Systemic chemotherapy is a major therapeutic approach for nearly all types and stages of cancer. Success of this treatment depends not only on the efficacy of the therapeutics but also on the transport of the drug to all tumor cells in sufficient concentrations. Intratumoral drug transport is limited by characteristics of the tumor microenvironment such as elevated interstitial pressure and sparse, irregular vascularization. Moreover, poor tumor selectivity, leads to systemic toxicity. Bacteria possess a host of characteristics that address the aforementioned challenges in conventional drug delivery approaches including tumor selectivity, preferential tumor colonization, effective tumor penetration, which can be augmented via genetic engineering. However, in clinical trials conducted to date, bacteria have rarely been able to inhibit tumor growth solely by their presence in the tumor. The overall goal of this doctoral dissertation is to develop a novel tumor treatment system based on Salmonella Typhimurium VNP20009 (genetically modified for preferential tumor colonization and attenuation) coupled with biodegradable copolymer, poly(lactic-co-glycolic acid) nanoparticles, hereafter referred to as NanoBEADS (Nanoscale Bacteria Enabled Autonomous Drug Delivery System). To this end, a NanoBEADS fabrication procedure that is robust and repeatable was established and a microfluidic chemotaxis-based sorting platform for the separation NanoBEADS from unattached nanoparticles was developed. The transport efficacy of NanoBEADS compared to the commonly used passively-diffusing nanoparticle was investigated in vitro and in vivo and the intratumoral penetration of the therapeutic vectors was quantified using a custom image processing algorithm. The mechanism of intratumoral penetration was elucidated through 2D and 3D invasion assays. Lastly, we developed a biophysical model of intratumoral transport of NanoBEADS based on the intratumoral penetration experimental results towards the theoretical evaluation of the drug transport profile following the administration of NanoBEADS. / PHD / Currently, the transport of chemotherapeutic drugs into tumors is limited by numerous characteristics of the tumor microenvironment. This problem is exacerbated by poor tumor selectivity, leading to severe side effects to patients. Bacteria possess a host of characteristics that address the aforementioned shortcomings in conventional drug delivery approaches including preferential tumor colonization and anti-tumor effects, which may be mediated naturally or enhanced via genetic engineering. The overall goal of this doctoral dissertation is to develop a novel tumor treatment system based on genetically modified bacteria for safety and efficiency, Salmonella Typhimurium VNP20009 coupled with a polymeric nanoparticles, hereafter referred to as NanoBEADS (Nanoscale Bacteria Enabled Autonomous Drug Delivery Systems). To this end, a NanoBEADS fabrication procedure that is robust and repeatable was established and a microfluidic chemotaxis-based sorting platform for the separation NanoBEADS from unattached nanoparticles was developed. The transport efficiency of NanoBEADS compared to the commonly used nanoparticle was investigated in vitro and in vivo and the intratumoral penetration of the therapeutic vectors was quantified using a custom image processing algorithm. The mechanism of intratumoral penetration was elucidated through 2D and 3D invasion assays. Lastly, we developed a biophysical model of intratumoral transport of NanoBEADS based on the intratumoral penetration experimental results towards the theoretical evaluation of the drug transport profile following the administration of NanoBEADS.

Yes / The hydrophobicity of a drug can be a major challenge in its development and prevents the clinical translation of highly potent anti-cancer agents. We have used a lipid-based nanoemulsion termed Lipid-Oil-Nanodroplets (LONDs) for the encapsulation and in vivo delivery of the poorly bioavailable Combretastatin A4 (CA4). Drug delivery with CA4 LONDs was assessed in a xenograft model of colorectal cancer. LC-MS/MS analysis revealed that CA4 LONDs, administered at a drug dose four times lower than drug control, achieved equivalent concentrations of CA4 intratumorally. We then attached CA4 LONDs to microbubbles (MBs) and targeted this construct to VEGFR2. A reduction in tumor perfusion was observed in CA4 LONDs-MBs treated tumors. A combination study with irinotecan demonstrated a greater reduction in tumor growth and perfusion (P = 0.01) compared to irinotecan alone. This study suggests that LONDs, either alone or attached to targeted MBs, have the potential to significantly enhance tumor-specific hydrophobic drug delivery. / The work was funded by the Medical Research Council (grant number: MR/L01629X MRC Medical Bioinformatics Centre) and the EPSRC (grant number EP/P023266/1 Health Impact Partnership). EPSRC (EP/I000623/1, EP/K023845/1). Laura E. McVeigh was funded by an EPSRC PhD Studentship (EP/L504993/1).

