Mosquitoes are vectors for many diseases that cause significant mortality and morbidity across the globe such as malaria, dengue fever and Zika. As mosquito populations expand their range into new areas, they may undergo mate-finding Allee effects such that their ability to successfully reproduce becomes difficult at low population densities. With new technology, creating target specific gene modification may now be a viable method for mosquito population control. We develop a mathematical model to investigate the effects of releasing transgenic mosquitoes into newly established low-density mosquito populations. Our model consists of two life stages (aquatic and adult), which are further divided into three genetically distinct groups: heterogeneous and homogeneous transgenic alleles that cause female infertility and a homogeneous wild type. We perform analytical and numerical analyses on the equilibria to determine the level of saturation needed to eliminate mosquitoes in a given area. This model demonstrates the potential for a gene drive system to reduce the spread of invading mosquito populations. / Master of Science / Mosquitoes spread many diseases that cause significant death across the globe such as malaria, dengue fever and Zika. As mosquito populations expand their range into new areas, they may not be able to successful reproduce at small population. With new technology, creating target specific gene modification may now be a viable method for mosquito population control. We develop a mathematical model to investigate the effects of releasing mosquitoes which have a gene modification into newly established low-density mosquito populations. Our model consists of two life stages (aquatic and adult), which are further divided into three genetically distinct groups. We perform analytical and numerical analyses on the equilibria to determine the level of saturation needed to eliminate mosquitoes in a given area. This model demonstrates the potential for a gene modified mosquito to reduce the spread of invading mosquito populations.

京都大学 / 新制・論文博士 / 博士(医学) / 乙第13607号 / 論医博第2317号 / 新制||医||1073(附属図書館) / その他リバプール熱帯医学研究科国際公衆衛生学コース / (主査)教授 長尾 美紀, 教授 川上 浩司, 教授 近藤 尚己 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

L’un des défis actuels de la lutte contre la tuberculose est de développer un traitement plus court et plus efficace. La modélisation mathématique constitue une approche qui peut nous aider à comprendre les problèmes actuels et favoriser les innovations thérapeutiques. L’objectif de ce travail est de construire un modèle thérapeutique mathématique de la tuberculose pulmonaire basé sur des éléments pharmacocinétiques, pharmacodynamiques et physiopathologiques. La mise en application du modèle pharmacodynamique a été précédée d’une étude théorique sur l’équation de Hill. Cette synthèse a permis de dégager les bases rationnelles de son utilisation en modélisation pharmacologique. En utilisant une approche de population, un modèle pharmacocinétique de diffusion pulmonaire a permis de décrire les concentrations en rifampicine dans le plasma et le poumon chez 34 sujets. Le modèle a ensuite été utilisé pour analyser la valeur d’indices pharmacodynamiques corrélés à l’effet chez 10 000 sujets fictifs, par simulation de Monte Carlo. Les résultats indiquent que la dose de standard de rifampicine conduit à des concentrations globalement peu efficaces et pouvant favoriser la résistance bactérienne. Un premier modèle mathématique du traitement de la tuberculose par la rifampicine, incluant un modèle physiopathologique formel, a enfin été construit. Il permet de simuler la dynamique bactérienne du premier jour de l’infection au dernier jour de traitement. L’ensemble des résultats conduit à une remise en question de la dose standard de rifampicine et suggère une nouvelle hypothèse sur les causes de la persistance de Mycobacterium tuberculosis au cours du traitement antituberculeux / There is a critical need for a shorter tuberculosis treatment to improve tuberculosis control. Mathematical models may be helpful to understand current problems associated with tuberculosis therapy and to suggest innovation resources. The objective of this study is to set up a full mathematical model of tuberculosis treatment by rifampin, based on pharmacokinetic, pharmacodynamic and physiological submodels. Prior to its application in the pharmacodynamic modeling framework, the Hill equation has been the focus of a theoretical study. The various properties of this equation have been reviewed and the rationale of its use in pharmacological modelling has been clarified. Rifampin pharmacokinetics in plasma and lungs was modelled in a population of 34 volunteers by use of a nonparametric population approach. Then, a 10,000 subject Monte Carlo simulation was performed to explore Mycobacterium tuberculosis killing effect and prevention of resistance by rifampin. The results suggest that rifampin pulmonary concentrations obtained with the standard dose are too low to be highly effective and prevent drug resistance in most subjects. Finally, a full mathematical model of tuberculosis treatment, including a physiological model, has been implemented. The model is able to simulate the time-course of bacterial counts from the first day of infection to the last day of treatment. Overall results of this modelling effort indicate that current dosage regimens of rifampin may be optimized. In addition, this work suggests a new hypothesis regarding the bacterial persistence during tuberculosis treatment.

