No / MicroRNAs are a relatively new class of small, noncoding RNA species that represent a cornerstone of cell biology, with diverse roles ranging from embryonic development to aging. miRNAs function to regulate posttranscriptional gene expression, are critical to the normal function of cells, and as such are frequently dysregulated during disease processes. In this chapter, we discuss the biogenesis and mechanism of action of miRNA and their role in cancer initiation, promotion, and progression. In addition, we discuss the most recently identified dual roles of miRNA in epigenetic gene regulation; how they are both regulators and regulated. Finally, we discuss the emerging roles of miRNA as epigenetic anti-cancer therapeutics, the current research examining inhibition of oncogenic miRNAs, and studies now establishing the potential of replacing lost, tumor-suppressive miRNA.

The dissertation “Informal Economic Activities” takes a comprehensive approach to the informal economy by studying traditional shadow economic activities, household DIY activities, and the smuggling of illegal and legal goods. Chapter 2 analyzes shadow economic and DIY activities and presents a dual estimation for the development of both types of informal economic activities in Germany from 1970 to 2005. It also considers the impact of German reunification on shadow economic and DIY activities and employs a proper estimate of domestic currency in circulation within Germany as an indicator variable for the shadow economy. Chapter 3 studies an informal economic activity that has attracted much attention recently: legal goods smuggling, or the illegal trade of otherwise legal goods. The main channel of this type of smuggling is the falsification of trade documents. By reporting false amounts of exports and/or imports to authorities smugglers, or trade misinvoicers, seek to avoid paying taxes and/or tariffs. Chapter 4 widens the analysis of smuggling to the smuggling of illegal goods and studies the smuggling of legal and illegal goods across the U.S.-Mexico border in order to improve the understanding of illegal trade. Studying the U.S.-Mexican case is particularly interesting as most illegal drugs and immigrants enter the United States via the Mexican border. The empirical analyses in the dissertation “Informal Economic Activities” are based on structural equation models (SEMs). The results demonstrate that the informal economy is significant and that growth of the informal economy is not exclusive to developing countries, although it is a more serious problem in these countries. Moreover, although the informal economy covers a wide range of rather diverse economic activities, the dissertation works out that a few similarities exist. These are important, especially for policymakers, in first understanding what drives informal economic activities and second designing appropriate policies to deter them.

The dissertation “Informal Economic Activities” takes a comprehensive approach to the informal economy by studying traditional shadow economic activities, household DIY activities, and the smuggling of illegal and legal goods. Chapter 2 analyzes shadow economic and DIY activities and presents a dual estimation for the development of both types of informal economic activities in Germany from 1970 to 2005. It also considers the impact of German reunification on shadow economic and DIY activities and employs a proper estimate of domestic currency in circulation within Germany as an indicator variable for the shadow economy. Chapter 3 studies an informal economic activity that has attracted much attention recently: legal goods smuggling, or the illegal trade of otherwise legal goods. The main channel of this type of smuggling is the falsification of trade documents. By reporting false amounts of exports and/or imports to authorities smugglers, or trade misinvoicers, seek to avoid paying taxes and/or tariffs. Chapter 4 widens the analysis of smuggling to the smuggling of illegal goods and studies the smuggling of legal and illegal goods across the U.S.-Mexico border in order to improve the understanding of illegal trade. Studying the U.S.-Mexican case is particularly interesting as most illegal drugs and immigrants enter the United States via the Mexican border. The empirical analyses in the dissertation “Informal Economic Activities” are based on structural equation models (SEMs). The results demonstrate that the informal economy is significant and that growth of the informal economy is not exclusive to developing countries, although it is a more serious problem in these countries. Moreover, although the informal economy covers a wide range of rather diverse economic activities, the dissertation works out that a few similarities exist. These are important, especially for policymakers, in first understanding what drives informal economic activities and second designing appropriate policies to deter them.