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5 Title: Methylene-bis(phosphonate) Derivatives for Modification of Biomolecules Author: Tomáš David Department: Department of Inorganic Chemistry, Faculty of Science Supervisor: RNDr. Vojtěch Kubíček, Ph.D. Supervisor's e-mail address: vvvojta@seznam.cz Abstract The aim of this work was to prepare derivatives of methylen-bis(phosphonic) acid. Thirty compounds (from which 29 are new) were prepared with moderate or good yields. All compounds were fully characterized by NMR and MS. Four new crystal structures were obtained by RTG monocrystal analysis. Derivative containing 4-nitrobenzyl group in the side chain was used for study of bis(phosphonates) adsorption parametres to hydroxyapatite (with quantification by UV-Vis spectroscopy). Several derivatives containing characteristic functi- onal groups (-NH2, -COOH, -NCS) were prepared. These compound are suitable for further derivatization, mainly for conjugation with more complex structures through amide bond or thiourea bridge. Conjugates of building blocks with fluorescent probe (fluorescein and dansyl) were prepared for potencial optical imaging. Further modification of one of the dansyl derivative afforded trifunctional molecule - contating bis(phosphonate) as a vector for a bone tissue, a fluorescent probe for a possible fluorescent imaging and a free...

This thesis analyzes the connection between monetary policies and belief-driven fluctuation, and discusses the effects of monetary policies in a small open economy. We construct an endogenous growth model that introduces the role of money into the production function and allows elastic labor supply. In departing from the findings proposed by Benhabib and Farmer (1994), we find that belief-driven fluctuation can be easily encouraged, as long as there is lower increasing return to scale under money growth rate targeting. However, if there is a higher level of increasing return to scale, the increase of the growth rate of nominal money supply will only increase the economic growth rate temporarily, and money is super-neutral in the long run. More importantly, we show that under inflation rate targeting, the central bank will eliminate possibilities of belief-driven fluctuation in the small open economy, but lose the efficacy of monetary policy on the short-term economic growth at the same time.

Price Level Targeting with Imperfect Rationality: A Heuristic Approach Vojtěch Molnár Abstract The thesis compares price level targeting and inflation targeting regimes in a New Keynesian model without rational expectations hypothesis. Economic agents instead form their expectations using heuristics-they choose between a few simple rules based on their past forecasting performance. Two main specifications of the price level targeting model are examined-the agents form expectations either about price level or about inflation, which is ex ante not equivalent because of sequential nature of the model. In addition, several formulations of the forecasting rules are considered. According to the results, price level targeting is preferred in the case with expectations created about price level under the baseline calibration; but it is sensitive to some model parameters. Furthermore, when expectations are created about inflation, price level targeting over time loses credibility and leads to divergence of the economy. On the other hand, inflation targeting model functions stably. Therefore, while potential benefits of price level targeting have been confirmed under certain assumptions, the results suggest that inflation targeting constitutes significantly more robust choice for monetary policy.