A computational model for mitochondrial function has been developed from oxygen concentration data measured in the Oroboros Oxygraph-2k and oxygen consumption rates measured in the Seahorse XF24 Analyzer. Measurements were acquired using embryonic-cultured cortical neurons and isolated mitochondria from CD1 mice. Based on the biological mechanism of mitochondrial activity, a computational model was developed using biochemical kinetic modelling. To modulate mitochondrial activity, dysfunctions were introduced by injecting the inhibiting reagents oligomycin, rotenone, and antimycin A, and the uncoupling reagent carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP) during measurements. To incorporate these changes, model equations were adapted and globally calibrated to experimental data using the genetic algorithm developed by Jason Fiege of the University of Manitoba by fitting oxygen concentration data. The model was coded in MATLAB R2014a along with the development of a graphical user interface for simulating mitochondrial bioenergetics in silico. / October 2016

<p style="text-align: justify;">U disertaciji je prikazan matematički model<br />gasifikacije otpadnih automobilskih pneumatika.<br />Modelom je istražen uticaj količine ubačenog vazduha<br />i vodene pare u gasifikator i temperatura gasifikacije<br />na prinos gasovitih produkata. Numerička procedura<br />je rije&scaron;ena Newton-Raphson metodom a brojne<br />vrijednosti molskih udjela gasovitih komponenata u<br />ravnotežnoj mje&scaron;avini dobijene su kori&scaron;ćenjem<br />programskog jezika C.<br />U drugom dijelu disertacije prikazano je<br />eksperimentalno ispitivanje pirolize otpadnih<br />automobilskih pneumatika. Eksperimentalni rezultati<br />ukazuju da na prinos gasa, odnosno na prinos čvrstog<br />(koksnog) ostatka značajno utiču parametri: veličina<br />čestice otpadne gume, temperatura pirolize i brzina<br />zagrijavanja uzorka.</p> / <p>The dissertation presents a mathematical model of<br />gasification of waste automotive tires. The model<br />examined the impact of the amount of the loaded air and<br />water vapor in the gasifier and gasification temperature<br />to yield gaseous products. The numerical procedure is<br />resolved Newton-Raphson method and the numerical<br />values of mole portions of gaseous components in the<br />equilibrium mixture obtained using the programming<br />language C.<br />In the second part of the thesis is shown<br />experimentally testing pyrolysis of waste automotive<br />tires. Experimental results indicate that the yield of gas,<br />or to yield a solid (coke) significantly affect the rest of the<br />parameters: the size of the particles of waste rubber<br />pyrolysis temperature and heating rate of the sample.</p>

<p>U doktorskoj disertaciji vr&scaron;eno je ispitivanje procesa pirolize i gasifikacije<br />oklaska kukuruza. Istraživanje procesa pirolize obuhvatalo je definisanje<br />uticaja procesnih parametara (temperature pirolize, reakcionog vremena,<br />brzine zagrevanja i veliĉine ĉestica) na prinos ĉvrstog ostatka i pirolitiĉkog<br />gasa. Osim toga, vr&scaron;eno je ispitivanje sastava gasa u zavisnosti od<br />temperature. UtvrĊeno je da ispitivani procesni parametri imaju uticaj na<br />prinos ĉvrstog ostatka i bio-ulja, kao i na prinos i sastav pirolitiĉkog gasa.<br />Tokom ispitivanja procesa gasifikacije razvijen je funkcionalni matematiĉki<br />model gasifikacije oklaska kukuruza u struji vazduha koji bi trebalo da<br />omogući optimizaciju procesa gasifikacije goriva u cilju dobijanja gasovitog<br />proizvoda.</p> / <p>Doctoral dissertation investigates pyrolysis and gasification of corncob.<br />Investigation of pyrolysis process included defining the influence of process<br />parameters (pyrolysis temperature, reaction time, heating rate and particle<br />size) on pyrolysis gas and char yield. Also, temperature dependence of<br />pyrolysis gas composition was investigated. It was confirmed that process<br />parameters influence char and bio-oil yield and pyrolysis gas yield and<br />composition. A functional mathematical model of air-stream gasification of<br />corncob was developed in order to enable optimization of gasification<br />process with the objective of obtaining gaseous product.</p>

