Therapeutic efficacy of drugs depends on their ability to reach the treatment target. Drugs that exert their effect within cells are constrained by an inability to cross the cell membrane. Methods are being developed to overcome this barrier including biochemical and biophysical strategies. The application of ultrasound with microbubbles increases the permeability of cell membranes allowing molecules, which otherwise would be excluded, to enter the intracellular space of cells; a phenomenon known as sonoporation. This thesis describes studies aimed at improving our understanding of the mechanism underpinning sonoporation and of the exposure parameters affecting sonoporation efficiency. Cancer cells (KHT-C) in suspension were exposed to ultrasound and microbubbles – total of 97 exposure conditions. The effects on cells were assessed through uptake of cell-impermeable molecules (10 kDa to 2 MDa FITC-dextran), cell viability and microscopic observations of the plasma membrane using flow cytometry, colony assay and electron microscopy techniques. Sonoporation was a result of the interaction of ultrasound and microbubbles with the cell membrane. Disruptions (30-100 nm) were generated on the cell membrane allowing cell impermeable molecules to cross the membrane. Molecules up to 2 MDa in size were delivered at high efficiency (~70% permeabilisation). Sonoporation was short lived; cells re-established their barrier function within one minute, which allowed compounds to remain inside the cell. Following uptake, cells remained viable; ~50% of sonoporated cells proliferated. Sonoporation efficiency depended on ultrasound and microbubble exposure conditions. Microbubble disruption was a necessary but insufficient indicator of ultrasound-induced permeabilisation. The exposure conditions can be tailored to achieve a desired effect; cell permeability of ~70% with ~25% cell death versus permeability of ~35% with ~2% cell death. In addition, sonoporation depended on position in the cell cycle. Cells in later stages were more prone to being permeabilised and killed by ultrasound and microbubbles. This study indicated that sonoporation can be controlled through exposure parameters and that molecular size may not be a limiting factor. However, the transient nature may necessitate that the drug be in close vicinity to target cells in sonoporation-mediated therapies. Future work will extend the investigation into in vivo models.

Projektinis valdymas, tai moderniųjų viešojo administravimo paradigmų instrumentas, kuriuo siekiama tobulinti viešųjų institucijų veiklą ir tai daryti apjungiant geriausias verslo bei viešojo sektoriaus praktikas. Lietuvoje projektinis valdymas intensyviau pradėtas taikyti tik atsiradus galimybei įsisavinti Europos Sąjungos paramą, todėl šis instrumentas yra ganėtinai naujas mūsų šalyje. Šiuo metu Lietuvoje populiarėja stambūs investiciniai projektai, kurių metu siekiant konkretaus tikslo yra sudaromos įvairaus tipo bendradarbiavimo sutartys tarp viešųjų institucijų ir privačių atstovų ir tokiu būdu sukuriami užsakovo ir vykdytojo santykiai. Darbo eigoje bus nagrinėjamas investicinis projektas, kaip instrumentas, o taip pat analizuojamas jo įgyvendinimo procesas. Be to, remiantis dvejomis teorijomis bus pristatytas koncepcinis tyrimo modelis, kurio pagalba galima analizuoti sąveikas tarp užsakovo (viešosios institucijos) bei vykdytojo (privataus sektoriaus atstovo). Trečiojoje dalyje bus aiškinamasi, kokie veiksniai lemia nesklandumus investicinio projekto valdyme. Darbo tikslas yra išnagrinėti investicinių projektų įgyvendinimo problematiką Lietuvoje, santykių tarp užsakovo ir rangovo bei projekto darbų priežiūros aspektu. Tikslui pasiekti bus nagrinėjamas Kauno pramogų ir sporto rūmų Nemuno saloje investicinis projektas. Pasitelkus surinktą informaciją bus nustatytos pagrindinės priežastys, kurios lemia investicinio projekto įgyvendinimo nesklandumus. Galiausiai darbo... [toliau žr. visą tekstą] / Project management is an instrument of modern Public administration paradigms. It is used in order to make public institutions more efficient. This instrument is quite new in Lithuania and was started to use intensively when European Union gave opportunity soak up support from EU funds. Now in Lithuania big investment projects are becoming more and more popular. The main purpose of these projects is to create efficient relations between principal (public organization) and agent (private organization). Both participants are maximizing their efforts in order to reach some particular purpose with less money and more quality. In this paper it will be analysed the concept of investment project and implementation of investment project. Besides, there will be presented the model of research, which can help to analyse the interactions between principal and agent. This model is based on two theories – Principal agent ant Contract theory. In third part of this paper there will be research of principal and agent interactions. This research should reveal, which factors cause problems in investment project implementation. The main purposes of this paper are to analyse the implementation of investment projects in Lithuania, to investigate interactions in investment projects and to reveal the way of control in projects implementation. The base of research will be the analyse of investment project “Kauno pramogų ir sporto rūmai Nemuno saloje“. At the end of this paper will be revealed why... [to full text]

