ALBERT

Notes: Abstract Approximate equations for epithelial solute and water transport have been combined with the relations of mass conservation to yield a single differential equation representing volume flow along the proximal tubule. This flow equation is first order, quasilinear and may be integrated directly. For the steady state, the result is an implicit relation between volume flow and distance along the tubule. For two time-dependent problems (step change of tubule inlet velocity or osmolality) the trajectories (distance as a function of transit time) of a fluid element starting at the inlet are obtained. Differentiation of the steady-state relation with respect to the inlet velocity yields a first-order differential equation relating inlet and outlet velocity. This equation is considered in detail, particularly with regard to the influence of solute-linked water reabsorption. Model calculations with parameters representing rat proximal tubule indicate that it will be difficult to discern coupled water flux in this epithelium from only outlet and inlet flows. Calculations using lower transport rates and lower permeabilities suggest that this equation may be useful in quantifying coupled water flow in proximal tubules from other species.

Notes: Abstract The branching characteristic of the arterial system is such that blood pressure pulses propagate with minimum loss. This characteristic depends on the geometric and elastic properties of branching vessels. In the current investigation, mathematical relations of branching geometry and elastic properties are formulated and their relative contributions to pulse reflection at an arterial junction are analyzed. Results show that alteration of pulse transmission through the junction is more significantly affected by changes in branching vessel radii and wall thickness than by corresponding percentage changes in vessel wall elastic moduli.

Notes: Abstract Galerkin's finite element-Laplace transform technique (GAFELTTE) has been used to study transient temperature distribution in human skin and subcutaneous tissues. This study incorporates heat conduction, heat carried by perfusion of blood in the capillary beds and metabolic heat generation in the tissues. Different values of various quantities have been considered in all three parts, namely epidermis, dermis and subcutaneous tissues, depending on physiological considerations. The GAFELTTE provides interface temperatures for a wide range of the values of skin surface temperatures. These values have been used to obtain temperature profiles in the region considered. Steady-state temperature distribution has been deduced from the solution obtained by GAFELTTE and has been compared with the results obtained by using different methods.

Notes: Abstract Necessary and sufficient conditions are given for three equilibria to occur in a predatorprey model and conditions are given for two of these to be stable. The existence of two stable equilibria requires predator intraspecific competition for either space or food, and the lower the prey growth rate the stronger this predator self-regulation must be. A prey growth rate that is skewed to the right, the ability of a few predators to survive at low prey densities, and predators with high searching effectiveness, long handling times, and large maximum per capita rate of increase all make two stable equilibria more likely.

Notes: Abstract Drawing evidence from a variety of cardiovascular studies on the heart rate in homeothermic animals, the author establishes the following thesis. The servocontrol (i.e. the autonomic and reflex control) by the medulla oblongata of the heart (rate) is a negative feedback dynamic which is isomorphic (i.e. ‘diffeomorphic’) to the dyamic underlying the heat rate control in those animals (cf. Kuyk,Bull. math. Biol. 46, 81–102, 1984). In fact, unlike in the heat rate case, the qualitative evidence supporting this thesis can not be fully complemented by quantitative data stemming from experiments, because of a lack of pertinent experiments—which, indeed, should measuresimultaneously the heart rate state parameter and thefour control parameters at the input side of the medulla. The results of some of the existing experiments on animal preparations can nevertheless be adduced to recognize that this dynamic can be graphed by the five-dimensional butterfly catastrophe type. The theory leads to new ways of looking at experiments in the field and/or setting up such experiments in the future.

Notes: Abstract A model based upon minimization of surface energy is proposed as an explanation for compaction and internalization of cells during mammalian embryo development. The model is used to simulate and graphically display these phenomena on a computer.

Notes: Abstract This paper describes a growth model for binary topological trees. The model defines the branching probability of all segments in the tree. The branching probability of a segment is formulated as a function of two variables, one indicating its type (intermediate or terminal), the other representing its order, i.e. the topological distance to the root segment. The function is determined by two parameters, namely the ratio of branching probabilities of intermediate and terminal segments and the strength of the order dependency, implemented in an exponential form. Expressions are derived for the calculation of symmetry properties of the partitions and it is indicated which part of the parameter domain results in predominantly symmetrical trees.

Notes: Abstract The problem of cellular differentiation and consequent pattern generation during embryonic development has been mathematically investigated with the help of a reaction-diffusion model. It is by now a well-recognized fact that diffusion of micromolecules (through intercellular gap junctions), which is dependent on the spatial parameter (r), serve the purpose of ‘positional information’ for differentiation. Based on this principle the present model has been constructed by coupling the Goodwin-type equations for RNA and protein synthesis with the diffusion process. The homogeneous Goodwin system can exhibit stable periodic solution if the value of the cooperativity as measured by the Hill coefficient (ρ) is greater than 8, which is not biologically realistic. In the present work it has been observed that inclusion of a negative cross-diffusion can drive the system into local instability for any value of ρ and thus a time-periodic spatial solution is possible around the unstable local equilibrium, eventually leading to a definite pattern formation. Inclusion of a negative cross-diffusion thus makes the system biologically realistic. The cross-diffusion can also give rise to a stationary wave-like dissipative structure.

Notes: Abstract A nes software system is described for building simulation programs on micro- and minicomputers. Model equations are written as C subroutines, compiled and linked to the SCoP package to produce a menu-driven, interactive program. The system maintains a database of names, values, and units for all model parameters and variables. Run-time options include several methods for interactive parameter modification and both graphic and tabular outputs, with output values presented as they are calculated. Simulation output values can be compared with experimental data graphically and a companion program SCoPFit is provided for formal optimization of parameter values.

Notes: Abstract We consider the existence and global stability of aq-member equilibrium (1≤q≤n) in partially closed food-chains of lengthn having an abiotic component as resource. We observe that such existence demands bounds of resource supply rate and these bounds are weighted sums of interaction coefficients. Particular results of global sector-stability of partially feasible equilibria of simple food-chains obeying Lotka-Volterra dynamics are shown. Lastly the elasticity of such food-chains when a new species is introduced at the highest trophic level is investigated.

Notes: Abstract Criteria are established for three classes of models of single-species dynamics with a single discrete delay to have a globally asymptotically stable positive equilibrium independent of the length of delay.

Notes: Abstract The main concern of this paper is with survival or extinction of predators in models of predator-prey systems exhibiting group defence of the prey. It is shown that if there is no mutual interference among predators, enrichment could result in their extinction. However, if there is mutual interference, the predator population survives (at least deterministically).

