I arbetet implementerades två algoritmer som utvärderades genom att spela ett matcha-3-spel mot varandra. Den första algoritmen var Minimax som väljer sina drag genom att evaluera de möjliga dragen från ett tillstånd. För att inte sökrymden ska bli för stor begränsas algoritmen med ett sökdjup. Den andra algoritmen var en MCTS som utför flera simuleringar där den utför slumpmässiga drag till ett spelslut för att få en uppskattning över resultatet från de olika dragen. Spelet som de utvärderas på är av typen matcha-3-battle. Flera experiment utfördes sedan på de två algoritmerna, där de spelade flera matcher motvarandra på olika stora bräden, sökdjup och utforskningskonstanter. Testerna visade att i denna implementation var Minimax överlägsen i de fall. När sökrymden blev större presterade MCTS bättre än i mindre rymder, men lyckades aldrig nå en majoritet av vinster.

Within solid tumours, a microenvironment exists that causes resistance to chemotherapy. New drugs that target cells within this microenvironment are required, the first step in this process being the identification of new targets. The aim of this thesis was to characterise changes in the transcriptome and proteome within specific regions of multicell-tumour spheroids (MCTS), an experimental model that mimics many of the features of the tumour microenvironment. HT29 MCTS were separated by sequential trypsinisation into 3 main regions; the outer surface layer (SL) the peri-necroric region (PN) and the necrotic core (NC). Using an iTRAQ quantitative proteomics approach, the proteome of the different MCTS regions was investigated. A 2 dimensional separation approach using Agilent¿s OffGel system and RP-nano HPLC was incorporated prior to MS analysis. MS analysis was done using both MALDI-TOF-TOF (Bruker Ultraflex II) and ESI-Q-TOF (Agilent 6530 QTOF LC/MS) instruments. Gene expression profiles of the different MCTS were investigated and compared using Agilent¿s one-color oligonucleotide based microarrays. Transcriptomic and proteomic analysis identified several key differences in the proteins involved in cell metabolism between the SL and PN/NC regions. Similar metabolic changes were also noted between autophagic and normal monolayer cells. Many highlighted proteins represented established cancer associated proteins. Interestingly, a number of proteins were highlighted which have no previous association with cancer and may upon further validation, provide attractive leads for therapeutic intervention.

Monte Carlo tree search (MCTS) och Minimax är två sökalgoritmer som används inom artificiell intelligens och två-spelar-spel. I denna studie implementeras Minimax och MCTS som två AI-agenter för brädspelet Fyra i rad. Studien innehåller olika experiment i form av spelturneringar för att jämföra algoritmernas prestation. Algoritmerna beror på olika parametrar; Minimax har ett sökdjup och MCTS har en betänketid. Dessa parametrar undersöktes och ändrades för de olika turneringarna. Spelbräde utökades succesivt för att jämföra algoritmerna under olika förhållanden. Resultatet av studien visar att MCTS presterar bättre och vinner flest matcher på stora spelbräden och Minimax presterar bäst och vinner flest matcher på små spelbräden. Denna studie är ett bidrag till att få ytterligare förståelse för hur algoritmerna presterar och möjlighet till att utveckla de till mer avancerade och optimala algoritmer.

This work addresses applications of search theory where a mobile search agent seeks to find an unknown number of stationary targets randomly distributed in a bounded search domain. We assume that the search mission is subject to a time or distance constraint, and that the local environmental conditions affect sensor performance. Because the environment varies by location, the effectiveness of the search sensor also varies by location. Our contribution to search theory includes new decision-theoretic approaches for generating optimal search plans in the presence of false alarms and uncertain environmental variability. We also formally define the value of environmental information for improving the effectiveness of a search mission, and we develop methods for optimal deployment of assets that can acquire environmental information in order to improve search effectiveness. Finally, we extend our research to the case of multiple cooperating search agents. For the case that inter-agent communication is severely bandwidth-limited, such as in subsea applications, we propose a method for assessing the expected value of inter-agent communication relative to joint search effectiveness. Our results lead to a method for determining when search agents should communicate. Our contributions to search theory address important applications that range from subsea mine-hunting to post-disaster search and rescue applications. / PHD / We address search applications where a mobile search agent seeks to find an unknown number of stationary targets randomly distributed in a bounded search domain. The search agent is equipped with a search sensor that detects the targets at a location. Sensor measurements are often imperfect due to possible missed detections and false alarms. We also consider that the local environmental conditions affect the quality of the data acquired from the search sensor. For instance, if we are searching for a target that has a rocky shape, we expect that it will be harder to find that target in a rocky environment. We consider that the search mission is subject to a time or distance constraint, and thus, search can be performed on only a subset of locations. Our goal in this study is to formally determine where to acquire the search measurements so that the search effectiveness can be maximized. We also formally define the value of acquiring environmental information for improving the effectiveness of a search mission, and we develop methods for optimal deployment of assets that can acquire environmental information in order to improve search effectiveness. Finally, we address the cases where multiple search assets collaboratively search the environment and they can communicate their local information with each other. We are particularly interested in determining when a vehicle should communicate with another vehicle so that the joint search effectiveness can be improved. Our contributions to search theory address important applications that range from subsea mine-hunting to post-disaster search and rescue applications.

