and initial density are not addressed. Thus no predictions about the rate at which such aggregates will form is possible. In the present work the model of diffusion limited aggregation is extended to incorporate these parameters and make the corresponding predictions.