The current treatment for hepatitis C virus (HCV) infection – combination therapy with pegylated interferon and ribavirin – elicits sustained responses in only ~50% of the patients treated. Greater cumulative exposure to ribavirin increases response to interferon-ribavirin combination therapy. A key limitation, however, is the toxic sideeffect of ribavirin, hemolytic anemia, which often necessitates a reduction of ribavirin dosage and compromises treatment response. Maximizing treatment response thus requires striking a balance between the antiviral and hemolytic activities of ribavirin. Current models of viral kinetics describe the enhancement of treatment response due to ribavirin. Ribavirin-induced anemia, however, remains poorly understood and precludes rational optimization of combination therapy. Here, we develop a new mathematical model of the population dynamics of erythrocytes that quantitatively describes ribavirin-induced anemia in HCV patients. Based on the assumption that ribavirin accumulation decreases erythrocyte lifespan in a dose-dependent manner, model predictions capture several independent experimental observations of the accumulation of ribavirin in erythrocytes and the resulting decline of hemoglobin in HCV patients undergoing combination therapy, estimate the reduced erythrocyte lifespan in patients and describe inter-patient variations in the severity of ribavirin-induced anemia. Further, model predictions estimate the threshold ribavirin exposure beyond which anemia becomes intolerable and suggest guidelines for the usage of growth hormones. A small fraction of the population (~30%) with polymorphisms in the ITPA gene shows protection from ribavirin-induced anemia. The optimum dosage of ribavirin that can be tolerated is then dependent on the ITPA polymorphisms. Coupled with a previous population pharmacokinetic study, our model yields a facile formula for estimating the optimum dosage given a patient’s weight, creatinine clearance, pretreatment hemoglobin levels, and ITPA polymorphism. The reduced lifespan we predict is in agreement with independent measurements from breath tests as well as estimates derived from in vitro studies of ATP depletion. The latter estimates also agree with the extent of ATP depletion due to ribavirin that we predict from a detailed analysis of the nucleoside metabolism in erythrocytes. Our model thus facilitates in conjunction with models of viral kinetics the rational identification of treatment protocols. Our formula for optimum dose presents an avenue for personalizing ribavirin dosage. By keeping anemia tolerable, the predicted optimal dosage may improve adherence, reduce the need for drug monitoring, and increase response rates.

An object-oriented framework is presented for developing and simulating individual-based models of cell populations. The framework supplies classes to define objects called simulation channels that encapsulate the algorithms that make up a simulation model. These may govern state-updating events at the individual level, perform global state changes, or trigger cell division. Simulation engines control the scheduling and execution of collections of simulation channels, while a simulation manager coordinates the engines according to one of two scheduling protocols. When the ensemble of cells being simulated reaches a specified maximum size, a procedure is introduced whereby random cells are ejected from the simulation and replaced by newborn cells to keep the sample population size constant but representative in composition. The framework permits recording of population snapshot data and/or cell lineage histories. Use of the framework is demonstrated through validation benchmarks and two case studies based on experiments from the literature.

The paper is focused on the Predator-Prey model modified in the case of harvesting one or both populations. Firstly there is given a short description of the basic model and the sensitivity analysis. The first essential modification is percentage harvesting. This model could be easily converted to the basic one using a substitution. The next modification is constant harvesting. Solving this system requires linearization, which was properly done and brought valuable results applicable even for the basic or the percentage harvesting model. The next chapter describes regulation models, which could be used especially in applying environmental policies. All reasonable regulation models are shown after distinguishing between discrete and continuous harvesting. The last chapter contains an algorithm for maximizing the profit of a harvester using econometrical modelling tools.