Three dimensional multicell tumor spheroids (MCTS) provide an experimental model where the influence of microenvironmental conditions on protein expression can be determined. Sequential trypsin digestion of HT29 colon carcinoma MCTS enabled segregation into four populations comprising proliferating cells from the surface (SL), an intermediate region (IR), nonproliferating hypoxic cells from the perinecrotic region (PN), and a necrotic core (NC). Total protein was extracted from each population and subjected to iTRAQ-based quantitative proteomics analysis. From a total of 887 proteins identified, 209 were observed to be up-regulated and 114 were down-regulated in the PN and NC regions relative to the SL. Among the up-regulated proteins, components of glycolysis, TCA cycle, lipid metabolism, and steroid biosynthesis increased progressively toward the PN and NC regions. Western blotting, immunohistochemistry, and enzyme assays confirmed that significant changes in the expression of proteins involved in cellular metabolism occur in the nonproliferating fraction of cells within the viable rim. The presence of full length, functional proteins within the NC was unexpected, and further analysis demonstrated that this region contains cells that are undergoing autophagy. This study has identified possible targets that may be suitable for therapeutic intervention, and further studies to validate these are required.

L'hypothalamus est fortement impliqué dans la régulation nerveuse de l'homéostasie énergétique. Il existe dans cette structure des neurones spécialisés (gluco-sensibles) qui détectent notamment l’hyperglycémie puis déclenchent des réponses adaptées comme le maintien de la glycémie, en stimulant la sécrétion d’insuline ou encore le rassasiement. Les astrocytes sont suspectés de participer à la détection neuronale du glucose. Dans l’ensemble du cerveau, il existe un couplage métabolique entre astrocytes et neurones. Le lactate, issu de la métabolisation du glucose par les astrocytes, est transporté par les neurones par des transporteurs aux monocarboxylates (MCTs). De plus, il a récemment été montré que les jonctions gap (GJ), à l’origine de la formation de réseaux au sein des astrocytes sont indispensables au passage du glucose de la circulation sanguine vers les neurones en activité. Ces GJ astrocytaires sont formées majoritairement de connexines 43 et 30 (Cxs).Mon travail de thèse s’est orienté suivant deux axes, qui ont visé à étudier le rôle des astrocytes dans la détection hypothalamique du glucose et du lactate. Dans un premier temps, nous avons montré que le lactate, comme le glucose, est détecté au niveau central et induit une sécrétion d’insuline. Dans un modèle de rat hyperglycémique pendant 48h (qui présente aussi une hyperlactatémie), nous avons montré que la détection du glucose et du lactate est altérée. Ces modifications ne sont pas dues à une variation de l’expression protéique des MCTs astrocytaires ou neuronale de l’hypothalamus.Dans un deuxième temps, nous nous sommes intéressés au rôle des Cxs astrocytaires. La Cx43 est très exprimée autour des micro-vaisseaux sanguins de l’hypothalamus médio-basal (MBH), un site présentant de nombreux neurones gluco-sensibles. L’expression de la Cx30 est plus diffuse dans cette structure. Nous montrons également que l’expression protéique des Cxs astrocytaires varie très rapidement suite à des modifications du statut métabolique (jeûne, réalimentation, hyperglycémie). Afin d’évaluer l’implication de la Cx43 astrocytaire (majoritaire) dans la détection hypothalamique du glucose, nous avons inhibé son expression dans le MBH, in vivo, en injectant des siRNA permettant d’inhiber la synthèse de cette protéine. L’inhibition de la Cx43 (30% à 72h) induit une diminution de la prise alimentaire sans modification du poids, de la glycémie et de l’insulinémie comparée aux témoins. Suite à l’injection carotidienne de glucose (censée mimer une hyperglycémie), la sécrétion d’insuline est fortement inhibée chez les animaux siCx43. De même, l’effet satiétogène du glucose semble inhibé chez ces animaux lors de la réalimentation après un jeûne.Ces résultats montrent pour la première fois, de façon intégrée, l’importance des connexines, et probablement des réseaux astrocytaires, lors de la détection hypothalamique du glucose. Ces nouvelles données renforcent l’importance du rôle métabolique des astrocytes lors de fonctions neuronales précises / The hypothalamus plays a pivotal role in the nervous control of glucose homeostasis. This area contains gluco-sensitive neurons. Some of them detect increases in glucose levels and regulate glucose homeostasis by stimulating insulin secretion or inhibiting food intake. It is widely accepted that astrocytes are metabolically coupled to neurons. Lactate, resulting from the metabolism of glucose by astrocytes, is transported via the monocarboxylate transporters (MCTs). In addition, gap junctions (GJ), that form networks within astrocytes, are essential to transfer glucose from the bloodstream to the active neurons. These astroglial GJ mainly consist of connexins 43 and 30 (Cxs).The aims of my thesis are twofold: first, to show that an intracarotid lactate injection toward the brain, as for glucose, triggers insulin secretion and, second, to investigate the role of astroglial Cxs.Our results demonstrate that lactate and glucose sensing are altered in 48h hyperglycemic rats (accompanied by high blood lactate level). These alterations are not due to changes in protein expression of astroglial or neuronal MCTs in the hypothalamus. We then show that Cx43 is highly expressed in astrocytic end-feet enwraping blood vessels, in medio-basal hypothalamus (MBH) where many gluco-sensitive neurons are present. The Cx30 expression is more diffuse in this structure. We also show that the protein expression of astroglial Cxs varies very rapidly due to changes in metabolic status (fasting, refeeding and hyperglycemia). To evaluate the involvement of astroglial Cx43 (the major isoform) in the hypothalamic glucose sensing, we silenced its expression in the MBH in vivo by injecting specific siRNA. A 30% diminution in protein levels (after 72h) induced a decrease in food intake without changes in weight, blood glucose and insulin levels compared to vehicle treated animals. The central response to glucose is drastically inhibited in terms of insulin secretion in siCx43 animals. Similarly, an intracarotid injection of glucose towards the brain does not reduce refeeding in siRNA treated animals.These results demonstrate for the first time in vivo, the importance of connexins and astroglial networks in hypothalamic glucose sensing mechanism. These new data reinforce the importance of the metabolic role of astrocytes in specific neuronal functions

