The Significance of Hydrogen Bonding Interactions in the Cleavage of RNA

RNA is essential for all living organisms. It has important roles in protein synthesis, controlling gene expression as well as catalyzing biological reactions. Chemically RNA is a very stable molecule, although in biological systems many agents catalyze the cleavage of RNA, such as naturally occurring enzymes and ribozymes. Much effort has been put in the last decades in developing highly active artificial ribonucleases since such molecules could have potential in the therapeutic field and provide tools for molecular biology. Several potential catalysts have emerged, but usually detailed cleavage mechanism remains unresolved. This thesis is aimed at clarifying mechanistic details of the cleavage and isomerization of RNA by using simpler nucleoside models of RNA. The topics in the experimental part cover three different studies, one concerning the mechanism of catalysis by large ribozymes, one dealing with the reactivity of modified and unmodified RNA oligonucleotides and one showing an efficient catalysis of the cleavage and isomerization of an RNA phosphodiester bond by a dinuclear metal ion complex. A review of the literature concerning stabilization of the phosphorane intermediate of the hydrolysis and isomerization of RNA phosphodiester bond is first presented. The results obtained in the experimental work followed by mechanistic interpretations are introduced in the second part of the thesis. Especially the significance of hydrogen bonding interactions is discussed.

Understanding the Racial Nature of Police and Immigrant Relations In Finland. The Case of Africans in Turku