Le palmier babaçu (Attalea speciosa Mart. ex Spreng.) est une plante native de la forêt amazonienne. La déforestation a pour impact qu'il apparaît dans des milieux ouverts désormais anthropisés (pâturages, et champs cultivés). Le babaçu fait partie des ressources " extractivistes " du Brésil : activité de cueillette suivie de commercialisation de produits non ligneux. Cette activité concerne des personnes parmi les plus démunies du pays d'où l'importance de gérer au mieux sa durabilité dans un contexte conflictuel. Force est de constater que les connaissances du fonctionnement durable de l'espèce au sein de ces milieux anthropisés font cruellement défaut: son cycle de vie est peu connu et sa dynamique de population non étudiée.Le travail de thèse est donc pionnier et s'inscrit au sein d'un projet interdisciplinaire Open Science de la fondation Agropolis. L'objectif est double : il consiste à produire un modèle de la dynamique de population du babaçu validé par une analyse in situ et à capitaliser les connaissances issues de divers milieux scientifiques (biologistes, écologues, mathématiciens, informaticiens et économistes français et brésiliens). Le modèle, à plus long terme, doit étayer les recommandations relatives à la gestion durable de l'espèce.L'approche retenue a consisté à expliciter au sein de divers modèles, les connaissances partagées sur l'espèce et les modèles mathématiques potentiels ainsi que sur le contexte sociétal. Ceci nous a permis de proposer un modèle d'observation conforme aux préconisations d'OBOE (Ontologie relative a la sémantique des observations scientifiques) permettant la mise en place du protocole d'acquisition des données. L'acquisition in situ a été réalisée par le partenariat franco-brésilien entre 2013 et 2016 au sein du territoire de la communauté de Benfica (Pará, Brésil). La pérennisation des données s'est faite après conception, au sein d'une base de données spatiales prenant en compte l'aspect socio-économique.Enfin, nous proposons un modèle matriciel aléatoire ayant pour entrée des variables agrégées au niveau des stades biologiques de l'espèce. Les probabilités de la matrice de transition entre les stades sont modélisées selon un modèle hiérarchique Dirichlet-Multinomial. L'intégration des informations a priori a été formalisée grâce à une approche bayésienne. L'estimation et la validation du modèle ont été effectuées avec des critères bayésiens.Des simulations basées sur les paramètres estimés constituent une première ébauche d'étude du comportement de l'espèce. / The babassu palm tree (Attalea speciosa Mart. ex Spreng.) is an endemic species of the amazonian forests. The deforestation highlights henceforth this palm tree in the anthropogenic open areas (pastures and cultivated fields). The babassu is one of the "extractive" resources in Brazil: gathering activity followed by marketing of non-timber products. This activity involves people among the most disadvantaged in the country thus the importance to better manage its sustainability in a context of conflict. It is clear that knowledge of sustainable functioning of the species within these manmade environments is sorely lacking: its life cycle is not well known and its population dynamics unstudied.This PhD work is pioneer and is a part of an Open Science interdisciplinary project of the Agropolis foundation. The objective is twofold it is to generate a model of population dynamics of the babassu palm tree validated by in situ analysis and capitalizing knowledge from various scientific communities (biologists, ecologists, mathematicians, computer scientists and economists from France and Brazil). In the long-term the model should support the recommendations for the sustainable management of the species.Our approach explicit within different models the shared knowledge about the species and the potential mathematical models as well as the societal context. This has allowed us to provide an observation model compliant with the recommendations ofOBOE (Ontology on a semantic scientific observations) for the development of data acquisition protocol. The acquisition was made in situ by the French-Brazilian partnership between 2013 and 2016 in the community of Benfica (Pará, Brazil). The perpetuation of the data was made after conception, within a spatial database taking into account the socio-economic aspect.Finally, we proposed a random matrix model having as input aggregated variables based on the biological stages of the species. The probabilities of the between stages transition matrix are modeled using a hierarchical Dirichlet-Multinomial model. The integration of prior information was formulated through a Bayesian approach. The estimation and model validation were performed with Bayesian criteria.Simulations based on the estimated parameters represent a first outline of the study of the species behavior.