Notes: Abstract In this paper a general class of semi-Markov compartmental systems is studied. Two models for different input processes are analysed. Attention has been paid to the recurrence times associated with each compartment and to the distribution of the number of particles in each compartment. As an example, a three-compartment system is discussed to study the movement between three health states of patients with chronic diseases.

Notes: Abstract A strategy is presented for searching the gene and protein sequence data banks which combines the use of two previously described algorthms. The implementation of this strategy is thoroughly evaluated with respect to sensitivity, specificity and speed. The establishment of standard benchmarks for comparing programs that rearch the sequence data banks for homology is proposed.

Notes: Abstract During functional linkage, ligand receptors are coupled to other receptors and to the cell's metabolic-transport apparatus. The linkage guides the cellular processing of matter, energy and information. Previous conceptions of functional linkage have used the ideas of classical physics appropriate to macroscopic objects. This study presents an initial quantum mechanical model of functional linkage in the case of ligands moving through lipid bilayers and hydrophilic transmembrane channels (‘pores’) of molecular dimensions. On the basis of permeability data, energy surfaces consisting of piecewise-constant potential regions are used to model the lipid bilayers and transmembrane channels. The centre-of-mass wavefunction for a ligand on such energy surfaces is analysed and the permeability coefficients calculated from the wavefunction's transmission characteristics. It is found that quasi-bound states in the several ligand-binding regions of a bilayer or pore system can functionally link to facilitate the passage of the molecule across the permeability barrier. Appearance of the linkage is a sensitive function of the ligand's energy. If the centre-of-mass energies are distributed as in a thermalized fluid, the flux via the quantum functional linkage can equal or exceed that of a classical flux for proton transport through rigid pores in which the intrasite barriers are relatively high (0.25–1 eV) and narrow (0.1–1 Å). The functional linkage plays a less important role in bilayer (rather than pore) energy surfaces and at higher molecular weights. If the ligand-receptor interaction is accompanied by energy transfer to or from ligands, the flux via the quantum functional linkage can equal or exceed the classically expected flux at all relevant ligand molecular weights. These findings are discussed in relation to earlier work and the limitations of the model emphasized.

Notes: Abstract A new measure of subalignment similarity is introduced. Specifically, similaritys(l,c) is defined as the logarithm to the basep of the probability of findingc or fewer mismatches in a subalignment of lengthl, wherep is the probability of a match. Previous algorithms can not use this measure to find locally optimal subalignments because, unlike Needleman-Wunsch and Sellers similarities, this measure is nonlinear. A new pattern recognition algorithm is described for finding all locally optimal subalignments of two nucleotide sequences. The DD algorithm can uses(l, c) or any other reasonable similarity function to assess the relative interest of subalignments. The DD algorithm searches only the diagonal graph, which lacks insertions and deletions. This search strategy greatly decreases the computation time and does not require an arbitrary choice of gap cost. The paths of the resulting DD graph usually draw attention to likely locations for insertions and deletions. A heuristic formula is derived for estimating significance levels fors(l, c) in the context of the lengths of the two aligned sequences. The DD algorithm has been used to find interesting subalignments between the nucleotide sequences for human and murine interleukin 2.

Notes: Abstract We present a new symmetric model of the idiotypic immune network. The model specifies clones of B-lymphocytes and incorporates: (1) influx and decay of cells; (2) symmetric stimulatory and inhibitory idiotypic interactions; (3) an explicit affinity parameter (matrix); (4) external (i.e. non-idiotypic) antigens. Suppression is the dominant interaction, i.e. strong idiotypic interactions are always suppressive. This precludes reciprocal stimulation of large clones and thus infinite proliferation. Idiotypic interactions first evoke proliferation, this enlarges the clones, and may in turn evoke suppression. We investigate the effect of idiotypic interactions on normal proliferative immune responses to antigens (e.g. viruses). A 2-D, i.e. two clone, network has a maximum of three stable equilibria: the virgin state and two asymmetric immune states. The immune states only exist if the affinity of the idiotypic interaction is high enough. Stimulation with antigen leads to a switch from the virgin state to the corresponding immune state. The network therefore remembers antigens, i.e. it accounts for immunity/memory by switching beteen multiple stable states. 3-D systems have, depending on the affinities, 9 qualitatively different states. Most of these also account for memory by state switching. Our idiotypic network however fails to account for the control of proliferation, e.g. suppression of excessive proliferation. In symmetric networks, the proliferating clones suppress their anti-idiotypic suppressors long before the latter can suppress the former. The absence of proliferation control violates the general assumption that idiotypic interactions play an important role in immune regulation. We therefore test the robustness of these results by abandoning our assumption that proliferation occurs before suppression. We thus define an “escape from suppression” model, i.e. in the “virgin” state idiotypic interactions are now suppressive. This system erratically accounts for memory and never for suppression. We conclude that our “absence of suppression from idiotypic interactions” does not hinge upon our “proliferation before suppression” assumption.

Notes: Abstract Analytical bounding functions for diffusion problems with Michaelis-Menten kinetics were recently presented by Anderson and Arthurs, 1985 (Bull. math. Biol. 47, 145–153). Their methods, successful to some extent for a small range of parameters, has the disadvantage of providing a weak upper bound. The optimal approach for the use of one-line bounding kinetics is presented. The use of two-line bounding kinetics is also shown, in order to give, sufficient accuracy in those cases where the one-line approach does not provide satisfactory results. The bounding functions provide excellent upper and lower bounds on the true solution for the entire range of kinetic and transport parameters.

Notes: Abstract Thresholds for survival and extinction are important for assessing the risk of mortality in systems exposed to exogeneous stress. For generic, rudimentary population models and the classical resource-consumer models of Leslie and Gallopin, we demonstrate the existence of a survival threshold for situations where demographic parameters are fluctuating, generally, in a nonperiodic manner. The fluctuations are assumed, to be generated by exogenous, anthropogenic stresses such as toxic chemical exposures. In general, the survival threshold is determined by a relationship between mean stress measure in organisms to the ratio of the population intrinsic growth rate and stress response rate.

