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.

From protein structure to function with bioinformatics

It has long been known that amino acids are the building blocks for proteins and govern their folding into specific three-dimensional structures. However, the details of this process are still unknown and represent one of the main problems in structural bioinformatics, which is a highly active research area with the focus on the prediction of three-dimensional structure and its relationship to protein function. The protein structure prediction procedure encompasses several different steps from searches and analyses of sequences and structures, through sequence alignment to the creation of the structural model. Careful evaluation and analysis ultimately results in a hypothetical structure, which can be used to study biological phenomena in, for example, research at the molecular level, biotechnology and especially in drug discovery and development. In this thesis, the structures of five proteins were modeled with templatebased methods, which use proteins with known structures (templates) to model related or structurally similar proteins. The resulting models were an important asset for the interpretation and explanation of biological phenomena, such as amino acids and interaction networks that are essential for the function and/or ligand specificity of the studied proteins. The five proteins represent different case studies with their own challenges like varying template availability, which resulted in a different structure prediction process. This thesis presents the techniques and considerations, which should be taken into account in the modeling procedure to overcome limitations and produce a hypothetical and reliable three-dimensional structure. As each project shows, the reliability is highly dependent on the extensive incorporation of experimental data or known literature and, although experimental verification of in silico results is always desirable to increase the reliability, the presented projects show that also the experimental studies can greatly benefit from structural models. With the help of in silico studies, the experiments can be targeted and precisely designed, thereby saving both money and time. As the programs used in structural bioinformatics are constantly improved and the range of templates increases through structural genomics efforts, the mutual benefits between in silico and experimental studies become even more prominent. Hence, reliable models for protein three-dimensional structures achieved through careful planning and thoughtful executions are, and will continue to be, valuable and indispensable sources for structural information to be combined with functional data.

Foreign exchange exposure management in a fuel procurement company operating in the commodity markets

Fluctuating commodity prices, foreign exchange rates and interest rates are causing changes in cash flows, market value and the companies’ profit. Most of the commodities are quoted in US dollar. Companies with non-dollar accounting face a double risk in the form of the commodity price risk and foreign exchange risk. The objective of this Master’s thesis is to find out how companies under commodity should manage foreign exchange exposure. The theoretical literature is based on foreign exchange risk, commodity risk and foreign exchange exposure management. The empirical research is done by using constructive modelling of a case company in the oil industry. The exposure is model with foreign exchange net cash flow and net working capital. First, the factors affecting foreign exchange exposure in case company are analyzed, then a model of foreign exchange exposure is created. Finally, the models are compared and the most suitable method is defined. According to the literature, foreign exchange exposure is the foreign exchange net cash flow. However, the results of the study show that foreign exchange risk can be managed also with net working capital. When the purchases, sales and storage are under foreign exchange risk, the best way to manage foreign exchange exposure is with combined net cash flow and net working capital method. The foreign exchange risk policy of the company defines the appropriate way to manage foreign exchange risk.

Vuorovaikutusasiantuntijuus ja hiljainen tieto luokanopettajan työssä

Tämä tutkimus perehtyy luokanopettajan vuorovaikutukseen liittyvään asiantuntijuuteen. Sen tarkoituksena on selvittää, kuinka tämä osa opettajan asiantuntijuutta syntyy, millaista tietoa ja osaamista siihen sisältyy ja kuinka tällaista tietoa liikkuu työyhteisössä. Tutkimuksen kirjallisuuskatsaus perehtyy opettajan ammatin luonteeseen asiantuntijuutta käsittelevän kirjallisuuden, hiljaisen tiedon käsitteistön ja tutkimustiedon sekä työyhteisöön liittyvien julkaisujen avulla. Tutkimuksen empiriaosuus toteutettiin laadullisin menetelmin haastattelemalla viittä luokanopettajaa. Opettajan vuorovaikutusasiantuntijuuteen liittyy kiinteästi hiljaista ja toiminnallista tietoa, joka on henkilökohtaista ja omiin kokemuksiin pohjautuvaa selkärankatietämystä. Tutkimuksen tuloksien mukaan valtaosa tällaisesta asiantuntijuudesta hankitaan omassa työssä kokemusten kautta. Opettajat reflektoivat omaa työtään ja sopeuttavat toimintaansa ympäristön mukaan. Hiljainen tieto oli soveltuviksi koettuja toimintamalleja tietynlaisten oppilaiden ja tilanteiden kohdalla. Erityisesti uran alkuvaiheessa korostui samaistumiseen perustuva ammatillinen itsensä kehittäminen, jossa painottuu tiedon siirtyminen kokeneemmalta kokemattomammalle. Lisäksi opettajayhteisössä jaettiin osaamista ja kokemuksia erilaisissa vapaamuotoisissa tilanteissa syntyvissä käytäntöyhteisöissä, joissa etsittiin ratkaisuja myös uudenlaisiin ongelmiin. Käytäntöyhteisöillä näyttikin olevan olennainen merkitys opettajan vuorovaikutusasiantuntijuuden kehittymiselle. Aineiston ja kirjallisuuskatsauksen perusteella tutkimus esittää vuorovaikutusasiantuntijuuden kehittymisen syklin, joka on kehitysprosessia ja sen yhteyttä ympäristöön kuvaava toimintamalli. Tutkimuksen mukaan opettajan vuorovaikutusasiantuntijuus on henkilökohtainen ja koko uran mittainen kehitysprosessi, mutta se saa tukea työyhteisöstä. Luonnollisten verkostojen ohella työnantaja voi tarjota täydennyskoulutusta tai työnohjausta opettajan työn tueksi.