L'objectif de cette étude est de développer un modèle théorique du champ de pression acoustique réfléchi au-dessus d'un réseau constitué de N cavités rectangulaires. Pour cela, une adaptation de la méthode Kobayashi Potentiel (KP) a été effectuée au cas d'une cavité rectangulaire dans un écran rigide à épaisseur non négligeable. Ce modèle ainsi adapté a été généralisé au cas de réseaux contenant plusieurs cavités rectangulaires parallèles, puis étendu au cas de réseaux de cavités rectangulaires non parallèles. Une étude du couplage a été menée pour comprendre la variation de l'interaction acoustique existant entre les cavités en fonction de l'espacement et de la fréquence. Ce modèle a été comparé aux résultats théoriques, issus de la méthode des éléments finis (FEM), et aux résultats expérimentaux obtenus dans une chambre semi-anéchoïque pour une seule cavité, des réseaux de cavités rectangulaires parallèles et non parallèles. La validité du modèle théorique est soutenu par l'accord observé entre les résultats théoriques et expérimentaux / The purpose of this research project was to develop a theoretical model dealing with reflection of acoustic waves over a grating of N rectangular cavities. Thus, the diffracted acoustic fields were determined by adapting the Kobayashi Potential (KP) method to the case of a cavity. Then, this developed model was generalized to the case of parallel rectangular cavities gratings and then extended to the case of non parallel rectangular cavities ones. A study of the coupling was achieved in order to understand the variation in the acoustic interaction between cavities with spacings and frequency. This model was compared with theoretical results obtained from the finite element method (FEM) and experimental results obtained in a semi-anechoic chamber for a single cavity and gratings of parallel and non-parallel rectangular cavities. The validity of the theoretical model is supported by the agreement between the numerical and experimental results observed

A thesis submitted to the Faculty of Science, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree of Doctor of Philosophy. Johannesburg, 2016. / Gold mining of the Witwatersrand Basin reefs has been responsible for the rise of Johannesburg as an economic centre of South Africa. While mining provided a base for business and infrastructure development for the region, it has also generated social and environmental problems for the country. Tailings storage facilities (TSFs), a common sighting around Johannesburg and across the entire basin, have been built to contain the processed waste following extraction of gold from the pyrite containing quartzite ore. When the fine grained waste is exposed to atmospheric conditions, oxidation of remnant sulphides occurs resulting in acidic, metal rich and sulphate rich plumes that enter the environment through surface and groundwater systems. This thesis sought to better understand the release, transport, dispersal and fate of metals emanating from TSFs and their remnant footprints on the Witwatersrand. These metals included aluminium, copper, chromium, iron, manganese, nickel and uranium and are known to be toxic to humans depending on their concentration and speciation. Traditionally, analytical methods have been employed in studies focussing on the characterisation of some of these processes in the region. While these studies have generally conducted quantitative assessment of the extent of pollution, little comprehensive interrogation and fingerprinting of the processes that are influential in determining the potential risk posed by metals has been done. This has largely been due to the shortcomings of analytical methods to determine these. To this end, this research has employed geochemical modelling to complement the traditional analytical methods. The approach to study the release of metals from TSFs involved assessment of the partitioning of metals within tailings and their potential release using batch and sequential extraction methods. Processes of metal release within the tailings were simulated through geochemical modelling (using the PHREEQC and Geochemist’s Workbench codes). The simulations were based on the percolation of rainwater through these layers and the changes in its chemistry along the path. The potential seepage of this plume along the path was then correlated to observed efflorescent mineral crusts that are temporary sinks for metals and are a common feature in the vicinity of the tailings and water bodies such as ponds and streams. The potential impact of the mineral crusts on the water chemistry of receiving water systems following their dissolution was assessed using forward geochemical modelling. The transport of the metals in groundwater was also studied. This involved simulations of the transition in chemistry of a plume from a TSF along an aquifer of known composition. This was based on a 1-D reactive transport model constructed using information from sequential extraction work on the aquifer rock (to identify the key minerals to consider) and site data (mainly flow rates) from previous studies. The processes occurring in the removal of metals from acid mine drainage (AMD) through a permanent sink in the form of a pump-and-treat plant in the Central Goldfield of the basin were simulated using PHREEQC. The findings from the research showed that two different plumes were produced from an abandoned TSF as a result of rainwater percolation, notably a plume produced from the dissolution of secondary salts formed in the oxidised layer and a sulphuric acid rich plume in the unoxidised layer. These differences were apparent in the geochemical composition of the mineral crusts collected on the walls of tailings dumps and from a pond into which the plumes were draining. On dissolution, mineral crusts were found to produce acidic solutions with crusts containing predominantly Fe producing pH values below 3. The simulated dissolution of various types of mineral crusts gave insight into the impact of minerals present in the smallest amount. This showed that the bulk mineralogy as determined by analytical techniques such as PXRD and remote sensing could not be used with confidence to deduce the impact of the mineral crusts on receiving water bodies. The characteristics of surface plumes released from tailings TSF were compared to other water systems in the area around Soweto, with complementary interpretation conducted using chemometric methods. From principal component analysis (PCA), surface water systems were found to form distinct groups largely influenced by mineral solubility, alkalinity and dissolved oxygen content. The 1-D reactive transport simulations involved acidic, metal and sulphate rich water ingressing the aquifer (below the TSF). Several scenarios were modelled including simulations with different dolomite contents; allowing for surface complexation and the presence of cation exchange surfaces. At a point 500 m from the water ingress in the dolomite rich aquifer, Fe and Mn were largely precipitated out (as confirmed by sequential extraction results on the aquifer rock) while the sulphate concentration was reduced by almost half. On the other hand, Ca concentrations were conservative largely because of continuous dissolution of dolomite and precipitation of gypsum along the flow path. The simulations of the high density sludge treatment plant involved forward modelling of the treatment process with the sludge responsible for the removal of trace metals from the incoming acid mine drainage. The model can be of use for cost and process optimisation at the facility. This research has had notable outputs in the form of publications; models on metal release, transport and attenuation; and models on pump-and-treat processes. These will form an important repository of information and for benchmarking any further studies related to AMD. / MT2016