The focus of this study is to examine the role of police and immigrants’ relations, as less is known about this process in the country. The studies were approached in two different ways. Firstly, an attempt was made to examine how immigrants view their encounters with the police. Secondly, the studies explored how aware the police are of immigrants’ experiences in their various encounters and interactions on the street level. An ancillary aim of the studies is to clarify, analyse and discuss how prejudice and stereotypes can be tackled, thereby contributing to the general debate about racism and discrimination for better ethnic relations in the country. The data in which this analysis was based is on a group of adults (n=88) from the total of 120 Africans questioned for the entire study (n=45) police cadets and (n=6) serving police officers from Turku. The present thesis is a compilation of five articles. A summary of each article findings follows, as the same data was used in all five studies. In the first study, a theoretical model was developed to examine the perceived knowledge of bias by immigrants resulting from race, culture and belief. This was also an attempt to explore whether this knowledge was predetermined in my attempt to classify and discuss as well as analyse the factors that may be influencing immigrants’ allegations of unfair treatment by the police in Turku. The main finding shows that in the first paper there was ignorance and naivety on the part of the police in their attitudes towards the African immigrant’s prior experiences with the police, and this may probably have resulted from stereotypes or their lack of experience as well as prior training with immigrants where these kinds of experience are rampant in the country (Egharevba, 2003 and 2004a). In exploring what leads to stereotypes, a working definition is the assumption that is prevalent among some segments of the population, including the police, that Finland is a homogenous country by employing certain conducts and behaviour towards ethnic and immigrant groups in the country. This to my understanding is stereotype. Historically this was true, but today the social topography of the country is changing and becoming even more complex. It is true that, on linguistic grounds, the country is multilingual, as there are a few recognised national minority languages (Swedish, Sami and Russian) as well as a number of immigrant languages including English. Apparently it is vital for the police to have a line of communication open when addressing the problem associated with immigrants in the country. The second paper moved a step further by examining African immigrants’ understanding of human rights as well as what human rights violation means or entails in their views as a result of their experiences with the police, both in Finland and in their country of origin. This approach became essential during the course of the study, especially when the participants were completing the questionnaire (N=88), where volunteers were solicited for a later date for an in-depth interview with the author. Many of the respondents came from countries where human rights are not well protected and seldom discussed publicly, therefore understanding their views on the subject can help to explain why some of the immigrants are sceptical about coming forward to report cases of batteries and assaults to the police, or even their experiences of being monitored in shopping malls in their new home and the reason behind their low level of trust in public authorities in Finland. The study showed that knowledge of human rights is notably low among some of the participants. The study also found that female respondents were less aware of human rights when compared with their male counterparts. This has resulted in some of the male participants focussing more on their traditional ways of thinking by not realising that they are in a new country where there is equality in sexes and lack of respect on gender terms is not condoned. The third paper focussed on the respondents’ experiences with the police in Turku and tried to explore police attitudes towards African immigrant clients, in addition to the role stereotype plays in police views of different cultures and how these views have impacted on immigrants’ views of discriminatory policing in Turku. The data is the same throughout the entire studies (n=88), except that some few participants were interviewed for the third paper thirty-five persons. The results showed that there is some bias in mass-media reports on the immigrants’ issues, due to selective portrayal of biases without much investigation being carried out before jumping to conclusions, especially when the issues at stake involve an immigrant (Egharevba, 2005a; Egharevba, 2004a and 2004b). In this vein, there was an allegation that the police are even biased while investigating cases of theft, especially if the stolen property is owned by an immigrant (Egharevba, 2006a, Egharevba, 2006b). One vital observation from the respondents’ various comments was that race has meaning in their encounters and interaction with the police in the country. This result led the author to conclude that the relation between the police and immigrants is still a challenge, as there is rampant fear and distrust towards the police by some segments of the participating respondents in the study. In the fourth paper the focus was on examining the respondents’ view of the police, with special emphasis on race and culture as well as the respondents’ perspective on police behaviour in Turku. This is because race, as it was relayed to me in the study, is a significant predictor of police perception (Egharevba, 2005a; Egharevba and Hannikianen, 2005). It is a known scientific fact that inter-group racial attitudes are the representation of group competition and perceived threat to power and status (Group-position theory). According to Blumer (1958) a sense of group threat is an essential element for the emergence of racial prejudice. Consequently, it was essential that we explored the existing relationship between the respondents and the police in order to have an understanding of this concept. The result indicates some local and international contextual issues and assumptions that were of importance tackling prejudice and discrimination as it exists within the police in the country. Moreover, we have to also remember that, for years, many of these African immigrants have been on the receiving end of unjust law enforcement in their various countries of origin, which has resulted in many of them feeling inferior and distrustful of the police even in their own country of origin. While discussing the issues of cultural difference and how it affects policing, we must also keep in mind the socio-cultural background of the participants, their level of language proficiency and educational background. The research data analysed in this study also confirmed the difficulties associated with cultural misunderstandings in interpreting issues and how these misunderstandings have affected police and immigrant relations in Finland. Finally, the fifth paper focussed on cadets’ attitudes towards African immigrants as well as serving police officers’ interaction with African clients. Secondly, the police level of awareness of African immigrants’ distrustfulness of their profession was unclear. For this reason, my questions in this fifth study examined the experiences and attitudes of police cadets and serving police officers as well as those of African immigrants in understanding how to improve this relationship in the country. The data was based on (n=88) immigrant participants, (n=45) police cadets and 6 serving police officers from the Turku police department. The result suggests that there is distrust of the police in the respondents’ interaction; this tends to have galvanised a heightened tension resulting from the lack of language proficiency (Egharevba and White, 2007; Egharevba and Hannikainen, 2005, and Egharevba, 2006b) The result also shows that the allegation of immigrants as being belittled by the police stems from the misconceptions of both parties as well as the notion of stop and search by the police in Turku. All these factors were observed to have contributed to the alleged police evasiveness and the lack of regular contact between the respondents and the police in their dealings. In other words, the police have only had job-related contact with many of the participants in the present study. The results also demonstrated the complexities caused by the low level of education among some of the African immigrants in their understanding about the Finnish culture, norms and values in the country. Thus, the framework constructed in these studies embodies diversity in national culture as well as the need for a further research study with a greater number of respondents (both from the police and immigrant/majority groups), in order to explore the different role cultures play in immigrant and majority citizens’ understanding of police work.

Ligniinin hienojauhatus planeettamyllyllä

Kirjallisuusosassa tarkastellaan ligniiniä luonnon polymeerinä sekä sen kemiallisia perustietoja. Aiheena on myös sen tuotanto ja käyttö uusiutuvana raaka-ainelähteenä energian-, materiaali- ja kemikaalituotantoon sekä niiden mahdolliset tulevaisuudennäkymät. Mekaanisten prosessien osalta keskitytään kiintoaineen hienontamiseen. Lisäksi perehdytään planeettamyllyn toiminnan teoriaan sekä tuoreimpiin tutkimuksiin planeettamyllyjauhatukseen liittyen. Työn kokeellisen osan tarkoituksena oli tutkia ligniinin jauhautuvuutta, sillä partikkelien pienentämisellä voidaan kasvattaa ligniininijauheen ominaisalaa ja tasoittaa sen kokojakaumaa. Jauhautuvuuden avulla voidaan esimerkiksi arvioida ligniinille tehtävän hienojauhatuksen kannattavuutta jatkoprosesseja varten. Tutkimuskysymyksinä oli ”kuinka hyvin ligniini jauhautuu planeettamyllyllä?”, ”onko kylmäkäsittelyllä vaikutusta jauhatustulokseen?”, ”miten eri parametrit (jauhatusaika, kuulakoko ja kierrosnopeus) vaikuttavat jauhatustulokseen?” sekä ”muuttaako hienojauhatus ligniinin kemiallista koostumusta?”. Tutkittavana materiaalina oli kaupallinen kraft-ligniini ja koelaitteena käytettiin planeettamyllyä. Syötölle ja kaikille jauhatustuotteille suoritettiin partikkelikokoanalyysi, ja lisäksi syötölle ja erittäin hienoksi jauhetulle tuotteelle suoritettiin FTIR-analyysi. Kokeiden mukaan ligniini oli hyvin jauhautuvaa, eikä kylmäkäsittelyllä ollut merkittävää vaikutusta jauhatukseen. Kuulakoon pienentäminen sekä jauhatusajan ja kierrosnopeuden kasvattaminen alensivat ligniininjauheen partikkelikokoa. Lisäksi hienojauhatuksen ei todettu muuttaneen ligniinin kemiallista koostumusta.