Notes: Abstract A stochastic analog to a deterministic model describing subpopulation emergence in heterogeneous tumors is developed. The resulting system is described by the Fokker-Planck or forward Kolmogorov equation. A finite element approach for the numerical solution to this equation is described. Four biological and clinical scenarios are simulated (emergence of heterogeneity, exclusion of a subpopulation, and induction of drug resistance in both pure and heterogeneous tumors). The results of the simulations show that the stochastic model describes the same basic dynamics as its deterministic counterpart via a convective component, but that for each simulation a distribution of tumor sizes and mixes can also be derived from a diffusive component in the model. These distributions yield estimates for subpopulation extinction probabilities. The biological and clinical relevance of these results are discussed.

Notes: Abstract Nonlinear similarity functions are often better than linear functions at distinguishing interesting subalignments from those due to chance. Nonlinear similarity functions useful for comparing biological sequences are developed. Several new algorithms are presented for finding locally optimal subalignments of two sequences. Unlike previous algorithms, they may use any reasonable similarity function as a selection criterion. Among these algorithms are VV-1, which finds all and only the locally optimal subalignments of two sequences, and CC-1, which finds all and only the weakly locally optimal subalignments of two sequences. The VV-1 algorithm is slow and interesting only for theoretical reasons. In contrast, the CC-1 algorithm has average time complexityO(MN) when used to find only very good subalignments.

Notes: Abstract A resource-based competition model of two consumer species and one resource species is formulated in the form of a Lotka-Volterra system. The competition involves both exploitation and interference. By a method of asymptotic estimates, sufficient conditions are derived for the three species system to converge ast→∞ to an equilibrium point with all three species present; a generalization of the result forn≥2 and single resource species is indicated. The strong form of equilibrium perisistence of the three species consumer-resource system is achieved by the ability of each of the consumer species to exploit the resource and interfere with others in such a way which will avoid exclusion by the other.

Notes: Abstract Two algorithms for the efficient identification of segment neighborhoods are presented. A segment neighborhood is a set of contiguous residues that share common features. Two procedures are developed to efficiently find estimates for the parameters of the model that describe these features and for the residues that define the boundaries of each segment neighborhood. The algorithms can accept nearly any model of segment neighborhood, and can be applied with a broad class of best fit functions including least squares and maximum likelihood. The algorithms successively identify the most important features of the sequence. The application of one of these methods to the haemagglutinin protein of influenza virus reveals a possible mechanism for conformational change through the finding of a break in a strong heptad repeat structure.

Notes: Abstract Given a sequenceA and regular expressionR, theapproximate regular expression matching problem is to find a sequence matchingR whose optimal alignment withA is the highest scoring of all such sequences. This paper develops an algorithm to solve the problem in timeO(MN), whereM andN are the lengths ofA andR. Thus, the time requirement is asymptotically no worse than for the simpler problem of aligning two fixed sequences. Our method is superior to an earlier algorithm by Wagner and Seiferas in several ways. First, it treats real-valued costs, in addition to integer costs, with no loss of asymptotic efficiency. Second, it requires onlyO(N) space to deliver just the score of the best alignment. Finally, its structure permits implementation techniques that make it extremely fast in practice. We extend the method to accommodate gap penalties, as required for typical applications in molecular biology, and further refine it to search for substrings ofA that strongly align with a sequence inR, as required for typical data base searches. We also show how to deliver an optimal alignment betweenA andR in onlyO(N+logM) space usingO(MN logM) time. Finally, anO(MN(M+N)+N 2logN) time algorithm is presented for alignment scoring schemes where the cost of a gap is an arbitrary increasing function of its length.

Notes: Abstract The stochastic complexity of a data base of 365 protein-coding regions is analysed. When the primary sequence is modeled as a spatially homogeneous Markov source, the fit to observed codon preference is very poor. The situation improves substantially when a non-homogeneous model is used. Some implications for the estimation of species phylogeny and substitution rates are discussed.

Notes: Abstract We present, in an easy to use form, the large deviation theory of the binomial distribution: how to approximate the probability ofk or more successes inn independent trials, each with success probabilityp, when the specified fraction of successes,a≡k/n, satisfies 0〈p〈a〈1.

Notes: Abstract A linear segment in which a number of pairs of intervals of equal length are identified as potential stems is the subject of a folding problem analogous to inference of RNA secondary structure. A quantity of free energy (or equivalently, energy per unit length) is associated with each stem, and the various types of loops are assigned energy costs as a function of their lengths. Inference of stable structures can then be carried out in the same way as in RNA folding. More important, perturbation of stem lengths and energy densities (modelling various mutational processes affecting nucleotide sequences) allows the delineation of domains of stability of various foldings, through the explicit calculation of their boundaries, in a low-dimensional parameter space.

Notes: Abstract In sensory physiology, various System Identification methods are implemented to formalized stimulus-response relationships. We applied the Volterra approach for characterizing input-output relationships of cells in the medial geniculate body (MGB) of an awake squirrel monkey. Intraspecific communication calls comprised the inputs and the corresponding cellular evoked responses—the outputs. A set of vocalization was used to calculate the kernels of the transformation, and these kernels subserved to predict the responses of the cell to a different set of vocalizations. It was found that it is possible to predict the response (PSTH) of MGB cells to natural vocalizations, based on envelopes of the spectral components of the vocalization. Some of the responses could be predicted by assuming a linear transformation function, whereas other responses could be predicted by non-linear (second order) kernels. These two modes of transformation, which are also reflected by a distinct spatial distribution of the linearvis-à-vis non-linear responding cells, apparently representa new revelation of parallel processing of auditory information.

Notes: Abstract The time-dependent surface coverage of antigen-antibody complexes for a sensor in which antigens are bound to surface immobilized antibodies is determined analytically. Assuming a reversible first order reaction between the antigens and antibodies, a model is derived describing the dynamical response of the sensor. The surface coverage is related explicitly to the antigen concentration which is of special interest in experimental situations. The stationary state and short time behaviour are determined explicitly. Several illustrations of the full solution are provided.

Notes: Abstract Simple reaction time is the minimum time required to respond to a signal such as a steady light or tone. Such a reaction time is taken to be the time required for transmission of a fixed quantity of information, ΔH, from stimulus to subject. That is, information summation replaces energy summation. This information is calculated from consideration of the quantum nature of the stimulus. The theoretically derived equation for reaction time is fitted to experimental data. Piéron's empirical law for reaction time is obtained as an approximation from a proposed informational equation. The exponent in Piéron's law is found to be the same as the exponent in the power law of sensation. Threshold appears to be the smallest stimulus capable of transmitting the quantity of information ΔH.