O objetivo deste trabalho é o desenvolvimento de um modelo matemático dos sistemas térmico e respiratório humanos que permita, a partir das condições do ambiente e do nível de atividade física, determinar a distribuição da temperatura e das concentrações de oxigênio e dióxido de carbono ao longo do corpo. No modelo representou-se o corpo humano dividido em quinze segmentos: cabeça, pescoço, tronco, braços, antebraços, mãos, coxas, pernas e pés. Cada segmento contém um compartimento arterial e um compartimento venoso, os quais representam os grandes vasos. O sangue nos pequenos vasos foi considerado juntamente com os tecidos músculo, gordura, pele, osso, cérebro, pulmão, coração e vísceras. Os gases O2 e CO2 são transportados pelo sangue e armazenados nos tecidos, dissolvidos e reagidos quimicamente. Nos tecidos ocorre metabolismo, que consome oxigênio e produz dióxido de carbono e calor. A pele troca calor com o ambiente por condução, convecção, radiação e evaporação. O trato respiratório o faz pela ventilação, por convecção e evaporação. Nos pulmões ocorre transferência de massa, por difusão entre um compartimento alveolar e diversos compartimentos capilares pulmonares. Para modelar o transporte de massa e o transporte de calor nos tecidos foram usadas duas formas distintas. No caso da transferência de massa, os tecidos foram representados por compartimentos nos segmentos modelados. No caso da transferência de calor, foram representados por camadas nos segmentos, sendo que estes ora têm a geometria de um cilindro (seção transversal circular), ora a de um paralelogramo no caso das mãos e dos pés. O sistema regulador do corpo humano foi divido em quatro formas de atuação: metabolismo, circulação, ventilação e sudorese. O metabolismo varia com o calafrio (que depende da temperatura corporal) e a atividade física; a circulação depende da concentração dos gases no corpo, da temperatura e do metabolismo; a ventilação, da concentração dos gases; a sudorese, da temperatura. Para solucionar as equações diferenciais do modelo foram usados métodos numéricos implícitos. As equações diferenciais parciais foram discretizadas pelo método dos volumes finitos. Comparações com trabalhos experimentais encontrados na literatura mostraram que o modelo é adequado para representar variações climáticas, exposições a quantidades reduzidas de oxigênio e elevadas de dióxido de carbono, e situações de exercício físico. Outros resultados gerados pelo modelo demonstraram que acidentes de descompressão tornam-se mais severos quando associados à queda da temperatura ambiente, por causa do aumento do consumo de O2 pelo calafrio. Este também aumenta o risco de uma intoxicação por CO2, devido ao aumento da sua produção. O modelo mostrou-se ainda capaz de prever diversas interações entre os sistemas térmico e respiratório, como a diminuição da temperatura corpórea pelo aumento da ventilação (que depende das concentrações de O2 e CO2), ou a diminuição da pressão parcial dos gases nos segmentos mais extremos, em consequência do efeito da temperatura na capacidade do sangue de transportá-los. / The aim of this work is the development of a mathematical model of the human body respiratory and thermal systems. The model allows the determination of the temperature, oxygen and carbon dioxide distributions, depending on the ambient conditions and the physical activity level. The human body was divided into 15 segments: head, neck, trunk, arms, forearms, hands, thighs, legs and feet. Each segment contains an arterial and a venous compartment, representing the large vessels. The blood in the small vessels is considered together with the tissues muscle, fat, skin, bone, brain, lung, heart and viscera. The gases