Aqueous-phase reforming of renewables for selective hydrogen production in the presence of supported platinum catalysts

The evolution of our society is impossible without a constant progress in life-important areas such as chemical engineering and technology. Innovation, creativity and technology are three main components driving the progress of chemistry further towards a sustainable society. Biomass, being an attractive renewable feedstock for production of fine chemicals, energy-rich materials and even transportation fuels, captures progressively new positions in the area of chemical technology. Knowledge of heterogeneous catalysis and chemical technology applied to transformation of biomass-derived substances will open doors for a sustainable economy and facilitates the discovery of novel environmentally-benign processes which probably will replace existing technologies in the era of biorefinary. Aqueous-phase reforming (APR) is regarded as a promising technology for production of hydrogen and liquids fuels from biomass-derived substances such as C3-C6 polyols. In the present work, aqueous-phase reforming of glycerol, xylitol and sorbitol was investigated in the presence of supported Pt catalysts. The catalysts were deposited on different support materials, including Al2O3, TiO2 and carbons. Catalytic measurements were performed in a laboratory-scale continuous fixedbed reactor. An advanced analytical approach was developed in order to identify reaction products and reaction intermediates in the APR of polyols. The influence of the substrate structure on the product formation and selectivity in the APR reaction was also investigated, showing that the yields of the desired products varied depending on the substrate chain length. Additionally, the influence of bioethanol additive in the APR of glycerol and sorbitol was studied. A reaction network was advanced explaining the formation of products and key intermediates. The structure sensitivity in the aqueous-phase reforming reaction was demonstrated using a series of platinum catalysts supported on carbon with different Pt cluster sizes in the continuous fixed-bed reactor. Furthermore, a correlation between texture physico-chemical properties of the catalysts and catalytic data was established. The effect of the second metal (Re, Cu) addition to Pt catalysts was investigated in the APR of xylitol showing a superior hydrocarbon formation on PtRe bimetallic catalysts compared to monometallic Pt. On the basis of the experimental data obtained, mathematical modeling of the reaction kinetics was performed. The developed model was proven to successfully describe experimental data on APR of sorbitol with good accuracy.

Combination of pulsed corona discharge with TiO2 photocatalysis: verification of hypothesis

The oxidation potential of pulsed corona discharge concerning aqueous impurities is limited in respect to certain refractory compounds. This may be enhanced in combination of the discharge with catalysis/photocatalysis as developed in homogeneous gas-phase reactions. The objective of the work consists of testing the hypothesis of oxidation potential enhancement in combination of the discharge with TiO2 photocatalysis applied to aqueous solutions of refractory oxalate. Meglumine acridone acetate was included for meeting the practical needs. The experimental research was undertaken into oxidation of aqueous solutions under conditions of various target pollutant concentrations, pH and the pulse repetition rate with plain electrodes and the electrodes with TiO2 attached to their surface. The results showed no positive influence of the photocatalyst, the pollutants were oxidized with the rate identical within the accuracy of measurements. The possible explanation for the observed inefficiency may include low UV irradiance, screening effect of water and generally low oxidation rate in photocatalytic reactions. Further studies might include combination of electric discharge with ozone decomposition/radical formation catalysts.

Cell Model Systems in Characterizing Alpha2-Adrenoceptors as Drug Targets.