O camarão rosa (Farfantepenaeus subtilis) explotado pela pesca industrial na plataforma continental amazônica brasileira possui um ciclo de vida curto, mas complexo, habitando áreas oceânicas, mais ao norte da área de ocorrência, na fase adulta e larval, e áreas estuarinas e lagunares na fase de pós-larva e juvenil. O período de maior intensidade de reprodução se estende de maio a setembro e logo após a reprodução as larvas eclodem e iniciam sua migração para áreas costeiras, passando por diversas fases, onde se assentam e residem principalmente entre junho e outubro. A partir de setembro até janeiro do ano seguinte é maior a intensidade de recrutamento de juvenis às áreas oceânicas, onde passam a amadurecer e, a partir de dezembro, começam a ser capturados pela pesca industrial. A maior abundância da população adulta em termos de biomassa vai de março a agosto quando também se verificam as maiores capturas. As fêmeas crescem mais que os machos e estão presentes sempre em maior proporção nas capturas (61%). Os comprimentos assintóticos foram estimados em 231 mm ( k = 1,6 \'ano POT.-1\') e 205 mm (k = 0,94 \'ano POT.-1\'), para fêmeas e machos respectivamente. A população apresenta taxa de mortalidade natural relativamente elevada, 2,53 \'ano POT.-1\' para fêmeas e 1,83 \'ano POT.-1\' para machos, sendo observadas acentuadas flutuações de recrutamento e abundância, com evidências de que são fortemente governadas pelas condições ambientais. O estoque vem sendo explotado em níveis moderados nos anos recentes (E = 0,45), embora tenha sofrido elevadas taxas de explotação na década de 80, o que levou a uma redução do tamanho da população. O rendimento máximo sustentável, considerado uma média de longo prazo, foi estimado em 4.032 toneladas de cauda por ano, para um esforço de pesca de 19.370 dias de mar. Nos últimos anos, se observa uma tendência de recuperação da biomassa populacional, mas com as oscilações anuais características da espécie. A vazão do rio Amazonas é o fator ambiental que governa com mais intensidade as condições do ambiente costeiro na região e verificou-se que suas flutuações estão correlacionadas a alterações na abundância da população da espécie. Postula-se que o aporte e sobrevivência das larvas e pós-larvas no ambiente costeiro seja influenciada pela intensidade da vazão do rio. O período em que se assentam nos berçários na zona costeira coincide com a estação de vazante do rio, sendo a sobrevivência favorecida por vazões abaixo da média e vice-versa. Portanto, medidas de ordenamento voltadas para o uso sustentável do recurso devem estar associadas ao conhecimento das condições ambientais nesta fase, bem como a estudos sobre a abundância de pós-larvas e juvenis na faixa costeira. / The brown shrimp (Farfantepenaeus subtilis) exploited by the industrial fishery on the continental shelf of the Brazilian Amazon has a short but complex life cyele, inhabiting oceanic areas, at the north of the area of occurrence, during the adult and larval stages, and estuarine areas and lagoons in post-larval and juvenile. The period of highest intensity of reproduction extends from May to September and soon after the hatch, the larvae start their migration to coastal areas, passing through several stages, where they settle and remain resident between June and October. From September to January of the following year the intensity of recruitment to ocean areas is higher, and once there they start to mature and are caught by the industrial fishery from December on. The highest abundance of the adult population in terms of biomass is observed from March to August when the largest catches also occur. Females grow larger than males and are always present in greater proportion in catches (61%). The asymptotic lengths were estimated at 231 mm (k = 1.6 \'year POT.-1\') and 205 mm (k = 0.94 \'year POT.-1\') for females and males respectively. The population has a natural mortality rate relatively high, 2.53 \'year POT.-1\' for females and 1.83 \'years POT.-1\' for males, and pronounced fluctuations in recruitment and abundance are observed, with evidence of being strongly governed by environmental conditions. The stock has been exploited at moderate levels in recent years (E = 0.45), although it has suffered high rates of exploitation in the 80\'s, which led to a reduction in population size. The maximum sustainable yield, considered a long-term average, was estimated at 4,032 ton of tail per year for a fishing effort of 19,370 days at sea. In recent years, it is observed a tendency of recovering of the population biomass, but annual fluctuations are characteristics of the species. The flow of the Amazon River is the main environmental facto r that governs the conditions of the coastal environment in the region and it was found that it is correlated with the fluctuatícn of the brown shrimp population abundance. It is postulated that the uptake and survival of larvae and post larvae in the coastal environment is lnfluenced by the intensity of river flow, The period during which they settle at the nurseries in the coastal zone coincides with the dry season and their survival is favored when the flow of the river is below the average, and vice versa. Therefore, management measures aimed at sustainable use of the resource must be associated with the knowledge of environmental conditions during this phase, as well as studies on the abundance of post-larvae and juveniles in the coastal zone.