Notes: Abstract This paper is a brief historical review of linear singular systems, followed by a survey of results on their solution and properties. The frequency domain and time domain approaches are discussed together to sketch an overall picture of the current status of the theory.

Notes: Abstract The performance of a symmetric nonrecursive filter can be improved by multiple use of the same filter. The method is based on an Amplitude Change Function (ACF). An approach to the design of nonrecursive filters using an ACF is discussed in this paper. The prototype filter chosen is a Recursive Running Sum (RRS) filter which does not require any multipliers for its implementation. The required filter specifications are met by multiple use of the RRS filters. The overall filter requires a much smaller number of multiplications and adders than the one designed using the conventional method. It is shown that this method provides reduced noise due to coefficient quantization and product quantization compared with the conventional design technique.

Notes: Abstract This paper establishes the large-sample accuracy properties of two nonlinear least-squares estimators (NLSE) of sine-wave parameters: the basic NLSE, which ignores the possible correlation of the noise, and the optimal NLSE, which, besides the sine-wave parameters, also estimates the noise correlation (appropriately parametrized). It is shown that these two NLS estimators have thesame accuracy in large samples. This result provides complete justification for preferring the computationally less expensive basic NLSE over the “optimal” NLSE. Both estimators are shown to achieve the Cramér-Rao Bound (CRB) as the sample size increases. A simple explicit expression for the CRB matrix is provided, which should be useful in studying the performance of sine-wave parameter estimators designed to work in the colored-noise case.

Notes: Abstract Multidimensional lossless networks are of special interest for use as reference structures for multidimensional wave digital filters [l]–[3]. The starting point of the presented synthesis procedure for two-dimensional representatives of the networks mentioned is a scattering matrix description of the desired multiport. This given matrix is assumed to have those properties which have turned out to be necessary [9], [10] for any scattering matrix of a multidimensional lossless network. The method presented for the synthesis of 2-D reactancem-ports is based mainly on known properties of block-companion matrices and the factorization of a univariable rational matrix which is discrete para-Hermitian and nonnegative definite on the unit circle. The resulting network always contains only a minimal number of frequency-dependent building elements. No restrictions are made concerning the coefficients of the rational entries of the scattering matrix; they may be either real or complex, so as to include even complex networks which are of special interest for multi-dimensional wave digital filters [3].

Notes: Abstract Examples are given concerning the range of applicability of recent representation results that provide a means of studying the input-output properties of nonlinear systems in terms of the familiar impulse-response concept, and which extend the concept of integral transformation to nonlinear maps. We show that such representations, which we call “g-” and “h-representations,” exist for important classes of systems governed by nonlinear integral equations. In particular, it is proved that a large class of maps that have Volterra series representations also have these representations.

Notes: Abstract An understanding of the comparative statics of biological communities is important both as a means of explaining the long-term effects of changes in environmental conditions, and as a framework for viewing community time trajectories. A general formulation of community dynamics is presented here which, given full information about a particular community's dynamic behavior, describes the impact of a change in environmental conditions on the community steady state. However, since such full information is often lacking in studies of biological communities, various approaches to partial information analysis of comparative statics are presented and compared, including a generalized protocol for isocline analysis. The suggested isocline protocol is shown to be a useful tool for both full and partial information analyses, as well as for both general and partial equilibrium studies.

Notes: Abstract Fujita's diagrams in phyllotaxis, showing the frequencies of divergence angles as a function of these angles for low phyllotactic patterns such as (2, 1) and (3, 2), which are approximately normal curves centered at the limitdivergence angle of 137.51°, are shown to be puzzling when compared to results and observations in the field. An analysis of these diagrams is proposed, in the context of Fujita's methodology, of data from other sources, of a mathematical theorem on lattices, and of the contact pressure theory of phyllotaxis.

Notes: Abstract It is shown that a representative Fisher-Wright model withn(≥3) diallelic loci admits a necessary condition for existence of a time-independent steady-state probability distribution. This necessary condition states that a global integral depending on the phenotype fitness functions of natural selection must be larger than a certain quantity depending on the parameters associated with genetic drift.

Notes: Abstract Equations for the time-dependent concentrations of all species involved in the general mechanism of human plasminogen activation proposed by Wohlet al. (J. biol. Chem. 255, 2005–2013, 1980) have been derived. These equations are valid for the whole course of the reaction: for both the transient phase and the steady state. In addition, we compare our results with the ones obtained by the above-mentioned authors for the steady state assuming rapid equilibrium conditions. Finally, we propose a method for the determination of all velocity constants.

Notes: Abstract A special class of interval graphs is defined and characterized, and an algorithm is given for their construction. These graphs are motivated by an important representation of DNA called restriction maps by molecular biologists. Circular restriction maps are easily included.

Notes: Abstract Over the past 25 years stepwise improvement in the cure of disseminated cancers has been good, fair or very poor depending on the particular cancer one is discussing. “Cancer chemotherapy provides variably effective treatment for the majority of forms of human cancer and curative treatment for some 12 categories.” We have been slow to gain and learn how to apply quantitative information on the biologic phenomena that underlie the responsiveness, or lack of responsiveness, of many different cancers to single drugs and combinations of drugs delivered in different ways. I am of the opinion that continuing development and integration of rational biomathematical models based on principles already identified, and testing them for compatibility with much already available experimental and clinical data, will lead to models that will help in planning more effective treatment regimens for cancers now classified as moderately refractory or very refractory to chemotherapy. Some of the critical variables are considered briefly. My advice, for what it is worth, is “try to be sure that the biologic concepts that you use in modeling are almost as good as the arithmetic.”

Notes: Abstract A discussion of the bases of physiological pharmacokinetics is followed by a brief review of the fundamental mass balance equations of the models. Some examples are outlined, together with a listing of published reviews which give many more references and detailed examples. Finally, some thoughts on future research directions are presented.

Notes: Abstract The use of stochastic simulation languages in cell kinetics research is discussed. Two special purpose simulation languages; CELLSIM and CELLGROW are described and example problems are presented.