The three alpha2-adrenoceptor (alpha2-AR) subtypes belong to the G protein-coupled receptor superfamily and represent potential drug targets. These receptors have many vital physiological functions, but their actions are complex and often oppose each other. Current research is therefore driven towards discovering drugs that selectively interact with a specific subtype. Cell model systems can be used to evaluate a chemical compound's activity in complex biological systems. The aim of this thesis was to optimize and validate cell-based model systems and assays to investigate alpha2-ARs as drug targets. The use of immortalized cell lines as model systems is firmly established but poses several problems, since the protein of interest is expressed in a foreign environment, and thus essential components of receptor regulation or signaling cascades might be missing. Careful cell model validation is thus required; this was exemplified by three different approaches. In cells heterologously expressing alpha2A-ARs, it was noted that the transfection technique affected the test outcome; false negative adenylyl cyclase test results were produced unless a cell population expressing receptors in a homogenous fashion was used. Recombinant alpha2C-ARs in non-neuronal cells were retained inside the cells, and not expressed in the cell membrane, complicating investigation of this receptor subtype. Receptor expression enhancing proteins (REEPs) were found to be neuronalspecific adapter proteins that regulate the processing of the alpha2C-AR, resulting in an increased level of total receptor expression. Current trends call for the use of primary cells endogenously expressing the receptor of interest; therefore, primary human vascular smooth muscle cells (SMC) expressing alpha2-ARs were tested in a functional assay monitoring contractility with a myosin light chain phosphorylation assay. However, these cells were not compatible with this assay due to the loss of differentiation. A rat aortic SMC cell line transfected to express the human alpha2B-AR was adapted for the assay, and it was found that the alpha2-AR agonist, dexmedetomidine, evoked myosin light chain phosphorylation in this model.

Novel technology for preparation of optically active chemicals

Asymmetric synthesis using modified heterogeneous catalysts has gained lots of interest in the production of optically pure chemicals, such as pharmaceuticals, nutraceuticals, fragrances and agrochemicals. Heterogeneous modified catalysts capable of inducing high enantioselectivities are preferred in industrial scale due to their superior separation and handling properties. The topic has been intensively investigated both in industry and academia. The enantioselective hydrogenation of ethyl benzoylformate (EBF) to (R)-ethyl mandelate over (-)-cinchonidine (CD)-modified Pt/Al2O3 catalyst in a laboratory-scale semi-batch reactor was studied as a function of modifier concentration, reaction temperature, stirring rate and catalyst particle size. The main product was always (R)-ethyl mandelate while small amounts of (S)-ethyl mandelate were obtained as by product. The kinetic results showed higher enantioselectivity and lower initial rates approaching asymptotically to a constant value as the amount of modifier was increased. Additionally, catalyst deactivation due to presence of impurities in the feed was prominent in some cases; therefore activated carbon was used as a cleaning agent of the raw material to remove impurities prior to catalyst addition. Detailed characterizations methods (SEM, EDX, TPR, BET, chemisorption, particle size distribution) of the catalysts were carried out. Solvent effects were also studied in the semi-batch reactor. Solvents with dielectric constant (e) between 2 and 25 were applied. The enantiomeric excess (ee) increased with an increase of the dielectric coefficient up to a maximum followed by a nonlinear decrease. A kinetic model was proposed for the enantioselectivity dependence on the dielectric constant based on the Kirkwood treatment. The non-linear dependence of ee on (e) successfully described the variation of ee in different solvents. Systematic kinetic experiments were carried out in the semi-batch reactor. Toluene was used as a solvent. Based on these results, a kinetic model based on the assumption of different number of sites was developed. Density functional theory calculations were applied to study the energetics of the EBF adsorption on pure Pt(1 1 1). The hydrogenation rate constants were determined along with the adsorption parameters by non-linear regression analysis. A comparison between the model and the experimental data revealed a very good correspondence. Transient experiments in a fixed-bed reactor were also carried out in this work. The results demonstrated that continuous enantioselective hydrogenation of EBF in hexane/2-propanol 90/10 (v/v) is possible and that continuous feeding of (-)-cinchonidine is needed to maintain a high steady-state enantioselectivity. The catalyst showed a good stability and high enantioselectivity was achieved in the fixed-bed reactor. Chromatographic separation of (R)- and (S)-ethyl mandelate originating from the continuous reactor was investigated. A commercial column filled with a chiral resin was chosen as a perspective preparative-scale adsorbent. Since the adsorption equilibrium isotherms were linear within the entire investigated range of concentrations, they were determined by pulse experiments for the isomers present in a post-reaction mixture. Breakthrough curves were measured and described successfully by the dispersive plug flow model with a linear driving force approximation. The focus of this research project was the development of a new integrated production concept of optically active chemicals by combining heterogeneous catalysis and chromatographic separation technology. The proposed work is fundamental research in advanced process technology aiming to improve efficiency and enable clean and environmentally benign production of enantiomeric pure chemicals.