Submitted by Ricardo Cedraz Duque Moliterno (ricardo.moliterno@uefs.br) on 2016-07-11T23:08:58Z No. of bitstreams: 1 Jumara Marques Souza_tese.pdf: 2615056 bytes, checksum: b21b8de1cf3cd6d4e050ce8ae830c183 (MD5) / Made available in DSpace on 2016-07-11T23:08:58Z (GMT). No. of bitstreams: 1 Jumara Marques Souza_tese.pdf: 2615056 bytes, checksum: b21b8de1cf3cd6d4e050ce8ae830c183 (MD5) Previous issue date: 2015-09-28 / Conselho Nacional de Pesquisa e Desenvolvimento Cient?fico e Tecnol?gico - CNPq / Disturbances affect plant populations in different ways, and their understanding is extremely important to define management strategies and biodiversity conservation. Such disturbances may be natural, as in the case of fire initiated by lightning, or can be anthropogenic, as the extraction of natural products. In both cases, populations of plants under interference from disturbances may increase or decrease, being necessary to understand its effects on populations in the long run. A key plant for conservation is Vellozia aff. sincorana L.B.Sm. & Ayensu (Velloziaceae), is an important species for the conservation of rupestrian fields of the western portion of the Serra do Sincor?, which is endemic. The largest area of distribution of this species, popularly know as candomba, is within the limits of the Chapada Diamantina National Park (CDNP), Bahia, Brazil, where it has a elevated cover. Candomb? branches are target of extraction in the region, which are destined to ignite wood stoves. In addition to this anthropic disturbance, V. aff. sincorana is also frequently affected by fires, which despite being a natural phenomenon are largely generated by human activity in CDNP. The fire has a marked effect on V. aff. sincorana, as it stimulates their mass flowering and synchronic, with no registration of flowering in this species in the absence of fire. This study evaluated the effects of fire in individuals of V. aff. sincorana in space and stages structure and the population dynamics of this species. In addition, simulations were performed with different frequencies fire, harvest intensities, and the association of fire and harvesting in order to assess the possibilities of using fire as management tool of harvest to this species. For analyzes involving harvest, the two techniques used by candomb? collectors in the region (removal of whole adult plants or branches) were simulated. For this study, individuals of V. aff. sincorana were marked, measured and monitored on 16m? plots over two censuses (2012 and 2013) in six populations, three unaffected by fire since 2008, and three affected by recent fires (2011 or 2012), approximately 40 days before the first census. In total, we monitored 1,617 individuals in 56 plots. The results showed that the recent fire affects individuals of V. aff. sincorana stimulating flowering and increases in canopy area, plant height and number of rosettes. Populations had lower rates of mortality and recruitment, however, in areas without recent fire, both the recruitment by seeds and mortality of juveniles were higher. The distribution of individuals was aggregate in all populations, averaging two individuals per m?. The recent fire caused changes in distribution of individuals in class of life stages. In general, populations tended to have higher concentration of adults. The reproduction stimulus by fire increases fertility and causes growth of recent fire populations, so the recent fire encourages population increase of V. aff. sincorana, while in absence of fire populations tended to decrease. The simulation results showed that populations of V. aff. sincorana tend to decrease with increasing the gap between the fire events. In harvest simulations, the growth of population was negatively affected by the decrease in harvest intervals and no fire. The results showed that the harvesting technique of whole adult is not sustainable and that the maintenance of the populations of V. aff. sincorana depends on the survival of individuals, mostly adults. In general, we