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This work presents a Cellular Automata model to characterize the social and environmental factors which contribute for the analysis of the expansion process of Schistosoma mansoni infection in Pernambuco - Brazil. The model has been experimented with a set of two years real data from a study area at North Coast of Pernambuco – Brazil. The main constraint equations, the modelling process and the results obtained until now with the simulating scenarios generated are presented here. The results identify, as in field works, endemic areas and human risk infection areas. Furthermore, predictive scenarios for a look ahead with a perspective into fifteen years are also presented., Peer Reviewed, Postprint (published version)

Variability is a hallmark of microbial systems. On the one hand, microbes are subject to environmental heterogeneity and undergo changeable conditions in their immediate surroundings. On the other hand, microbial populations exhibit high cellular diversity. The relation between microbial diversity and variability of population dynamics is difficult to assess. This connection can be quantitatively studied from a perspective that combines in silico models and thermodynamic methods and interpretations. The infection process of Plasmodium falciparum parasitizing human red blood cells under laboratory cultivation conditions is used to illustrate the potential of Individual-based models in the context of predictive microbiology and parasitology. Experimental data from several in vitro cultures are compared to the outcome of an individual-based model and analysed from a thermodynamic perspective. This approach allows distinguishing between intrinsic and external constraints that give rise to the diversity in the infection forms, and it provides a criterion to quantitatively define transient and stationary regimes in the culture. Increasing the ability of models to discriminate between different states of microbial populations enhances their predictive capability which finally leads to a better the control over culture systems. The strategy here presented is of general application and it can substantially improve modelling of other types of microbial communities., Postprint (published version)

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La malària és encara avui en dia una malaltia que causa aproximadament un milió de morts a l'any a tot el món. La seva eradicació suposa un gran repte per a la humanitat i per a la comunitat científica, en particular. El cultiu in vitro del paràsit és essencial per al desenvolupament de nous medicaments. Els mètodes de cultiu actuals es basen en l'heurística i requereixen millores. En aquesta tesi es presenta una aproximació teòrica al procés d'infecció a eritròcits en cultius in vitro amb Plasmodium falciparum, un dels protozous paràsits causants de la malària. El treball està centrat en la construcció i avaluació de models d'una complexitat adequada per tractar els problemes específics detectats pels experts en l'àmbit, i inclou també la formulació d'algorismes de simulació i el disseny de protocols experimentals. Aquest tipus de treball requereix de la col·laboració multidisciplinària. La visió dels experts en malària es complementa amb la modelització i simulació, que permet la comprovació dels supòsits preestablerts, la comprensió de fenòmens observats i la millora dels mètodes de cultiu actuals. Així doncs, cal establir i desenvolupar eines que permetin crear, analitzar i compartir models amb grups que estudien la malària des d'altres perspectives. En aquesta tesi, s'ha optat per la modelització basada en l'individu (IbM) i orientada a la reproducció de múltiples patrons (PoM). El model s'ha formulat seguint l'ODD, un protocol estàndard en el camp de l'ecologia teòrica, que s'ha adaptat a la representació de comunitats microbianes. Els models basats en l'individu (IbMs) defineixen un conjunt de normes que regeixen el comportament de cada cèl·lula i les seves interaccions amb les altres cèl·lules i amb el seu entorn immediat. A partir d'aquestes regles, i tenint en compte una certa diversitat dins de la població i un cert grau d'aleatorietat en els processos individuals, els IbMs mostren explícitament el comportament emergent del sistema en conjunt., Malaria is still a major burden that causes approximately one million deaths annually worldwide. Its eradication supposes a great challenge to the humanity and to the scientific community, in particular. In vitro cultivation of the parasite is essential for the development of new drugs. Current culture methods are based on heuristics and demand for specific improvements. The present thesis is a theoretical approach to in vitro cultivation of the protozoan parasite Plasmodium falciparum infecting human red blood cells. It mainly focuses on the process of building a model of appropriate complexity to deal with the specific demands above mentioned, but it also includes the formulation and implementation of algorithms, and the design and execution of experimental trials. This kind of work requires multidisciplinary collaboration: the insight of the experts in malaria research is complemented with modeling and simulation, which allows for checking settled assumptions, increasing the understanding on the system and improving the current culturing methods. The use of tools for building, analyzing and sharing models is an imperative to this end. In this thesis, Pattern-oriented Modeling (PoM) has been adopted as the most appropriate way for raising of models and the ODD protocol (Objectives, Design Concepts and Details) has been proposed as the standard tool for communicating them. Individual-based Modeling (IbM) has been used to tackle malaria culture systems. IbMs define a set of rules governing each cell, its interactions with others and with its immediate surroundings. From this set of rules, and taking into account diversity within the population and a certain degree of randomness in the individual processes, IbMs explicitly show the emerging behavior of the system as a whole. Methods from statistical thermodynamics have been applied to understand the emergence of macroscopic patterns from the population structure (e.g. distribution of infection stages, Postprint (published version)

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In the framework of microbiology, Individual-based Models are discrete models in which the main entities are microbes. Their use in simulations as ‘virtual experiments’ to predict the evolution of populations under specific conditions requires accurate setting of the parameters involved. We adapted and tested two optimization methods for Individual-based Model parameter estimation: the Nelder-Mead Threshold Accepting (NMTA) and the NEWUOA. These methods presented no convergence problems, and the best results in terms of time expenditure were derived with the latter., Peer Reviewed, Postprint (published version)