Diagnosis code assignment is a field that looks at automatically assigning diagnosis codes to free-text clinical notes. Assigning a diagnosis code to clinical notes manually needs expertise and time. Being able to do this automatically makes getting structured data from free-text clinical notes in Electronic Health Records easier. Furthermore, it can also be used as decision support for clinicians where they can input their notes and get back diagnosis codes as a second opinion. This project investigates the effects of using the hierarchies the diagnosis codes are structured in when training the diagnosis code assignment models compared to models trained with a standard loss function, binary cross-entropy. This has been done by using the hierarchy of two systems of diagnosis codes, ICD-9 and SNOMED CT, where one hierarchy is more detailed than the other. The results showed that hierarchical training increased the recall of the models regardless of what hierarchy was used. The more detailed hierarchy, SNOMED CT, increased the recall more than what the use of the less detailed ICD-9 hierarchy did. However, when using the more detailed SNOMED CT hierarchy the precision of the models decreased while the differences in precision when using the ICD-9 hierarchy was not statistically significant. The increase in recall did not make up for the decrease in precision when training with the SNOMED CT hierarchy when looking at the F1-score that is the harmonic mean of the two metrics. The conclusions from these results are that using a more detailed hierarchy increased the recall of the model more than when using a less detailed hierarchy. However, the overall performance measured in F1-score decreased when using a more detailed hierarchy since the other metric, precision, decreased by more than what recall increased. The use of a less detailed hierarchy maintained its precision giving an increase in overall performance. / Diagnoskodstilldeling är ett fält som undersöker hur man automatiskt kan tilldela diagnoskoder till fri-text läkaranteckningar. En manuell tildeling kräver expertis och mycket tid. Förmågan att göra detta automatiskt förenklar utvinning av strukturerad data från fri-text läkaranteckningar i elektroniska patientjournaler. Det kan även användas som ett hjälpverktyg för läkare där de kan skriva in sina läkaranteckningar och få tillbaka diagnoskoder som en andra åsikt. Detta arbete undersöker effekterna av att ta användning av hierarkierna diagnoskoderna är strukturerade i när man tränar modeller för diagnoskodstilldelning jämfört med att träna modellerna med en vanlig loss-funktion. Det här kommer att göras genom att använda hierarkierna av två diagnoskod-system, SNOMED CT och ICD-9, där en av hierarkierna är mer detaljerad. Resultaten visade att hierarkisk träning ökade recall för modellerna med båda hierarkierna. Den mer detaljerade hierarkien, SNOMED CT, gav en högre ökning än vad träningen med ICD-9 gjorde. Trots detta minskade precision av modellen när man den tränades med SNOMED CT hierarkin medan skillnaderna i precision när man tränade hierarkiskt med ICD-9 jämfört med vanligt inte var statistiskt signifikanta. Ökningen i recall kompenserade inte för minskningen i precision när modellen tränades med SNOMED CT hierarkien som man kan see på F1-score vilket är det harmoniska medelvärdet av de recall och precision. Slutsatserna man kan dra från de här resultaten är att en mer detaljerad hierarki kommer att öka recall mer än en mindre detaljerad hierarki ökar recall. Trots detta kommer den totala prestandan, som mäts av F1-score, försämras med en mer detaljerad hierarki eftersom att recall minskar mer än vad precision ökar. En mindre detaljerad hierarki i träning kommer bibehålla precision så att dens totala prestandan förbättras.

<p>HIV-1 protease inhibitors are important in the most frequently used regimen for the treatment of HIV/AIDS, the highly active antiretroviral therapy (HAART). For patients with access to this treatment, an HIV infection is no longer lethal, but rather a manageable, chronic infection. However, the HIV-1 protease inhibitors are generally associated with serious shortcomings such as adverse events, development of drug resistance and poor pharmacokinetic properties. Most of the approved inhibitors suffer from high protein binding, rapid metabolism and/or low membrane permeability. </p><p>In this project, novel HIV-1 protease inhibitors comprising a rarely used tertiary alcohol in the transition-state mimic were designed, synthesized and evaluated. The rationale behind the design was to achieve ‘masking’ of the tertiary alcohol by for example, intramolecular hydrogen bonding, which was believed could enhance transcellular transport. </p><p>A reliable synthetic protocol was developed and a series of highly potent inhibitors was obtained exhibiting excellent membrane permeation properties in a Caco-2 cell assay. However, the cellular antiviral potencies of these compounds were low. In an attempt to improve the anti-HIV activity, microwave-accelerated, palladium-catalyzed cross-coupling reactions and aminocarbonylation of aryl bromide precursors were employed to produce P1'-extended test compounds. Inhibitors demonstrating up to six times higher antiviral effect were obtained, the best derivatives having para 3- or 4-pyridyl elongations in P1'.</p><p>Fast metabolic degradation was observed in liver microsome homogenate, which is believed, at least partly, to be attributable to benzylic oxidation of the indanol P2 group of the inhibitors. To enable facile variation of the P2 side chain a new synthetic route was developed using an enantiomerically pure, benzyl-substituted epoxy carboxylic acid as the key intermediate. Cyclic and amino-acid-residue-derived P2 groups were evaluated, and inhibitors equipotent to the series containing an indanol moiety were produced.</p>