Notes: Abstract Mathematical models predicting tissue doses of chemical toxicants can be either highly complex or simple, depending upon the end results needed. As an example of a highly complex mathematical model, the Miller Model of the distribution of reactive gases in human and animal lungs is described. The Miller Model accounts for the convection, the radial and axial diffusion, and the chemical reactions of gases as an inhaled breath passes down the airways. The geometry and physiology of human and animal lungs are used to calculate the convection and diffusion likely in each generation or bifurcating series of airways commencing with the trachea and extending 24 generations in humans. The chemical reactivity of ozone, an air pollutant, is accounted for by simulating second-order chemical reactions with the fluid lining materials of the lung and tissue biological molecules. The flux of ozone into three compartments (pulmonary tissue, overlying liquid layer and capillary blood) in each generation of the lung is calculated to provide molecular doses of ozone reaching each region of the lung. These results of calculated molecular dose are then used to construct dose-response curves for a variety of biological endpoints. A much simpler model is also described which recognizes the saturable or Michaelis-Menten type of kinetics controlling the removal of nickelous ion (nickel) from the lung. This model is used to calculate the chronic lung burden of the human lung for occupational, environmental and cigarette smoking exposure scenarios. In both the complex Miller Model and the simpler nickel lung burden model, the results can be used to calculate molecular doses at the potential site of action of these environmental chemicals and to unify a wide variety of studies. The predictions made are more likely to be valid since multiple investigators using a variety of animal species have participated in generation of the primary data. As a methodology, mathematical modeling based on physiological, physicochemical and anatomical principles provides a means of eliminating non-scientific considerations from the important process of regulating and recognizing toxic or cancer causing chemicals in the human environment.

Notes: Abstract This paper presents a brief review of applications of kinetic simulation of multi-enzyme networks to the study of antimetabolite drugs used as anticancer agents. Kinetic models consist of systems of nonlinear differential equations that describe changes in concentrations of cellular metabolites with respect to time. Such models have been used to predict the effect of changes in activity of enzymes, or changes in enzyme kinetic parameters, on sensitivity to inhibition. Kinetic simulation has provided insight into several aspects of the biochemical pharmacology of antimetabolites, including drug sensitivity and resistance, and drug-drug interactions. Two specific studies are described in detail. The first concerns the importance of the ratio of competing enzymes in determining the selectivity of inhibitors of one of the competing enzymes, studied by a simple model. The second case study examines the effect of alternative biosynthetic pathways, thede novo and salvage pathways of pyrimidine nucleotide biosynthesis, on the selectivity of antipyrimidine drugs, as studied by a detailed model of 27 reactions of pyrimidine metabolism.

Notes: Abstract General (deterministic) ordinary differential equations for the representation of cancer growth are presented when the growth is perturbed due to the action of a chemotherapeutic agent. The Verhulst-Pearl equation is introduced as a particular example of a growth equation applicable to human tumors. An optimal control problem with general performance criterion and state equation is formulated and shown to possess a novel feedback control relationship. This relationship is used in two continuous drug delivery problems involving the Verhulst-Pearl equation.

Notes: Abstract Complex networks of biological processes are analogous to electrical circuits. For each step in a biological or electrical network, flow is dependent on the driving force and the conductivity of the step. The relationship between biological flows and their driving forces can therefore be expressed as relationships between analogous currents and voltages. The time dependence of approach to equilibrium or a steady state is determined by the rates of depletion of material in various compartments. Electrical capacitance is therefore analogous to compartment volume. Once these generalized concepts of flow, force and capacitance are recognized, it becomes clear that computer programs designed for analysis of electrical circuits may be used for simulation of biological networks. A set of simple mathematical descriptions of the individual steps and a diagram showing how the steps are arranged with respect to each other are all that is necessary to perform a simulation; there is no need for computer programming skills or differential equations. The use of SPICE2 for simulation of the cellular and plasma pharmacokinetics of cytosine arabinoside (araC) is described as an example. A network model is developed which considers cellular pharmacokinetics (membrane transport, intracellular phosphorylation and dephosphorylation), and plasma pharmacokinetics following infusions of araC.

Notes: Abstract Developments in computer hardware and software are making significant improvements in the availability of simulation for biomedical researchers. This paper reviews past and present techniques for digital computer simulation and looks at improvements likely in the near future. In the area of hardware, personal computers are making computing and simulation more widely available and at the same time, supercomputers and special-purpose numerical processors are making it possible to solve larger problems. Software developments for simulation are reducing the time, effort and special skills required to produce a simulation program. A new hierarchical linker is proposed to make it easy to synthesize a global model by combining existing submodels. In the more distant future, computer models may be constructed graphically and with the assistance of intelligent programs capable of analysis and information retrieval.

Notes: Abstract Modeling is a ubiquitous and often misunderstood enterprise in which data from diverse disciplines are analyzed by techniques from other diverse disciplines in an attempt to confirm or falsify a set of hypotheses about the real world. Guidelines are offered for designing models to match the goals of modeling biological systems. Techniques for the construction and interpretation of models are discussed. The requirements for credibility of models are detailed, and tests are suggested for their validation.

Notes: Abstract Presentations and discussions at the symposium illustrate some general issues in biomedical modeling for cancer research. Given the motivations for modeling and assumptions concerning who should be involved in the modeling process, one can identify some basic needs to be met in supports to modelers. These concern both the models themselves and ways of presenting them to users. In conclusion, some thoughts are offered on economic and educational issues that may affect the infusion of modeling into biomedical research.

Notes: Abstract This article extends the use of dynamic programming algorithms in molecular sequence comparison to the alignment of the α-carbon (Cα-) coordinates of two protein structures in three dimensions. The algorithm is described in detail and is applied to the comparison of α-lactalbumin with both hen egg white lysozyme and T4 lysozyme. In the first case, the structures are similar, while the second comparison is between two distantly related molecules. References are made to the usual sequence alignments. A variety of complementary methods are introduced to display the results.

Notes: Abstract The composition of naturally occurring DNA sequences is often strikingly heterogeneous. In this paper, the DNA sequence is viewed as a stochastic process with local compositional properties determined by the states of a hidden Markov chain. The model used is a discrete-state, discreteoutcome version of a general model for non-stationary time series proposed by Kitagawa (1987). A smoothing algorithm is described which can be used to reconstruct the hidden process and produce graphic displays of the compositional structure of a sequence. The problem of parameter estimation is approached using likelihood methods and an EM algorithm for approximating the maximum likelihood estimate is derived. The methods are applied to sequences from yeast mitochondrial DNA, human and mouse mitochondrial DNAs, a human X chromosomal fragment and the complete genome of bacteriophage lambda.