I början av 2014 ifrågasatte revisorernas branschförening FAR användandet av progressiva avskrivningar i bostadsrättsföreningar, då avskrivningsmetoden ansågs skjuta upp stora minusposter på framtida generationer. Argument fördes, från byggbolag och bostadsrättsinnehavare, om att alternativet; en linjär avskrivningsmetod, skulle bidra till höjda avgifter och i förlängningen en avstannande bostadsmarknad. Denna uppsats använder de båda avskrivningsmetoderna för att undersöka vilka konsekvenser avskrivningsmetodvalet kan få på bostadsrättsföreningars ekonomi i framtiden. Detta görs genom en omräkning av tre bostadsrättsföreningars årsredovisningar. Möjliga effekter på föreningars resultat, medlemsavgifter samt alternativa lösningar på avgiftshöjningsproblemet diskuteras. Slutsatser dras om att en linjär avskrivningsmetod i kombination med mindre avgiftshöjningar och negativa resultat är bäst lämpad för användning.

Decision making problems are amongst the most common challenges facing managers at different management levels in the organisation: strategic, tactical, and operational. However, prior reaching decisions at the operational level of the management hierarchy, operations management departments frequently have to deal with the optimisation process to evaluate the available decision alternatives. Industries with complex supply chain structures and service organisations that have to optimise the utilisation of their resources are examples. Conventionally, operational decisions used to be taken centrally by a decision making authority located at the top of a hierarchically-structured organisation. In order to take decisions, information related to the managed system and the affecting externalities (e.g. demand) should be globally available to the decision maker. The obtained information is then processed to reach the optimal decision. This approach usually makes extensive use of information systems (IS) containing myriad of optimisation algorithms and meta-heuristics to process the high amount and complex nature of data. The decisions reached are then broadcasted to the passive actuators of the system to put them in execution. On the other hand, recent advancements in information and communication technologies (ICT) made it possible to distribute the decision making rights and proved its applicability in several sectors. The market-based approach is as such a distributed decision making mechanism where passive actuators are delegated the rights of taking individual decisions matching their self-interests. The communication among the market agents is done through market transactions regulated by auctions. The system’s global optimisation, therefore, raise from the aggregated self-oriented market agents. As opposed to the centralised approach, the main characteristics of the market-based approach are the market mechanism and local knowledge of the agents. The existence of both approaches attracted several studies to compare them in different contexts. Recently, some comparisons compared the centralised versus market-based approaches in the context of transportation applications from an algorithm perspective. Transportation applications and routing problems are assumed to be good candidates for this comparison given the distributed nature of the system and due to the presence of several sources of uncertainty. Uncertainty exceptions make decisions highly vulnerable and necessitating frequent corrective interventions to keep an efficient level of service. Motivated by the previous comparison studies, this research aims at further investigating the features of both approaches and to contrast them in the context of a distributed task allocation problem in light of environmental uncertainty. Similar applications are often faced by service industries with mobile workforce. Contrary to the previous comparison studies that sought to compare those approaches at the mechanism level, this research attempts to identify the effect of the most significant characteristics of each approach to face environmental uncertainty, which is reflected in this research by the arrival of dynamic tasks and the occurrence of stochasticity delays. To achieve the aim of this research, a target optimisation problem from the VRP family is proposed and solved with both approaches. Given that this research does not target proposing new algorithms, two basic solution mechanisms are adopted to compare the centralised and the market-based approach. The produced solutions are executed on a dedicated multi-agent simulation system. During execution dynamism and stochasticity are introduced. The research findings suggest that a market-based approach is attractive to implement in highly uncertain environments when the degree of local knowledge and workers’ experience is high and when the system tends to be complex with large dimensions. It is also suggested that a centralised approach fits more in situations where uncertainty is lower and the decision maker is able to make timely decision updates, which is in turn regulated by the size of the system at hand.