find evidence that the conservation of V. aff. sincorana and its management for extractive purposes depend on periodic fire occurrence. / Os dist?rbios afetam as popula??es vegetais de diversos modos, sendo sua compreens?o de extrema import?ncia para defini??o de estrat?gias de manejo e conserva??o da biodiversidade. Tais dist?rbios podem ter origem antr?pica ou n?o, a exemplo do fogo iniciado por raio e da extra??o de produtos naturais. Em ambos os casos, as popula??es de plantas sob interfer?ncia podem crescer ou diminuir demasiadamente, sendo necess?ria a compreen??o dos efeitos em longo prazo dos dist?rbios nas popula??es. Vellozia aff. sincorana L.B.Sm. & Ayensu (Velloziaceae) ? uma esp?cie importante para a conserva??o dos campos rupestres da por??o ocidental da Serra do Sincor?, da qual ? end?mica. A maior ?rea de distribui??o dessa esp?cie, popularmente conhecida como candomb?, encontra-se dentro dos limites do Parque Nacional da Chapada Diamantina (PNCD), Bahia, Brasil, onde apresenta uma elevada cobertura. Os ramos do candomb? s?o alvo de extrativismo na regi?o, os quais s?o destinados a acender fog?es a lenha. Al?m desse dist?rbio antr?pico, V. aff. sincorana tamb?m ? frequentemente afetada por inc?ndios, que apesar de serem um fen?meno natural, s?o majoritariamente originados pela a??o humana no PNCD. O fogo tem um efeito marcante sobre V. aff. sincorana, j? que estimula sua flora??o em massa e sincr?nica, n?o havendo registros de flora??o da esp?cie na aus?ncia de fogo. O presente estudo avaliou os efeitos do fogo nos indiv?duos de V. aff. sincorana, na estrutura espacial e de est?dios, bem como na din?mica populacional dessa esp?cie. Al?m disso, foram realizadas simula??es com diferentes frequ?ncias de fogo, intensidades de colheita, e da associa??o entre fogo e colheita, a fim de avaliar as possibilidades do uso do fogo como ferramenta do manejo extrativista dessa esp?cie. Para as an?lises envolvendo colheita, foram simuladas as duas t?cnicas utilizadas pelos coletores de candomb? na regi?o (retirada de plantas adultas inteiras ou a de ramos). Para esse estudo, os indiv?duos de V. aff. sincorana foram marcados, medidos e acompanhados em parcelas de 16m? durante dois censos (2012 e 2013) em seis popula??es, tr?s n?o afetadas por fogo desde 2008, e tr?s afetadas por inc?ndios recentes (2011 ou 2012), aproximadamente 40 dias antes do primeiro censo. No total, foram acompanhados 1.617 indiv?duos distribu?dos em 56 parcelas. Os resultados evidenciaram que o fogo recente afeta os indiv?duos de V. aff. sincorana estimulando ? flora??o e aos incrementos em ?rea da copa, altura da planta e produ??o de rosetas. As popula??es apresentaram baixas taxas de mortalidade e recrutamento, por?m, nas ?reas sem fogo recente, tanto o recrutamento via sementes quanto a mortalidade de juvenis foram maiores. A distribui??o dos indiv?duos foi agregada em todas as popula??es, com m?dia de dois indiv?duos/m?. O fogo recente provocou mudan?as na distribui??o dos indiv?duos entre as classes de est?dios de vida. Em geral, as popula??es tenderam ? maior concentra??o de adultos. A reprodu??o estimulada por fogo aumenta a fertilidade e ocasiona crescimento das popula??es rec?m-incendiadas, de modo que o inc?ndio recente favoreceu o aumento populacional de V. aff. sincorana, enquanto na sua aus?ncia as popula??es tenderam ? diminui??o. Os resultados das simula??es evidenciaram que as popula??es de V. aff. sincorana tendem ? diminui??o com o aumento do intervalo entre os eventos de fogo. Nas simula??es de colheita, o crescimento das popula??es foi afetado negativamente pela diminui??o dos intervalos de colheita e aus?ncia de fogo. Os resultados evidenciaram que a t?cnica de colheita de adultos inteiros n?o ? sustent?vel e que a manuten??o das popula??es de V. aff. sincorana depende da sobreviv?ncia dos indiv?duos, principalmente os adultos. De modo geral, encontramos ind?cios de que a conserva??o de V. aff. sincorana e seu manejo para fins extrativistas dependem da ocorr?ncia peri?dica do fogo.