Tuotannon mittaristo- ja raportointitoimintatapojen kehittäminen elintarviketeollisuusyrityksessä

Mittaamista on tutkittu paljon ja kasvavissa määrin. Silti yrityksissä ei usein osata tehokkaasti hyödyntää mittaristosta saatavaa informaatiota johtamisen tukena. Tämän työn tavoitteena on selvittää, millainen on hyvä, informatiivinen ja käytännöllinen mittaristo, jota voidaan käyttää tuotantotoiminnan johtamiseen ja ohjaamiseen elintarviketeollisuusyrityksessä. Työn empiirinen osuus on suoritettu laadullisena case-tutkimuksena. Aineisto on kerätty henkilökohtaisilla haastatteluilla, jotka sisälsivät 16 tuotannon toimihenkilön sekä ylemmän toimihenkilön haastattelua. Johtopäätöksenä tutkimuksesta sekä kirjallisuuskatsauksesta esitetään mittaristo tuotantotoiminnan johtamisen apuvälineeksi. Mittaamisen tärkeimmät roolit ovat strategian jalkauttaminen, henkilöstöön vaikuttaminen, ulkoinen raportointi sekä kehityksen seuraaminen. Mittariston eri mittareiden tulee olla keskenään linjassa ja tavoitteiltaan yhdenmukaisia. Mittareiden tavoitteiden on tultava ylhäältä alas, eli ylimmästä johdosta portaittain työntekijätasolle. Mittaustulokset taas tulevat alhaalta ylös, eli työntekijätasosta ylös ylimpään johtoon. Mittauksen on aina oltava kustannustehokasta, eli siitä saatava hyöty on oltava panoksia suurempi. Mittaristo ei ole yrityksessä pysyvä työkalu vaan sitä on jatkuvasti päivitettävä Case-yrityksessä koettiin, ettei mittaristo ohjaa tekemistä eikä jalkauta strategiaa. Mittaamisesta ajateltiin, että mitataan, kun on aina mitattu. Johtamisjärjestelmä sekä mittaristo eri tasoilla koettiin sekavaksi ja epäyhtenäiseksi. Uusi mittaristo luotiin päivä-, viikko- ja kuukausitasolle. Johtamisjärjestelmää selkeytettiin ja johtamista ohjaava mittaristo tehtiin eri organisaatiotasojen välillä linjakkaaksi ja yhtenäiseksi. Mittariston viestimiseen työntekijätasolle luotiin suositukset.

From statin efficacy to everyday effectiveness: Studying the gap in between.

Statins are indicated for preventing cardiovascular disease events. Patients with diabetes have a risk of major cardiovascular events double the risk of their peers without diabetes. Thus, clinical treatment guidelines recommend statins for the management of diabetic dyslipidemia. The evidence base for statin use in cardiovascular disease derives from the randomized controlled statin trials designed to prove statin efficacy under ideal conditions, among a homogenous study population meeting strict trial eligibility criteria. This thesis was implemented as four pharmacoepidemiological statin studies using register data on realworld statin users. The overall purpose was to evaluate the trends, patterns and effectiveness of statin use in everyday life. More specifically, nationwide secular trends in statin use in Finland were analysed, especially among patient groups which had been underrepresented in the statin trials. Furthermore, the benchmarking statin trials in diabetes, the Heart Protection Study and the Collaborative Atorvastatin Diabetes Study, were evaluated for their representativeness for real-world diabetes care with the emphasis placed on adherence to statin use. The association between good adherence and the incidence of major cardiovascular events in the real-world was further investigated in diabetes. These studies demonstrate that statin initiations increased from 1995 to 2005 in Finland. The increase was most pronounced among those aged at least 75 years and was observed already before the publication of rigorous trial data conducted in elderly subjects. Thus, statins seem to have been initiated in clinical practice also going beyond the strict trial eligibility criteria. Nonetheless, low adherence to statin use among the real-world patients with diabetes was found not only to limit the representativeness of the trials for clinical care but also to attenuate in all likelihood their benefits in the real-world. In fact, good adherence to statin use was found to associate with a decreased risk for major cardiovascular events in patients with diabetes. In conclusion, these studies highlight the importance of good adherence to statin use in clinical practice in order to obtain the full therapeutic value demonstrated in the statin trials. Simply increasing the number of statin users will not alone suffice in sharing our common resources appropriately.