HIV-1 protease inhibitors are important in the most frequently used regimen for the treatment of HIV/AIDS, the highly active antiretroviral therapy (HAART). For patients with access to this treatment, an HIV infection is no longer lethal, but rather a manageable, chronic infection. However, the HIV-1 protease inhibitors are generally associated with serious shortcomings such as adverse events, development of drug resistance and poor pharmacokinetic properties. Most of the approved inhibitors suffer from high protein binding, rapid metabolism and/or low membrane permeability. In this project, novel HIV-1 protease inhibitors comprising a rarely used tertiary alcohol in the transition-state mimic were designed, synthesized and evaluated. The rationale behind the design was to achieve ‘masking’ of the tertiary alcohol by for example, intramolecular hydrogen bonding, which was believed could enhance transcellular transport. A reliable synthetic protocol was developed and a series of highly potent inhibitors was obtained exhibiting excellent membrane permeation properties in a Caco-2 cell assay. However, the cellular antiviral potencies of these compounds were low. In an attempt to improve the anti-HIV activity, microwave-accelerated, palladium-catalyzed cross-coupling reactions and aminocarbonylation of aryl bromide precursors were employed to produce P1'-extended test compounds. Inhibitors demonstrating up to six times higher antiviral effect were obtained, the best derivatives having para 3- or 4-pyridyl elongations in P1'. Fast metabolic degradation was observed in liver microsome homogenate, which is believed, at least partly, to be attributable to benzylic oxidation of the indanol P2 group of the inhibitors. To enable facile variation of the P2 side chain a new synthetic route was developed using an enantiomerically pure, benzyl-substituted epoxy carboxylic acid as the key intermediate. Cyclic and amino-acid-residue-derived P2 groups were evaluated, and inhibitors equipotent to the series containing an indanol moiety were produced.

In this thesis the synthesis of several hydrolytically stable carbohydrate mimics with the potential to function as glycosidase or lectin inhibitors are described. This work is presented in Chapters 2-5. Chapters 2 and 3 describe synthetic efforts for producing carbasugars, and include the first synthesis of 1,2-bis-epi-valienamine and the preparation of two previously known aminocarbasugars. All three compounds were synthesised starting from D-mannose, using ring-closing metathesis as the key step. 1,2-Bis-epi-valienamine was found to inhibit Cellulomonas fimi β-mannosidase with a Ki value of 140 mM. Also included is the development of a novel synthetic route from cheap D-fructose to three mannose-mimicking carbasugars using a ring-closing metathesis strategy. Two of the compounds are potential inhibitors of the FimH adhesin. In Chapters 4 and 5 the synthesis of a number of pseudodisaccharides are presented; valienamine- and epi-valienamine-containing pseudodisaccharides and a small library of S-linked pseudodisaccharides were prepared. Various synthetic strategies were explored, including an alkylation strategy, Mitsunobu couplings, and sulfonate displacements. This is the first report on the synthesis of a valienamine pseudodisaccharide with β-lyxo-configuration. Two of the S-linked pseudodisaccharides were found to bind to Concanavalin A with high affinity. The final chapter (Chapter 6) of this thesis focuses on the development of a carbohydrate epimerisation method using transition metal catalysis. Two equilibrium constants involving gluco/manno- and gluco/allo-alcohols were determined via this method. / At the time od doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Submitted. Paper 3: Manuscript. Paper 5: Manuscript.