This thesis presents a new approach to local decision-making in multi-agent systems with varying amounts of communication. Here, local decision-making refers to action choices which are made in a decentralized fashion by individual agents based on the information which is locally available to them. The work described here is set within the multi-agent decision process framework. Unreliable, faulty or stochastic communication patterns present a challenge to these settings which usually rely on precomputed, centralised solutions to control individual action choices. Various approximate algorithms for local decision-making are developed for scenarios with and without sequentiality. The construction of these techniques is based strongly on methods of Bayesian inference. Their performance is tested on synthetic benchmark scenarios and compared to that of a more conservative approach which guarantees coordinated action choices as well as a completely decentralized solution. In addition, the method is applied to a surveillance task based on real-world data. These simulation results show that the algorithms presented here can outperform more traditional approaches in many settings and provide a means for flexible, scalable decision-making in systems with varying information exchange between agents.

We investigate the properties of a new Multi-Agent Systems (MAS) for computer-aided composition called IPCS (pronounced “ipp-siss”) the Intermediate Performance Composition System which generates expressive performance as part of its compositional process, and produces emergent melodic structures by a novel multi-agent process. IPCS consists of a small-medium size (2 to 16) collection of agents in which each agent can perform monophonic tunes and learn monophonic tunes from other agents. Each agent has an affective state (an “artificial emotional state”) which affects how it performs the music to other agents; e.g. a “happy” agent will perform “happier” music. The agent performance not only involves compositional changes to the music, but also adds smaller changes based on expressive music performance algorithms for humanization. Every agent is initialized with a tune containing the same single note, and over the interaction period longer tunes are built through agent interaction. Agents will only learn tunes performed to them by other agents if the affective content of the tune is similar to their current affective state; learned tunes are concatenated to the end of their current tune. Each agent in the society learns its own growing tune during the interaction process. Agents develop “opinions” of other agents that perform to them, depending on how much the performing agent can help their tunes grow. These opinions affect who they interact with in the future. IPCS is not a mapping from multi-agent interaction onto musical features, but actually utilizes music for the agents to communicate emotions. In spite of the lack of explicit melodic intelligence in IPCS, the system is shown to generate non-trivial melody pitch sequences as a result of emotional communication between agents. The melodies also have a hierarchical structure based on the emergent social structure of the multi-agent system and the hierarchical structure is a result of the emerging agent social interaction structure. The interactive humanizations produce micro-timing and loudness deviations in the melody which are shown to express its hierarchical generative structure without the need for structural analysis software frequently used in computer music humanization.

In this thesis, we present a novel approach to solving optimization problems that are defined on agent-based models (ABM). The approach utilizes concepts in genetic programming (GP) and is demonstrated here using an optimization problem on the Sugarscape ABM, a prototype ABM that includes spatial heterogeneity, accumulation of agent resources, and agents with different attributes. The optimization problem seeks a strategy for taxation of agent resources which maximizes total taxes collected while minimizing impact on the agents over a finite time. We demonstrate how our GP approach yields better taxation policies when compared to simple flat taxes and provide reasons why GP-generated taxes perform well. We also look at ways to improve the performance of the GP optimization method. / McAnulty College and Graduate School of Liberal Arts; / Computational Mathematics / MS; / Thesis;