Notes: Abstract A new and apparently rather useful and natural concept in cluster analysis is studied: given a similarity measure on a set of objects, a sub-set is regarded as a cluster if any two objectsa, b inside this sub-set have greater similarity than any third object outside has to at least one ofa, b. These clusters then form a closure system which can be described as a hypergraph without triangles. Conversely, given such a system, one may attach some weight to each cluster and then compose a similarity measure additively, by letting the similarity of a pair be the sum of weights of the clusters containing that particular pair. The original clusters can be reconstructed from the obtained similarity measure. This clustering model is thus located between the general additive clustering model of Shepard and Arabie (1979) and the standard hierarchical model. Potential applications include fitting dendrograms with few additional nonnested clusters and simultaneous representation of some families of multiple dendrograms (in particular, two-dendrogram solutions), as well as assisting the search for phylogenetic relationships by proposing a somewhat larger system of possibly relevant “family groups”, from which an appropriate choice (based on additional insight or individual preferences) remains to be made.

Notes: Abstract An important component of computer programs for determining the solution conformation of proteins and other flexible molecules from nuclear magnetic resonance data are the so-called “bound smoothing algorithms”, which compute lower and upper limits on the values of all the interatomic distances from the relatively sparse set which can usually be measured experimentally. To date, the only methods efficient enough for use in large problems take account of only the triangle inequality, but an appreciable improvement in the precision of the limits is possible if the algebraic relations between the distances among each quadruple of atoms are also considered. The goal of this paper is to use a recently improved algorithm for computing these “tetrangle inequality limits” to determine just how much improvement really is possible, given the types of experimental data that are usually available.

Notes: Abstract We apply the concept of marginal stability hypothesis, which has been proposed for solving the problem of dendritic crystal growth, to the pattern selection problem in the Gierer-Meinhardt models. In the case of a large system, the system selects a definite wavelength of the ultimate spatial pattern when the unstable homogeneous steady state is locally disturbed. The numerical results are analyzed theoretically by means of the marginal stability hypothesis, and they are in good agreement with it. Biologically, these results imply why for large systems the Gierer-Meinhardt model (and presumably other reaction-diffusion schemes) have the ability to explain the observation that pattern-generating mechanisms are remarkably insensitive to a wide range of environmental and experimental conditions.

Notes: Abstract Small networks of threshold automata are used to model complex interactions between populations of regulatory cells (helpers and suppressors, antigen specific and anti-idiotypic) which participate in the immune response. The models, being discrete and semiquantitative, are well adapted to the situation of incomplete information often encounteredin vivo. However, the dynamics of many different network structures usually end up in the same attractor set. Thus, many different theories are equivalent in their explicative power for the same facts. This property, known as underdetermination of the theories by the facts, is given a quantitative estimate. It appears that such an underdetermination, as a kind of irreductible complexity, can be expected in manyin vivo biological processes, even when the number of interacting and functionally coupled elements is relatively small.

Notes: Abstract The “paradox of enrichment” predicts that increasing the growth rate of the resource in a resource-consumer dynamic system, by nutrient enrichment, for example, can lead to local instability of the system—that is, to a Hopf bifurcation. The approach to the Hopf bifurcation is accompanied by a decrease in resilience (rate of return to equilibrium). On the other hand, studies of nutrient cycling in food webs indicate that an increase in the nutrient input rate usually results in increased resilience. Here these two apparently conflicting theoretical results are reconciled with a model of a nutrient-limited resource-consumer system in which the tightly recycled limiting nutrient is explicitly modelled. It is shown that increasing nutrient input may at first lead to increased resilience and that resilience decreases sharply only immediately before the Hopf bifurcation is reached.

Notes: Abstract Statistical properties of topological binary trees are studied on the basis of the distribution of segments in relation to centrifugal order. Special attention is paid to the mean of this distribution in a tree as it will be used as a measure of tree topology. It will be shown how the expectation of the mean centrifugal order depends both on the size of the tree and on the mode of growth in the context of modelling the growth of tree structures. Observed trees can be characterized by their mean orders and procedures are described to find the growth mode that optimally corresponds to these data. The variance structure of the mean-order measure appears to be a crucial factor in these fitting procedures. Examples indicate that mean-order analysis is an accurate alternative to partition analysis that is based on the partitioning of segments over sub-tree pairs at branching points.

Notes: Abstract We propose certain general conditions that we believe are reasonable for any pattern recognition algorithm. We find that these conditions give rise to paradoxical identification. The algorithms are incapable of distinguishing composite patterns and must be able to distinguish patterns at an atomistic level.

Notes: Abstract A stratigraphically oriented series of the Miocene foraminiferal speciesBrizalina mandoroveensis from Ikang, Cameroon, was analyzed both by conventional multivariate morphometric procedures and by the tensor biometric method of Bookstein (1986;Statist. Sci. 1, 181–142), a method which analyzes sets of landmark points rather than specific variables of shape or size. The conventional analysis used five size-measures upon 170 specimens from five stratigraphic levels; the tensor analysis encompassed six landmarks (12 coordinates) upon 50 specimens. Whereas certain features appeared in both analyses, such as the separation between levels one and five, the techniques did not always agree with respect to the interpretation of those findings or about most details in the sequence of mean phenotypes. The canonical variate analysis bases its ordination upon a general size factor (the meaning of which is obscured by the foreshortening of within-group variation which is built into the technique). The tensor analysis locates a similar ordination using mainly features of shape.

Notes: Abstract In a separate paper, we developed a mathematical model describing HIV infection and used it to suggest experiments for quantifying characteristic viral parameters. In this paper we generalize the model to any well-mixed assay system. We also present complete and rigorous derivations of fundamental results needed for the design and analysis of HIV infectivity assays. The model is applicable to infectious agents with multiple receptors for their target cell (e.g. HIV, Epstein-Barr virus and Plasmodium), and to blockers (both reversible and irreversible), as long as blocker and target cells are the same diffusion compartment.

Notes: Abstract A general version of a model of Ebenman for the dynamics of a population consisting of competing juveniles and adults is analyzed using methods of bifurcation theory. A very general existence results is obtained for non-trivial equilibria and non-negative synchronous two-cycles that bifurcate simultaneously at the critical valuer=1 of the inherent net reproductive rater. Stability is studied in this general setting near the bifurcation point and conditions are derived that determine which of these two bifurcating branches is the stable branch. These general results are supplemented by numerical studies of the asymptotic dynamics over wider parameter ranges where various other bifurcations and stable attractors are found. The implications of these results are discussed with respect to the effects on stability that age class competition within a population can have and whether such competition is stabilizing or destabilizing.