Partout dans le monde, l’identification des personnes ou ménages bénéficiaires d’interventions sociales demeure un défi. Dans les pays où la majorité de la population travaille dans le secteur informel, vit d’une agriculture de subsistance et/ou vit sous le seuil de la pauvreté, le ciblage des personnes devant bénéficier d’une intervention fait appel à des méthodes différentes dont la vérification du revenu et la classification de la pauvreté sur base monétaire. En 2014, un projet-pilote intitulé Cadre commun des filets sociaux au Nord Mali (CCFS) a été mis en place au Mali. L’objectif de ce projet est d’identifier les populations en insécurité alimentaire et nutritionnelle et leur fournir une assistance (transferts monétaires, assistance alimentaire et prévention de la malnutrition pour les femmes enceintes et les enfants), particulièrement en périodes de soudure pastorale et agricole. La méthode de ciblage Household Economy Approach (HEA) est une des méthodes utilisées pour sélectionner les ménages bénéficiaires des transferts monétaires au Nord Mali. L’objectif de cette recherche est d’identifier les facteurs et le contexte qui influencent la mise en œuvre de la méthode HEA. Deux villages dans une commune agricole et deux sites de fraction dans une commune pastorale ont été choisis comme sites. Des entretiens (48 entretiens (12 effectués par l’étudiante et 36 par l’ONG de recherche)) et une collecte de 15 documents ont été réalisés. À l’aide des 23 facteurs du cadre d’analyse de la mise en œuvre de Durlak et Dupré (2008), une analyse thématique a été effectuée à l’aide du logiciel © QDA Miner. Les résultats démontrent que l’identification des ménages bénéficiaires des transferts monétaires au Nord Mali repose essentiellement sur le ciblage géographique et communautaire. Les facteurs qui influencent le processus de ciblage sont liés à la faible connaissance de la méthode HEA, à la lassitude et la faible motivation des personnes impliquées, à la gestion top down et au manque de transparence dans les processus décisionnels au niveau des structures organisationnelles, aux logiques de domination et relations de pouvoir au sein des communautés ainsi qu’aux enjeux liés au financement et aux rapports hégémoniques existants dans le monde de l’aide humanitaire et de l’aide publique au développement. La difficile coordination multisectorielle des acteurs de la protection sociale vient appuyer le besoin en recherches nouvelles sur la mise en place du régime social unifié (RSU) au Mali. / Around the world, the identification of people or households benefiting from social interventions remains a challenge. In countries where the majority of the population works in the informal sector, lives on subsistence agriculture and/or lives below the poverty line, targeting people who have to benefit from an intervention requires methods that are different from income verification and from the classification of poverty on a monetary basis. In 2014, an experimental project entitled Cadre commun des filets sociaux au Nord Mali (CCFS) was implemented in Mali. The objective of this project is to identify the populations who suffer from food and nutritional insecurity and provide them with assistance (cash transfers, food assistance and prevention of malnutrition for pregnant women and children), particularly during pastoral and agricultural lean periods. The Household Economy Approach (HEA) targeting method is one of the methods used to select beneficiary households for cash transfers in Northern Mali. The purpose of this research is to identify the factors and the context that influence the implementation of the HEA method. Two villages in an agricultural commune and two fractional sites in a pastoral commune were chosen as sites. Interviews (48 interviews (12 carried out by the student and 36 by research NGOs)) and a collection of 15 documents were conducted. Using the 23 factors in the Durlak and Dupré Implementation Analysis Framework (2008), a thematic analysis was conducted using the software © QDA Miner. The results show that the identification of households receiving cash transfers in Northern Mali is mainly based on geographical and community targeting. The factors that influence the targeting process are related to the low knowledge of the HEA method, to the weariness and low motivation of the people involved, to top down management and lack of transparency in the decision-making processes at the level of organizational structures, to the logic of domination and power relations within communities, and finally to the issues of funding and hegemonic relationships in the world of humanitarian aid and development cooperation. The difficult multisectoral coordination of social protection actors comes to support the need for new research on the establishment of a household registration system in Mali.

Is inflation targeting an appropriate framework for monetary policy? Experience from the inflation-targeting countries countries are optimistic about inflation targeting as a monetary-policy framework. South Africa is also following this trend. The international literature review of the topic offers lessons to be learnt from the common experience of the countries considered. It shows that inflation targeting is not a universal remedy to modern economic ills -- there is an emerging danger of assigning monetary policy a larger role than that which it can perform; a danger of expecting monetary policy to accomplish tasks that it cannot achieve; and a danger of preventing monetary policy from making the contribution that it is capable of doing. Therefore, inflation targeting cannot address all the macroeconomic problems that face many countries, except for inflation. Nonetheless, it plays a crucial role in improving macroeconomic performance. / Economics / M.A. (Economics)