Iron(III) as Lewis acid catalyst in organosilicon and carbonyl chemistry

Iron is one of the most common elements in the earth’s crust and thus its availability and economic viability far exceed that of metals commonly used in catalysis. Also the toxicity of iron is miniscule, compared to the likes of platinum and nickel, making it very desirable as a catalyst. Despite this, prior to the 21st century, the applicability of iron in catalysis was not thoroughly investigated, as it was considered to be inefficient and unselective in desired transformations. In this doctoral thesis, the application of iron catalysis in combination with organosilicon reagents for transformations of carbonyl compounds has been investigated together with insights into iron catalyzed chlorination of silanes and silanols. In the first part of the thesis, the synthetic application of iron(III)-catalyzed chlorination of silanes (Si-H) and the monochlorination of silanes (SiH2) using acetyl chloride as the chlorine source is described. The reactions proceed under ambient conditions, although some compounds need to be protected from excess moisture. In addition, the mechanism and kinetics of the chlorination reaction are briefly adressed. In the second part of this thesis a versatile methodology for transformation of carbonyl compounds into three different compound classes by changing the conditions and amounts of reagents is discussed. One pot reductive benzylation, reductive halogenation and reductive etherification of ketones and aldehydes using silanes as the reducing agent, halide source or cocatalyst, were investigated. Also the reaction kinetics and mechanism of the reductive halogenation of acetophenone are briefly discussed.

Aamiaiskahvilasta ötökkätarjontaan. Suomen kirjoitetun yleiskielen morfosyntaktisten yhdyssanarakenteiden produktiivisuus

Tämän tutkimuksen kohde on suomen kirjoitetun yleiskielen morfosyntaktisten yhdyssanarakenteiden produktiivisuus. Tutkimuksen tärkein päämäärä on selvittää, kuinka ahkerasti erilaisia suomen kielen suomia mahdollisuuksia käytetään uusien yhdyssanojen muodostuksessa. Käytännöllistä produktiivisuutta kartoittava tutkimus täydentää kielioppien ja sanastonkuvausten antamaa kuvaa kielestä. Tutkimuksen kohteena oleva kielimuoto on kaikille kielenkäyttäjille yhteinen kirjoitettu yleiskieli. Tutkimusaineisto koostuu 28 091 uudesta yhdyssanasta, jotka on kerätty painetun median kielestä vuosina 2000–2009. Aineiston pohjana on Kotimaisten kielten keskuksen Nykysuomen sanastotietokanta, johon poimitaan uusia ja uudella tavalla käytettyjä sanoja ensisijaisesti sanakirjatyön ja kielenhuollon tarpeisiin. Tutkimusaihetta lähestytään useiden yhdyssanan osien muotoa, sanaluokkaa, määrää ja pituutta koskevien alakysymysten kautta. Tutkimus etenee yksittäisten muut-tujien käsittelystä muuttujien keskinäisiä suhteita tarkasteleviin malleihin. Tutkimuksessa käytetään kaksivaiheista metodia: Metodin ensimmäinen askel on uudessa sanastossa havaittujen rakenteiden tyyppifrekvenssin tilastollinen analyysi. Toinen askel on varsinkin matalafrekvenssisten tai tilastollisessa analyysissa muuten poikkeavaksi osoittautuneiden rakenteiden kvalitatiivinen tarkastelu. Metodi on kehitetty tätä tutkimusta varten, sillä aiemmin produktiivisuuden mittaamisessa käytetyt menetelmät eivät sellaisenaan sovi suomen kielen yhdyssanarakenteiden tutkimukseen. Tutkimusmetodien kehittäminen on tutkimuksen keskeinen tavoite. Tutkimus osoittaa, että suomen kielen uudet yhdyssanat ovat rakenteeltaan homogeenisempiä, kuin aiempia kielenkuvauksia lukemalla voisi olettaa. Uusi suomen kielen yhdyssana on todennäköisimmin kahdesta substantiivista yhdistämällä muodostettu substantiivi, jonka alkuosa on nominatiivissa eikä kongruoi jälkiosan kanssa. Ennakko-oletusta huomattavasti yleisempiä ovat myös prefiksinkaltaisella alkuosalla alkavat yhdyssanat. Genetiivialkuiset yhdyssanat puolestaan ovat ennakko-oletusta harvinaisempia. Kaikki kieliopillisesti mahdolliset yhdyssanarakenteet eivät ole lainkaan produktiivisia kielenkäytön tasolla. Tutkimus on luonteeltaan kielen rakennetta kartoittavaa perustutkimusta. Tutkimustulosten tärkeimmät sovellusalat ovat kieliteknologia ja sananmuodostuksen opetus. Tutkimus avaa useita näkökulmia jatkotutkimukselle.