Paper [I] models a game, where two temporary work agencies (TWAs) compete to fill a vacancy at a client firm (CF). They simultaneously choose how much effort to expend, based on their expectation of how good their opponent’s best candidate will be. I then show that this will make the TWAs overconfident, as the rational way of judging your own probability of winning is not looking at the opponents expected best, but comparing how much effort your opponent will expend. Paper [II] examines the misaligned incentives in the temporary work agency sector, where we first look at pure recruiting contracts, that either require payment on delivery, or payment on some specified point in time. We then look at the incentives of recruit-and-rent contracts, where the worker is leased to the client firm. We assume that the better the worker, the higher the probability that the client firm is going to want to hire him/her. If that happens then the TWA will no longer get revenues from said worker, incentivizing the TWA to not always deliver the first match it finds, if it is too good. Lastly we look at how competition can dampen this perverse incentive. Paper [III] models the waiting behavior that can occur if a TWA is contracted to find a worker for a specific time far in the future; the TWA will postpone effort. This behavior is modeled for two types of TWAs; one that is rational and plans ahead, and another that does not plan ahead at all, but instead only looks at the immediate future. I find that the one that only looks at the immediate future starts exerting effort earlier than the planner. After looking at optimal contracts under perfect monitoring and hidden action I provide two extensions. I first show that for the principal to want to delegate search to a rational TWA, the agent has to be better than the CF, by some factor, as it has to make up in efficiency what the principal loses in moral hazard, when the agent waits longer than the principal would like it to. Lastly I prove that it is profit maximizing for the principal to contract one agent and give it a deadline earlier than when the principal would need the worker, and then replace that agent with a competitor if the first one has not succeeded by that earlier deadline. Paper [IV] estimates at the effect of family experience on relative transition probability into the temporary work agency sector. Using register data for all of Sweden we run a bias-reduced logistic regression, where we include various factors that affect the probability of young adults (aged 18-34) entering the sector. This paper ties in to the literature on occupational inheritance, as well as the literature on changing social norms. We find that having had a parent, sibling or partner in the TWA sector increases your probability of entering.

Advanced melanoma poses a major therapeutic challenge, and despite the development of recent promising therapeutic agents, resistance to treatment remains a problem. Until recently, despite low response rates, alkylating agents dacarbazine and temozolomide (TMZ) were the standard of care for the treatment of advanced melanoma. The cytotoxic effects of these agents relies upon the formation of alkylated base lesions such as O⁶-methylguanine (O⁶MeG), which is repaired by a protein implicated in TMZ resistance called O⁶-methylguanine-DNA methyltransferase (MGMT). Failure to resolve such alkylated bases results in DNA replication-associated double-strand breaks (DSBs). The type 1 insulin-like growth factor receptor (IGF-1R) mediates a number of characteristics common to cancers, including proliferation and survival, and evidence suggests it may also contribute to resistance to many anticancer agents. The aims of this study were to test whether melanoma cells could be sensitized to TMZ by small molecule IGF1R inhibitors, and to explore the mechanism of any chemosensitization. This study found an association between basal IGF1R phosphorylation and in vitro TMZ resistance in seven MGMT-proficient melanoma cell lines, suggesting that IGF1R activation may be linked with TMZ resistance. Furthermore, IGF1R inhibition caused dose-dependent sensitization of melanoma cells to TMZ, regardless of BRAF mutation status. This reduction in cell survival was not accompanied by an increase in apoptosis, but rather Chk2 activation and an accumulation of cells in the G2/M phase of the cell cycle, suggesting a possible effect of IGF1R inhibition on DNA repair. IGF1R depletion was found to increase MGMT protein levels and activity, but this effect was not seen in IGF1R inhibited cells. In addition, IGF1R inhibition was not epistatic with MGMT inhibition, and IGF1R inhibition reduced survival of TMZ treated MGMT-null cells. This suggested that TMZ sensitization by IGF1R inhibition was independent of MGMT. IGF1R inhibition did however cause an increase in the accumulation of TMZ-induced RPA foci, and delay in resolution of RAD51 foci. Together with the finding that IGF1R inhibition reduced survival in PARP inhibited melanoma cells, these results suggested that IGF1R inhibition influenced DSB repair by homologous recombination. Finally, the combination of IGF1R inhibition with TMZ was tested in a mouse model and was found to be tolerable. TMZ or IGF-1R inhibitor alone caused minor reduction in melanoma xenograft growth rates (rate reduction by 13% and 25% respectively), while combination treatment caused supra-additive growth delay (72%) that was significantly different from other treatment groups (p<0.05). The findings of this study suggest IGF1R inhibition as a possible option in overcoming alkylating drug resistance in melanoma.

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.