O2 and CO2 are transported by the blood and stored by the tissues dissolved and chemically reacted. Metabolism takes place in the tissues, where oxygen is consumed generating carbon dioxide and heat. The skin exchanges heat with the environment by conduction, convection, radiation and evaporation. The respiratory tract exchanges heat by convection and evaporation. In the lungs, mass transfer happens by diffusion between an alveolar compartment and several pulmonary capillaries compartments. Two different forms were used to model the transport of mass and heat in the tissues. For the mass transfer, the tissues were represented by compartments inside the segments. For the heat transfer, the tissues were represented by layers inside the segments, which have the geometry of a cylinder (circular cross-section) or a parallelogram hands and feet. The regulatory systems were divided into four mechanisms: metabolism, circulation, ventilation and sweating. The metabolism is modified by the shivering (which depends on the body temperature) and the physical activity; the circulation depends on the body gas concentrations, the temperature and the metabolism; the ventilation depends on the gas concentrations; the sweating depends on the temperature. Implicit methods were used to solve the differential equations. The discretization of the partial differential equations was obtained applying the finite volume method. Comparisons with experimental works found in literature show that the model is suitable to represent the exposure to cold and warm ambients, to low amounts of oxygen, to carbon dioxide, and physical activity. Other results of the developed model show that decompression accidents become more severe when associated to low ambient temperatures, because of the increase in the O2 consumption by shivering. The shivering also increases the danger of a CO2 intoxication, due to the increase of its production. The model showed as well the capacity to represent the several interactions between the thermal and respiratory systems, as the decrease of the body temperature because of the increase in the ventilation (which depends on the O2 and CO2 concentrations), or the decrease of the O2 and CO2 partial pressures in the more extreme segments, consequence of the temperature effect on their blood transport capacity.

Modelar a dinâmica de neurônios é relevante em estudos de neurociências. Neste trabalho, propõe-se um modelo computacional de neurônio baseado no comportamento dos canais iônicos presentes na sua membrana. O modelo combina elementos microscópicos, como o comportamento dos canais individuais, com elementos macroscópicos, como a tensão ao longo de um trecho de membrana. Simulações foram realizadas com o objetivo de reproduzir dados biológicos e resultados obtidos de modelos teóricos clássicos da área. Foi possível reproduzir com boa concordância o potencial de ação, o fenômeno da adaptação, a curva da corrente de entrada versus a frequência de disparos e o potencial excitatório pós-sináptico. / Modelling the dynamics of neurons is relevant in studies on neurosciences. In this work, a computational model of neuron based on the behavior of the ionic channels found in its membrane is proposed. The model comprises microscopic elements, as the behavior of the individual channels, and macroscopic elements, as the tension along a membrane patch. Simulations were performed with the aim of reproducing biological data and results derived from classical theoretical models of the field. It was possible to reproduce with good agreement the action potential, the phenomenon of adaptation, the curve of the input current versus the spike frequency, and the excitatory postsynaptic potential.