Background: Achieving an abnormal return on your investment is something investors are trying to achieve. A lot of attempts have been made to try and find an investment strategy that always generates abnormal returns, although none has been proven to be absolute. Efficient Market Hypothesis (EMH) proponents argue that when it comes to public available information, one could not get an abnormal advantage of this information. Behavioural Finance (BF) proponents however argue that there may still be possible for this due to human psychology. For markets to have the best possibilities for being efficient, it must be a large and competitive market where information transfers rapidly. When analysing aspects necessary for earning abnormal return for outsiders, there are indications that these aspects does exist and it might be profitable to mimic the insiders operating in the Swedish large-cap bank sector. The large-cap bank sector contains of Svenska Handelsbanken (SHB), Nordea, Swedbank and Skandinaviska Enskilda Banken (SEB). Purpose: The purpose of this thesis is to explore whether there exist an opportunity in the Swedish bank sector for outsiders to earn abnormal return based on insiders’ transactions. In the process an indirect test will be made to see if the semi-strong form of efficiency holds for the Swedish bank sector. Method: Observing the movements on the market when the information about insider trading becomes public. The results are tested for both statistical significance and economical significance. Conclusion: The purpose of this study was to try and determine whether or not outsiders could mimic the insider’s transactions in order to earn abnormal return in the Swedish bank sector. However, based on this study this seems not to be possible in the overall sector. The signs that indicated that this would be possible for the Swedish large-cap banks turned out to be false. The result that showed statistical difference from zero was negative and it was therefore concluded that the insider did not predict the future very well. This leads to the conclusion that there are stronger factors than the sign of insiders’ transactions determine the future stock price. Since the insiders could not predict the future stock prices, any attempt from outsiders to try to exploit their information would not be beneficial. This resulted in the BF assumptions of under- and overreaction in the price did not occur in this study and instead the results turned out to be in line with the EMH description of semi-strong markets. / Bakgrund: Att uppnå överavkastning på sin investering är något investerare ständigt försöker uppnå. Många försök har gjorts för att försöka hitta en investeringsstrategi som alltid genererar överavkastningen, dock har inga gjorts som visat sig vara kontinuerliga. Den Effektiva Marknads Hypotesens förespråkare hävdar att när det gäller offentligt tillgänglig information kan man inte få onormal fördel av detta. Dock hävdar förespråkare för Behavioural Finance att detta fortfarande kan vara möjligt och att detta beror delvis på mänsklig psykologi. För att marknader ska ha de bästa möjligheterna för att vara effektiv, måste de vara stora och konkurrenskraftiga där information överförs snabbt. När man analyserar vissa aspekter som är nödvändiga för att tjäna överavkastningen för utomstående, verkar det finnas tecken på att detta skulle kunna vara möjligt genom att imitera insynshandel i den Svenska large-cap bank sektorn. Sektorn består av Handelsbanken (SHB), Nordea, Swedbank och Skandinaviska Enskilda Banken (SEB). Syfte: Är att undersöka om det finns en möjlighet för utomstående att få överavkastningen baserad på insynspersonernas transaktioner. I processen görs ett indirekt test för att se om den Svenska banksektorn uppnår semi-stark effektivitet. Metod: Observera rörelserna på marknaden när information om insynshandel blev allmänt. Resultatet testas för både statistisk och ekonomisk signifikans. Slutsats: Syftet med denna studie var att försöka avgöra huruvida utomstående kunde imitera insynspersonernas transaktioner för att tjäna onormal avkastning i den Svenska banksektorn. Baserat på denna studie verkar detta inte vara möjligt i den totala sektorn. De tecken som indikerade att detta skulle vara möjligt för visade sig vara falskt. Resultatet som visade statistisk skillnad från noll var negativt och därför drogs slutsatsen att insynspersonerna inte kunde förutsäga framtiden särskilt väl. Detta leder till slutsatsen att det finns starkare faktorer än insynspersoners transaktioner som avgör framtida aktiekurser. Eftersom insynspersoner inte kunde förutse de framtida aktiekurserna, skulle varje försök från en utomstående att försöka utnyttja detta inte vara fördelaktigt. Detta resulterade i fenomenet av under- och överreaktioner som BF förespråkade, inte förekom i denna studie. Istället visade resultatet sig vara i linje med EMH beskrivningen av semi-starka marknader.