Genetics of inherited small vessel diseases – in search of a novel small vessel disease and modifiers of the clinical course of CADASIL

The genetic and environmental risk factors of vascular cognitive impairment are still largely unknown. This thesis aimed to assess the genetic background of two clinically similar familial small vessel diseases (SVD), CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) and Swedish hMID (hereditary multi-infarct dementia of Swedish type). In the first study, selected genetic modifiers of CADASIL were studied in a homogenous Finnish CADASIL population of 134 patients, all carrying the p.Arg133Cys mutation in NOTCH3. Apolipoprotein E (APOE) genotypes, angiotensinogen (AGT) p.Met268Thr polymorphism and eight NOTCH3 polymorphisms were studied, but no associations between any particular genetic variant and first-ever stroke or migraine were seen. In the second study, smoking, statin medication and physical activity were suggested to be the most profound environmental differences among the monozygotic twins with CADASIL. Swedish hMID was for long misdiagnosed as CADASIL. In the third study, the CADASIL diagnosis in the Swedish hMID family was ruled out on the basis of genetic, radiological and pathological findings, and Swedish hMID was suggested to represent a novel SVD. In the fourth study, the gene defect of Swedish hMID was then sought using whole exome sequencing paired with a linkage analysis. The strongest candidate for the pathogenic mutation was a 3’UTR variant in the COL4A1 gene, but further studies are needed to confirm its functionality. This study provided new information about the genetic background of two inherited SVDs. Profound knowledge about the pathogenic mutations causing familial SVD is also important for correct diagnosis and treatment options.

Metal oxides prepared through the nanocasting approach-mechanistic study, surface interactions and applications in separation

Mesoporous metal oxides are nowadays widely used in various technological applications, for instance in catalysis, biomolecular separations and drug delivery. A popular technique used to synthesize mesoporous metal oxides is the nanocasting process. Mesoporous metal oxide replicas are obtained from the impregnation of a porous template with a metal oxide precursor followed by thermal treatment and removal of the template by etching in NaOH or HF solutions. In a similar manner to the traditional casting wherein the product inherits the features of the mold, the metal oxide replicas are supposed to have an inverse structure of the starting porous template. This is however not the case, as broken or deformed particles and other structural defects have all been experienced during nanocasting experiments. Although the nanocasting technique is widely used, not all the processing steps are well understood. Questions over the fidelity of replication and morphology control are yet to be adequately answered. This work therefore attempts to answer some of these questions by elucidating the nanocasting process, pin pointing the crucial steps involved and how to harness this knowledge in making wholesome replicas which are a true replication of the starting templates. The rich surface chemistry of mesoporous metal oxides is an important reason why they are widely used in applications such as catalysis, biomolecular separation, etc. At times the surface is modified or functionalized with organic species for stability or for a particular application. In this work, nanocast metal oxides (TiO2, ZrO2 and SnO2) and SiO2 were modified with amino-containing molecules using four different approaches, namely (a) covalent bonding of 3-aminopropyltriethoxysilane (APTES), (b) adsorption of 2-aminoethyl dihydrogen phosphate (AEDP), (c) surface polymerization of aziridine and (d) adsorption of poly(ethylenimine) (PEI) through electrostatic interactions. Afterwards, the hydrolytic stability of each functionalization was investigated at pH 2 and 10 by zeta potential measurements. The modifications were successful except for the AEDP approach which was unable to produce efficient amino-modification on any of the metal oxides used. The APTES, aziridine and PEI amino-modifications were fairly stable at pH 10 for all the metal oxides tested while only AZ and PEI modified-SnO2 were stable at pH 2 after 40 h. Furthermore, the functionalized metal oxides (SiO2, Mn2O3, ZrO2 and SnO2) were packed into columns for capillary liquid chromatography (CLC) and capillary electrochromatography (CEC). Among the functionalized metal oxides, aziridinefunctionalized SiO2, (SiO2-AZ) showed good chemical stability, and was the most useful packing material in both CLC and CEC. Lastly, nanocast metal oxides were synthesized for phosphopeptide enrichment which is a technique used to enrich phosphorylated proteins in biological samples prior to mass spectrometry analysis. By using the nanocasting technique to prepare the metal oxides, the surface area was controlled within a range of 42-75 m2/g thereby enabling an objective comparison of the metal oxides. The binding characteristics of these metal oxides were compared by using samples with different levels of complexity such as synthetic peptides and cell lysates. The results show that nanocast TiO2, ZrO2, Fe2O3 and In2O3 have comparable binding characteristics. Furthermore, In2O3 which is a novel material in phosphopeptide enrichment applications performed comparably with standard TiO2 which is the benchmark for such phosphopeptide enrichment procedures. The performance of the metal oxides was explained by ranking the metal oxides according to their isoelectric points and acidity. Overall, the clarification of the nanocasting process provided in this work will aid the synthesis of metal oxides with true fidelity of replication. Also, the different applications of the metal oxides based on their surface interactions and binding characteristics show the versatility of metal oxide materials. Some of these results can form the basis from which further applications and protocols can be developed.