Small businesses are the largest employers in Sweden and employ most people on the labour market. Therefore they are considered one of the most important components for an economic growth in a country. However small businesses have problems regarding profitability and survival on the market. It is also considered hard to conduct business for smaller companies, where the lack of restricted resources is a crucial factor. The purpose of this study is to, through a producer perspective and with a qualitative approach, review whether and in what way small businesses uses marketing strategies in their planning. This will be done by answering the following research question: “In what sense do small businesses implement marketing strategies in their work with marketing?” The following conclusions were drawn from the study: • Small businesses implement marketing strategies in their everyday work in the sense that almost all of the small businesses that participated in the study have thought about the factors relating to the selection of target group and the company's own market position in relation to its competitors • Small businesses formulate its marketing strategies mentally rather than having a formal written strategy. • Small businesses mainly choose to segment the market by using geographic and demographic factors. • Small businesses opt out the use of price leadership as their competitive strategy. Instead small businesses try to stand out from their competitors in some unique way and their focus lies on quality rather than quantity. • Small businesses are working diligently to retain existing customers because it is a cheaper approach than trying to attract new customers. • Small businesses can benefit from being apart of a network with other active small, but the study also shows that most benefits can be drawn from startups that not yet enhold a solid knowledge about the market. / Småföretag är Sveriges största arbetsgivare och sysselsätter flest människor på arbetsmarknaden och anses vidare vara en av de viktigaste komponenterna för en ekonomisk tillväxt. Trots det har småföretag problem gällande lönsamhet och överlevnad på marknaden. Det är även svårt att bedriva verksamhet för mindre företag, där bland annat brist på resurser är en återkommande kritisk faktor. Syftet med studien är att, baserat på en kvalitativ metod och genom ett producentperspektiv, ta hjälp av fem stycken semistrukturerade intervjuer för att kartlägga huruvida och på vilket sätt småföretag använder sig av marknadsföringsstrategier i sitt planeringsarbete. Detta genom att besvara forskningsfrågan: “I vilken bemärkelse implementerar småföretag marknadsföringsstrategier i sitt arbete med marknadsföring?” Följande slutsatser kunde dras av studien: • Småföretag implementerar marknadsföringsstrategier i sitt vardagliga arbete i den bemärkelsen att nästan alla av de småföretag som deltog i studien funderat kring faktorer som rör val av målgrupp och företagets egen position på marknaden i relation till dess konkurrenter • Småföretag formulerar marknadsföringsstrategier mentalt i huvudet, snarare än att ha en formell nedskriven strategi. • Småföretag väljer att segmentera marknaden utefter geografiska- och demografiska faktorer. • Småföretag väljer bort användandet av ett prisledarskap som konkurrensstrategi. Istället väljer småföretag att försöka utmärka sig från sina konkurrenter på något unikt sätt och fokus ligger på ett kvalitetstänk snarare än kvantitet. • Småföretagen arbetar flitigt med att behålla befintliga kunder då det är billigare än att försöka attrahera nya kunder. Dock pågår det ett ständigt arbete att försöka locka till sig nya kunder samtidigt. • Småföretag kan dra nytta av att involveras i nätverk med andra verksamma småföretag, men studien visar på att mest fördelar finns att dra nytta av för nystartade småföretag som ännu inte besitter en gedigen kunskap om marknaden.

Neuraminidase (NA) is one of two major antigens on the surface of influenza A viruses. It is comprised of a single N-terminal transmembrane domain (TMD), a stalk domain, and a C-terminal enzymatic head domain that cleaves sialic acid, most notably to release new particles from the host cell surface. NA is only enzymatically active as a homo-tetramer. However, it is not known which properties facilitate the oligomerization of NA during assembly. Our results show that, apart from anchoring the protein to the membrane, the NA TMD also contributes to the assembly process by keeping the stalk in a tetrameric conformation. The ability of the TMD to oligomerize is shown to be dependent on its amphiphilic characteristics that was largely conserved across the nine NA subtypes (N1-N9). Over time the NA TMDs in human H1N1 viruses were found to have become more amphiphilic, which correlated with stronger oligomerization. An old H1N1 virus with a more recent N1 TMD had impaired growth, but readily acquired compensatory mutations in the TMD to restore growth, by reverting the TMD oligomerization strength back to that of the old TMD, demonstrating a biological role of the TMD in folding and assembly. NA and the other viral proteins are spatially and temporally coordinated to achieve optimal viral production. By using a co-transfection analysis, the high AU-content in the NA and HA ER-targeting sequence coding regions (for NA TMD as well as the HA signal sequence) were found to inhibit their expression. The inhibition was alleviated by the early expressed influenza RNA-binding protein NS1, which promoted translation and showed enriched foci at the endoplasmic reticulum (ER). NS1, which expresses early during infection, is therefore likely the regulator of NA and HA to prevent premature expression. These results show that the NA TMD is under substantial selection pressure at both the nucleotide and amino acid level to accommodate its roles in ER-targeting, protein folding, and post-transcriptional regulation. / <p>At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: Accepted.</p>