Ce mémoire présente une exploration des polymères à empreintes moléculaires (MIP) comme outils d’une libération contrôlée de bioactifs olfactifs ou pour le criblage/préselection de composés à activité antivirales ou anti-tumorales sur le site actif d’une enzyme. La première partie est une étude de la complexation de la vanilline sur des billes polymériques sphériques en vue d’une libération contrôlée (pH, salinité, …). Ces études portent sur les caractéristiques de l'absorption et la libération de la molécule d'intérêt dans le milieu aqueux sur les microsphères fonctionnalisées fourni par Merck ESTAPOR® Microsphères. Nous avons ensuite synthétisé divers MIP de vanilline au format monolithique. Plusieurs stratégies d’impression ont été étudiées: non covalente, covalente et semi-covalente. La composition du MIP préparé dans chaque approche a été optimisée pour obtenir les meilleures propriétés et performances. L'affinité, la sélectivité et la capacité du MIP ont été déterminées. Les MIPs ont été évalués par extraction en phase solide (SPE) d'analogues structuraux de la vanilline dans des échantillons naturels (extrait de vanille, vin). La deuxième partie de ce mémoire concerne l’évaluation de MIPs de l’adénosine 5’-monophosphate (AMP) Le polymère a été préparé par une approche non-covalente et son efficacité de recapture a été caractérisée par analyse frontale (FA). L’analyse frontale est une technique qui permet de discriminer des interactions spécifiques des non spécifiques et de comprendre les mécanismes de liaison dans des cavités spécifiques. / This thesis report presents the exploration of molecularly imprinted polymers (MIP) for the application in controlled release and targeting antivirus and anticancer drugs. The first part of this study describes the imprinting of vanillin as a monolith. Several strategies were studied: non-covalent, covalent and semi-covalent. The composition of the MIP prepared in each approach was optimized to obtain the best properties and performance. The affinity, selectivity and capacity of MIP were determined. MIPs were evaluated in solid-phase extraction (SPE) of structural analogues in natural samples (vanilla extract, wine). We also present the study of the exploration of spherical beads as potential tools for the controlled release of vanillin. These studies concern the characteristics of uptake and release of the molecule of interest in the aqueous medium on functionalised microspheres supplied by Merck ESTAPOR Microspheres®. The second part of this thesis is devoted to studies on the evaluation of MIP of adenosine 5'-monophosphate (AMP). The polymer was prepared in non-covalent approach and efficiency of binding was characterised using frontal analysis (FA). FA is a useful technique that allows discriminate specific and nonspecific interactions and to understand the binding mechanisms in specific cavities.

Les espèces réactives de l'oxygène (ROS) sont produites en continu dans tous les organismes aérobies et sont impliquées dans la signalisation cellulaire, les défenses contre les pathogènes, mais aussi le stress oxydant. Ce dernier correspond à un déséquilibre entre la production des ROS et leur prise en charge par les défenses anti-oxydantes de la cellule. Le stress oxydant est associé à de nombreuses pathologies, notamment les maladies inflammatoires chroniques de l'intestin (MICI). Parmi les métallo-enzymes qui contrôlent la concentration en ROS, les superoxide dismutases (SOD) jouent un rôle essentiel. Ces enzymes sont responsables de la régulation du superoxyde le premier ROS produit lors de la réduction du dioxygène. Dans ces travaux, des complexes de Mn(II) mimant l'activité de la Mn-SOD (SODm) ont été conçus en utilisant une approche biomimétique. Leur intérêt pour limiter le stress oxydant et l'inflammation dans un modèle cellulaire des MICI a été examiné. En particulier, leur activité biologique a été étudiée au vu de leurs propriétés physico-chimiques et de leur biodisponibilité. Les résultats obtenus avec un complexe parent ont mené à la conception d'une deuxième génération de SODm couplés à une sonde multimodale, à des peptides pénétrants, ou à des peptides adressant aux mitochondries. L'étude du complexe parent fonctionnalisé par des peptides polyarginines a démontré l'influence de charges positives portées par le ligand sur la constante de vitesse. Dans la continuité de l'approche biomimétique développée ici, la conception de SODm de novo est présentée et constitue un premier pas vers l'imitation de l'influence de la seconde sphère de coordination. / Reactive oxygen species (ROS) are produced continuously in all aerobic organisms and are involved in cell signaling, defenses against pathogens, but also oxidative stress. This latter corresponds to an imbalance between ROS production and their consumption by the antioxidant defenses of the cell. Oxidative stress is associated with numerous pathologies, such as inflammatory bowel diseases (IBD). Among the metalloenzymes controlling the concentration of ROS, superoxide dismutases (SOD) play a crucial role. These enzymes are responsibles for the regulation of superoxide, the first ROS produced by the reduction of oxygen. In this work, Mn(II) complexes mimicking the activity of the Mn-SOD (SODm) were designed using a biomimetic approach. Their relevance to limit oxidative stress and inflammation in a cellular model of IBD was investigated. In particular, their biological activity was studied in light of their physico-chemical properties and of their bioavailability. The results obtained with a parent complex led to the design of a second generation of SOD mimics conjugated with a single core multimodal probe, cell-penetrating peptides, or mitochondria-penetrating peptides. An effect of electrostatic interactions on the catalytic rate constant of the parent complex functionalized with polyarginines peptides was demonstrated, similarly to what is observed for the enzyme. In the continuity of the biomimetic approach envisioned here, the design of de novo SOD mimics is presented and constitutes a first step toward the mimicry of second sphere influence.