No description available.

No description available.

Les changements climatiques ont un impact certain sur les écosystèmes marins. Un déplacement vers le sud des principaux systèmes de front servant de sites de nourrissage pour de nombreuses espèces de prédateurs supérieurs est susceptible de se produire dans les zones subantarctiques. Les « central place foragers », tels que les pinnipèdes, sont susceptibles de faire face à une augmentation de la distance entre leurs lieux d'alimentation et leurs colonies d'élevage. Nous avons étudié l’impact des changements climatiques sur le succès d’élevage et la dynamique de population des otaries à fourrure (Arctocephalus gazella) des Îles Kerguelen par le biais du développement du modèle individu centré, MarCPFS (Marine Central Place Foragers Simulator) qui montre que la survie du couple femelle-jeune est particulièrement sensible à la répartition des proies (abondance et structure), à la capacité de mémorisation des meilleurs sites de nourrissages trouvés par la femelle pendant la période d'élevage, à la taille des femelles et à la distance qu'il faut parcourir pour trouver la ressource. Les résultats suggèrent qu’au cours des trois prochaines décennies un déplacement vers le sud supérieur à 2km an 1 pourrait compromettre la survie et la durabilité des populations. Un couplage avec un modèle de simulation de la dynamique océanique et de la ressource (SEAPODYM) a permis des projections jusqu’à la fin de ce siècle basées sur le scénarios RCP8.5 du GIEC (2014), confirmant les tendances mises à jour précédemment. Ces travaux montrent que les perspectives de maintien des populations sont pessimistes y compris en envisageant une adaptation de la taille des individus. / Climate change has certain impact on the marine ecosystems. A southward shift in productive frontal systems serving as the main foraging sites for many top predator species is likely to occur in the Subantarctic areas. Central place foragers, as seabirds and pinnipeds, are thus likely to cope with an increase in the distance between foraging locations and their land-based breeding colonies. We studied the impact of climate change on the breeding success and population dynamics of Antarctic fur seals (Arctocephalus gazella) at Kerguelen Islands by means of an individual based model we developped, MarCPFS (Marine Central Place Foragers Simulator) which showed that the survival of the female-pup pair is particularly sensitive to the distribution of preys (abundance and structure), to the memorization abilities of the best resource sites found by the female during the rearing period, to the female size and to the foraging distance which it is necessary to cover at each trip. The results suggest that during the next three decades a southward shift greater than 2 km year-1 could compromise the survival and the sustainability of the populations. A coupling with a model of simulation of the oceanic dynamics and the resource (SEAPODYM) allowed projections till the end of this century based on scenarios RCP8.5 of the IPCC (2014), confirming the trends previously obtained. Globally, these works lead us to conclude with pessimistic perspectives about the sustainability of populations even when considering an evolution through time towards individuals of greater sizes.

The evolution of metabolism regulation is an intertwined process, where different strategies are constantly being developed towards a cognitive ability to perceive and respond to an environment. Organisms depend on an orchestration of a complex set of chemical reactions: maintaining homeostasis with a changing environment, while simultaneously sending material and energetic resources to where they are needed. The success of an organism requires efficient metabolic regulation, highlighting the connection between evolution, population dynamics and the underlying biochemistry. In this work, I represent organisms as coupled information-processing networks, that is, gene-regulatory networks receiving signals from the environment and acting on chemical reactions, eventually affecting material flows. I discuss the mechanisms through which metabolism control is improved during evolution and how the nonlinearities of competition influence this solution-searching process. The propagation of the populations through the resulting landscapes generally point to the role of the rhythm of cell division as an essential phenotypic feature driving evolution. Subsequently, as it naturally follows, different representations of organisms as oscillators are constructed to indicate more precisely how the interplay between competition, maturation timing and cell-division synchronisation affects the expected evolutionary outcomes, not always leading to the \"survival of the fastest\".