Notes: Abstract Phototransduction is a process which links the absorption of photons by a rod or cone to the modulation of voltage across the cell membrane. An important feature of many vertebrate photoreceptors is a mechanism that adjusts the sensitivity and dynamics of the response to light according to the level of illumination. We construct a system of ordinary differential equations that models what are currently thought to be the important molecule mechanisms involved in phototransduction: this includes consideration of both intracellular enzyme kinetics and the properties of light-insensitive and light-sensitive conductances in the cone membrane. The system contains negative feedback whose functional form is determined by constraining the steady-state behaviour of the system. Despite the highly nonlinear nature of the system of ordinary differential equations, our methods permit us to derive an analytic expression for the first-order frequency response parametric in the steady-state value of only one dynamic variable, the light input. Various unknown kinetic parameters are found by fitting the model to experimental data on the first-order frequency response of cones measured at several mean light levels spanning a range of four log units. Good fits are obtained to the data, and the computed shape of the feedback function agrees qualitatively with recent experiment. Moreover, the model accounts for the dramatic speeding up of the response kinetics and the decrease in response gain with increasing light level.

Notes: Abstract Certain properties of solutions similar to set invariance, set attractivity, boundedness, BIBO stability, etc. are investigated for the semistate model $$P(t)\dot x = M(t,x)x + D(t,x)u,y = q(t,x,u).$$ For systems considered, it is assumed that the reduction to a normal form of lower order is not possible. Using the direct method of Liapunov, the properties of solutions are investigated without actual knowledge of solutions.

Notes: Abstract In this paper we extend the results on the multiple time-scale structure for linear autonomous systems of the form $$\dot x = A( \in )x$$ (cf. Coderchet al. [1]) to nonlinear autonomous systems. Our main result is in obtaining conditions under which the linearized system and the nonlinear system around an equilibrium point have the same time-scale structure.

Notes: Abstract The process of cooperative binding of ligands to DNA has been classified into different modes. An additional mode of cooperative interaction amongst ligands binding at sites on complementary strands has been emphasised. A statistical mechanical method has been applied to obtain an analytical expression for the fraction of nucleotide sites bound. Theoretical Scatchard plots have been drawn and analysed.

Notes: Abstract Suspensions of chemotactic bacteria develop spatial and temporal structures in response to an initial inhomogeneity in the medium. A theoretical model is presented for the analysis of spatial and temporal evolution of bacterial bands in response to several attractants. Applications of the model to various experimental cases give good agreement between theory and observation. The theoretical analysis provides further insight to the mechanisms governing band formation and band migration.

Notes: Abstract The theory of maximum principles is applied to a nonlinear differential equation representing a heat conduction model of the human head to obtain accurate analytical upper and lower bounding curves.

Notes: Abstract This paper is a general introduction to the field of biomathematical modeling. Biomathematical modeling is divided into three parts: the derivation of models, the fitting of models to data, and the simulation of data from models. This paper focuses on the simulation of data from models. The uses of simulation, the potential users of simulation, and simulation software are described.

Notes: Abstract A stochastic model for the chemotherapy of experimental tumors is presented. The focus of this model is on the presence of drug-resistant mutants and their influence on eventual treatment outcome. Equations are derived for the joint probability-generating function for the number of chemo-sensitive and chemo-resistant cells. The model is extended to two drugs and it is shown how the model may be used to make deductions regarding the optimum scheduling of therapy.

Notes: Abstract Earlier and some recent ideas about the possible modes of specification of the wiring-in of nervous systems are reviewed in the light of older and several recent experiments, and some new ideas are suggested. It is argued that certain general principles, notably the postulated ‘principle of alternative matching’ (PALMA) and a suggested and related ‘kaleidoscopic effect’ (KALEF), as well as the notion of an ‘extracellular guidance network’ (ECGN), are in good agreement with recent and older findings concerning axonal guidance during neural wiring-in. It seems possible that by means of genetically programmed processes, neurons become systematically combinatorially labelled to such a degree that possibly all neurons areuniquely specified, as regards the combination oftypes of cell labels they make. Yet, there remains considerable freedom as regards the modes of arrangements of cell labels within cell surface membranes and the KALEF permits to overcome apparent difficulties that confronted earlier versions of the cell labelling hypotheses (cf. Edelman,Science 219, 450–457, 1983, for mention of such difficulties). Apart from label specification, neural development seems to depend on trophic factors, which are also essential for the maintenance of the developed nervous system. The systematic programmes for cell labelling, apart from generating all the required neurons, also produces inappropriate neurons and synaptic connections. These are got rid of by systematic cell death and/or atrophy of inappropriate synapses and/or elimination of inappropriate axon collaterals. The resulting neural net seems then very specifically wired-in for each species, apparently without redundant neurons.

Notes: Abstract We first analyse a simple symmetric model of the idiotypic network. In the model idiotypic interactions regulate B cell proliferation. Three non-idiotypic processes are incorporated: (1) influx of newborn cells; (2) turnover of cells: (3) antigen. Antigen also regulates proliferation. A model of 2 B cell populations has 3 stable equilibria: one virgin, two immune. The twodimensional system thus remembers antigens, i.e. accounts for immunity. By contrast, if an idiotypic clone proliferates (in response to antigen), its anti-idiotypic partner is unable to control this. Symmetric idiotypic networks thus fail to account for proliferation regulation. In high-D networks we run into two problems. Firstly, if the network accounts for memory, idiotypic activation always propagates very deeply into the network. This is very unrealistic, but is an implication of the “realistic” assumption that it should be easier to activate all cells of a small virgin clone than to maintain the activation of all cells of a large (immune) clone. Secondly, graph theory teaches us that if the (random) network connectance exceeds a threshold level of one interaction per clone, most clones are interconnected. We show that this theory is also applicable to immune networks based on complementary matching idiotypes. The combination of the first “percolation” result with the “interconnectancr” result means that the first stimulation of the network with antigen should eventually affect most of the clones. We think this is unreasonable. Another threshold property of the network connectivity is the existence of a virgin state. A gradual increase in network connectance eliminates the virgin state and thus causes an abrupt change in network behaviour. In contrast to weakly connected systems, highly connected networks display autonomous activity and are unresponsive to external antigens. Similar differences between neonatal and adult networks have been described by experimentalists. The robustness of these results is tested with a network in which idiotypic inactivation of a clone occurs more generally than activation. Such “long-range inhibition” is known to promote pattern formation. However, in our model it fails to reduce the percolation, and additionally, generates semi-chaotic behaviour. In our network, the inhibition of a clone that is inhibiting can alter this clone into a clone that is activating. Hence “long-range inhibition” implies “long-range activation”, and idiotypic activation fails to remain localized. We next complicate this model by incorporating antibody production. Although this “antibody” model statically accounts for the same set of equilibrium points, it dynamically fails to account for state switching (i.e. memory). The switching behaviour is disturbed by the autonomous slow decay of the (long-lived) antibodies. After antigenic triggering the system now performs complex cyclic behaviour. Finally, it is suggested that (idiotypic) formation of antibody complexes can play only a secondary role in the network. In conclusion, our results cast doubt on the functional role of a profound idiotypic network. The network fails to account for proliferation regulation, and if it accounts for memory phenomena, it “explodes” upon the first encounter with antigen due to extensive percolation.