No description available.

Autonomous cars involve problems with control and planning. In thispaper, we implement and evaluate an autonomous agent based ona Monte-Carlo Tree Search in continuous action space. To facilitatethe algorithm, we extend an existing simulation framework and usea GPU for faster calculations. We compare three action generatorsand two rewards functions. The results show that MCTS convergesto an effective driving agent in static environments. However, it onlysucceeds at driving slow speeds in real-time. We discuss the problemsthat arise in dynamic and static environments and look to future workin improving the simulation tool and the MCTS algorithm. See code, https://github.com/felrock/PyRacecarSimulator

The expression of monocarboxylate transporters (MCTs) is linked to pathophysiological changes in diseases, including cancer, such that MCTs could potentially serve as diagnostic markers or therapeutic targets. We recently developed [18F]FACH as a radiotracer for non-invasive molecular imaging of MCTs by positron emission tomography (PET). The aim of this study was to evaluate further the specificity, metabolic stability, and pharmacokinetics of [18F]FACH in healthy mice and piglets. We measured the [18F]FACH plasma protein binding fractions in mice and piglets and the specific binding in cryosections of murine kidney and lung. The biodistribution of [18F]FACH was evaluated by tissue sampling ex vivo and by dynamic PET/MRI in vivo, with and without pre-treatment by the MCT inhibitor α-CCA-Na or the reference compound, FACH-Na. Additionally, we performed compartmental modelling of the PET signal in kidney cortex and liver. Saturation binding studies in kidney cortex cryosections indicated a KD of 118 ± 12 nM and Bmax of 6.0 pmol/mg wet weight. The specificity of [18F]FACH uptake in the kidney cortex was confirmed in vivo by reductions in AUC0-60min after pre-treatment with α-CCA-Na in mice (-47%) and in piglets (-66%). [18F]FACH was metabolically stable in mouse, but polar radio-metabolites were present in plasma and tissues of piglets. The [18F]FACH binding potential (BPND) in the kidney cortex was approximately 1.3 in mice. The MCT1 specificity of [18F]FACH uptake was confirmed by displacement studies in 4T1 cells. [18F]FACH has suitable properties for the detection of the MCTs in kidney, and thus has potential as a molecular imaging tool for MCT-related pathologies, which should next be assessed in relevant disease models.

No description available.