Suomalaisten yliopistojen life science-alan spin-off-yritysten rahoitustilanne, -lähteet ja –riskit

Life science-ala on rahoituksellisesti erittäin haastava, koska tuotekehitysputket ovat 10-15 vuoden pituisia ja voivat vaatia suuria etupainotteisia investointeja. Monet life science-alan yritykset ovat niin Suomessa kuin kansainvälisestikin syntyneet suoraan yliopistosta niin sanottuina spin-off-yrityksinä. Yrityksen perustaminen tutkimustiedon pohjalle on yksi akateemisen yrittäjyyden muodoista. Tässä tutkimuksessa tutkitaan akateemista yrittäjyyttä life science-alalla Suomessa. Suomessa life science-alan osaaminen on kansainvälistä huippua ja alalle on syntynyt useita spin-off-yrityksiä viime vuosina. Aiemmat tutkimukset ovat keskittyneet erityisesti agentti-päämiesongelmiin akateemisessa yrittäjyydessä ja life science alaa puolestaan on käsitelty usein pelkästään yhtenä alana. Tutkimuksessa pyritään analysoimaan life science-alan eri painopiste-alueita tarkemmin rahoitusstrategisesta näkökulmasta, koska ala ei ole homogeeninen. Akateemisen yrittäjyyden agenttiongelmaa pyritään tarkoittamaan Suomen yliopistomaailmassa life science-alalta käsin. Tutkimus toteutetaan kvalitatiivisena haastattelututkimuksena ja sitä tukevana tilinpäätöstietojen analysointina. Tutkimuksen tulokset vahvistavat agentti-päämiesongelmien olemassaolon suomalaisessa yliopistomaailmassa. Ongelmien osapuolina ovat niin akateemikot, yliopiston innovaatiopalvelut kuin TEKES:kin. Yrittäjät kaipaavat kokonaisvaltaisempaa apua, koska kokevat alalla liiketoimintaosaamisen puuttuvan monin paikoin. Alan vaatimien runsaiden tuotekehityspanostusten vuoksi alan yritykset ovat pitkään raskaasti tappiollisia. Yritysten valitsemat rahoitusratkaisut vaihtelevat suuresti. Kaikki tutkitut yritykset pyrkivät kasvamaan nykyisten ydintuotteidensa mukana ja ovat jo jossain määrin hankkineet rahoitusta kasvustrategiaansa varten. Alan pääomaintensiivisyydestä johtuen ovat monet yritykset kuitenkin suunnittelemassa tai jo päätyneet tekemään yhteistyötä integroituen alalla joko vertikaalisesti tai horisontaalisesti. Tutkimuksen tulokset vahvistavat aiemman käsityksen, jonka mukaan life science-alan yrityksiä on vaikea arvioida ulkopuolelta pelkästään tilinpäätöstietojen pohjalta, koska alkuvaiheessa rahoituskierrokset ja tappiolliset vuoden seuraavat toisiaan ja toisaalta yrityksen arvo sitoutuu pitkiin tuotekehitysputkiin, jotka eivät välttämättä näy tilinpäätöksessä. Tulokset tuovat esille merkittäviä yritysten kokemia ongelmia rahoituksen saannissa life science-alalla Suomessa sekä akateemisen yrittäjyyden epäkohtia yritystoiminnan näkökulmasta. Näiden tekijöiden huomioonottaminen ja laajempi kansainvälinen vertailu voivat auttaa suomalaisia yrityksiä tällä vahvalla osaamisalalla eteenpäin.