Notes: Abstract A new biomathematical description is given for the shape of the birch leaf roller's (Deporaus betulae) incisions. These incisions are investigated for different leaves. The theoretical patterns agree well with the real ones, and the presented mathematical expressions describe well the shape of the real incisions.

Notes: Abstract Nucleotide sequences carry genetic information of many different kinds, not just instructions for protein synthesis (triplet code). Several codes of nucleotide sequences are discussed including: (1) the translation framing code, responsible for correct triplet counting by the ribosome during protein synthesis; (2) the chromatin code, which provides instructions on appropriate placement of nucleosomes along the DNA molecules and their spatial arrangement; (3) a putative loop code for single-stranded RNA-protein interactions. The codes are degenerate and corresponding messages are not only interspersed but actually overlap, so that some nucleotides belong to several messages simultaneously. Tandemly repeated sequences frequently considered as functionless “junk” are found to be grouped into certain classes of repeat unit lengths. This indicates some functional involvement of these sequences. A hypothesis is formulated according to which the tandem repeats are given the role of weak enhancer-silencers that modulate, in a copy number-dependent way, the expression of proximal genes. Fast amplification and elimination of the repeats provides an attractive mechanism of species adaptation to a rapidly changing environment.

Notes: Abstract The kinematics of an area-conserving tank-treading disk-shaped red blood cell membrane is studied using the stream function method suggested by Secomb and Skalak (Q. Jl Mech. appl. Math. 35, Pt 2, 233–247, 1982). Two simple area-conserving velocity fields are superimposed to satisfy the continuity condition at the curved edges of the disk. A differential equation for the trajectory of any material point of the membrane is derived. The requirement of synchrony of the cycle for all membrane points leads to an integral equation which determines a magnitude function. An approximate solution is made possible by assuming small trajectory deflections.

Notes: Abstract The probability of becoming infected with HIV is formulated in terms of the total number of sexual contacts (N), the probability that a sexual act is infectious (r) and the prevalence (p). Using the appropriate equations we studied the effect of reducing each of the risk factors on lowering the probability of infection. We show that for many realistic situations the probability of becoming infected by multiple partners is equal to the probability of becoming infected by one partner in a monogamous relationship given that the prevalence is the same in both cases; however if the multiple partners are chosen over time from a pool of a growing prevalence, then one is better off in a monogamous relationship where that partner is chosen early in the epidemic.

Notes: Abstract In this article the question of reconstructing a phylogeny from additive distance data is addressed. Previous algorithms used the complete distance matrix of then OTUs (Operational Taxonomic Unit), that corresponds to the tips of the tree. This usedO(n 2) computing time. It is shown that this is wasteful for biologically reasonable trees. If the tree has internal nodes with degrees that are bounded onO(n*log(n)) algorithm is possible. It is also shown if the nodes can have unbounded degrees the problem hasn 2 as lower bound.

Notes: Abstract In this paper we analyse time series data as the growth of organisms using markers such as treerings and otolith deposits (fish). The series studied belong to two tree species (Pinus uncinata, Fagus sylvatica) and one fish species (Dicentrarchus labrax). Spectral analyses of the time series growth show that the main frequencies of fluctuation may be due to variations of the energy input. However, any causal explanation must consider the internal continuous readjustment in the system as reported by the corresponding chaotic properties of the asymptotic decay of the spectra time structure. Since the output of noisy and chaotic systems tend to show similar spectral densities, an attempt to differentiate them has been carried out. The chaotic behaviour has been characterized by the study of the attractors. The dimmensions of these multiple topologies were 3.2 and 3.4 for the tree species and 2.3 for the fish species. Therefore, we are dealing with fractal attractors and the minimum number of variables that can be used to describe the systems are 4 and 3 respectively. It is suggested that some of the variables that most influence growth are those obtained by the response functions in the case of trees.

Notes: Abstract A model of a predator-prey interaction, where the prey population consists of three genotypes with random mating and continuous, nonlinear birth and death processes with fertility differences, is proposed. Sufficiency conditions giving the existence of a globally stable equilibrium on one of the coordinate planes are given. This extends results of Freedman and Waltman [J. Math. Biol. 6, 367–374 (1978) andRocky Mountain J. Math. 12, 779–784 (1982)]. In addition, conditions are derived which guarantee the persistence of all components of the populations.

Notes: Abstract A theoretical study is made of three organ flow models with heterogeneity of capillary transit times. A new parametrization of Rose and Goresky's Model III facilitates in many cases a reduction to Goresky's Model II, accomplished by a special time shift. The shift parameter $$\tau _{c_z } = \tau _{c_m } - t_{APP} /b$$ defined here is critical in this analysis of Model III. A new expression of the series for outflow concentration in Model III is given and proves useful in examining the model as an operator and in relating it to Models I and II. A result on parameter optimization is given: if $$\tau _{c_z } \geqslant 0$$ then Model III cannot fit better than Model II. This is applied to some data from Rose and Goresky [Circulation Res. 39, 541–544 (1976)] and raises a new question about their model. A heart model of Levin and Bassingthwaighte based on regional flow measurement is shown to be a discretized generalization of Model II.

Notes: Abstract This paper analyses the diffusion effect on stability in Lotka-Volterra systems for a patch-type environment. Applying the extended stability theorem of LaSalle, some classes of patches for which the diffusion does not affect the system's stability are drawn. Further, complicated dynamical behaviours in two-prey, one-predator diffusion models are given when the patch does not belong to the above classes.