Several experimental trials exploring different settings have been carried out, covering haematocrit layer depths that ranged from 6 mm to 3 mm and separation between the walls of the culturing device that ranged from 7.5 mm to 9 mm. The obtained results have been analysed and compared to different system-level models and to an Individual-Based Model., Peer Reviewed, Postprint (published version)

The lag phase is the initial phase of a culture that precedes exponential growth and occurs when the conditions of the culture medium differ from the pre-inoculation conditions. It is usually defined by means of cell density because the number of individuals remains approximately constant or slowly increases, and it is quantified with the lag parameter l. The lag phase has been studied through mathematical modelling and by means of specific experiments. In recent years, Individual-based Modelling (IbM) has provided helpful insights into lag phase studies. In this paper, the definition of lag phase is thoroughly examined. Evolution of the total biomass and the total number of bacteria during lag phase is tackled separately. The lag phase lasts until the culture reaches a maximum growth rate both in biomass and cell density. Once in the exponential phase, both rates are constant over time and equal to each other. Both evolutions are split into an initial phase and a transition phase, according to their growth rates. A population-level mathematical model is presented to describe the transitional phase in cell density. INDividual DIScrete SIMulation (INDISIM) is used to check the outcomes of this analysis. Simulations allow the separate study of the evolution of cell density and total biomass in a batch culture, they provide a depiction of different observed cases in lag evolution at the individual-cell level, and are used to test the population-level model. The results show that the geometrical lag parameter l is not appropriate as a universal definition for the lag phase. Moreover, the lag phase cannot be characterized by a single parameter. For the studied cases, the lag phases of both the total biomass and the population are required to fully characterize the evolution of bacterial cultures. The results presented prove once more that the lag phase is a complex process that requires a more complete definition. This will be possible only after the phenomena governing, Postprint (published version)

Micro-organisms play a central role in every ecosystem and in the global biomass cycle. They are strongly involved in many fields of human interest, from medicine to the food industry and waste control. Nevertheless, most micro-organisms remain almost unknown, and nearly 99% of them have not yet been successfully cultured in vitro. Therefore, new approaches and new tools must be eveloped in order to understand the collective behaviour of microbial communities in any natural or artificial setting. In particular, theoretical and practical methodologies to deal with such systems at a mesoscopic level of description (covering the range from 100 to 108 cells) are required. Individualbased modelling (IBM) has become a widely used tool for describing complex systems made up of autonomous entities, such as ecosystems and social networks. Individual-based models (IBMs) provide some advantages over the traditional whole-population models: (a) they are bottom-up approaches, so they describe the behaviour of a system as a whole by establishing procedural rules for the individuals and for their interactions, and thus allow more realistic assumptions for the model of the individuals than population models do; (b) they permit the introduction of randomness and individual variability, so they can reproduce the diversity found in real systems; and (c) they can account for individual adaptive behaviour to their environmental conditions, so the evolution of the whole system arises from the dynamics that govern individuals in their pursuit of optimal fitness. However, they also present some drawbacks: they lack the clarity of continuous models and may easily become rambling, which makes them difficult to analyse and communicate. All in all, IBMs supply a holistic description of microbial systems and their emerging properties. They are specifically appropriate to deal with microbial communities in non-steady states, and spatially explicit IBMs are particularly appropriate to study labor, Postprint (published version)

Malaria is still one of the most fatal diseases in the world. Development of an effective treatment or vaccine requires the cultivation of the parasite that causes it: Plasmodium falciparum. Several methods for in vitro cultivation of P. falciparum infected erythrocytes have been successfully developed and described in the last 30 years. Some problems arising from the current harvests are the low parasitaemia and daily human supervision requirements. The lack of a suitable model for global culture behavior makes the assay of new methodologies a costly and tenuous task. In this paper we present a model and simulation tool for these systems. We use the INDividual DIScrete SIMulation protocol (INDISIM) to qualitatively reproduce the temporal evolution of the erythrocyte and merozoite populations. Whole system dynamics are inferred by setting the rules of behavior for each individual red blood cell, such as the nutrient uptake, metabolism and infection processes, as well as the properties and rules for the culture medium: composition, diffusion and external manipulation. We set the individual description parameters according to the values in published data, and allow population heterogeneity. Cells are arranged in a three-dimensional grid and the study is focused on the geometric constraints and physical design of experimental sets. Several published experimental cultures have been reproduced with computer simulations of this model, showing that the observed experimental behavior can be explained by means of individual interactions and statistical laws., Postprint (published version)

The lag phase has been widely studied for years in an effort to contribute to the improvement of food safety. Many analytical models have been built and tested by several authors. The use of Individual-based Modelling (IbM) allows us to probe deeper into the behaviour of individual cells; it is a bridge between theories and experiments when needed. INDividual DIScrete SIMulation (INDISIM) has been developed and coded by our group as an IbM simulator and used to study bacterial growth, including the microscopic causes of the lag phase. First of all, the evolution of cellular masses, specifically the mean mass and biomass distribution, is shown to be a determining factor in the beginning of the exponential phase. Secondly, whenever there is a need for an enzyme synthesis, its rate has a direct effect on the lag duration. The variability of the lag phase with different factors is also studied. The known decrease of the lag phase with an increase in the temperature is also observed in the simulations. An initial study of the relationship between individual and collective lag phases is presented, as a complement to the studies already published. One important result is the variability of the individual lag times and generation times. It has also been found that the mean of the individual lags is greater than the population lag. This is the first in a series of studies of the lag phase that we are carrying out. Therefore, the present work addresses a generic system by making a simple set of assumptions., Postprint (published version)