Avainasiakassuhteiden analysointi ja -kehittämisstrategioiden luonti business-to-business markkinoilla toimivalle pk-yritykselle

Tutkimuksen tavoitteena oli tunnistaa tutkittavan yrityksen (Starlike Oy) avainasiakassuhteiden tila sekä luoda strategioita näiden asiakassuhteiden kehittämiseksi. Asiakassuhteiden tilaa pyrittiin analysoimaan tarkastelemalla kolmea suhteen osatekijää; ilmapiiriä, transaktiohistoriaa ja toimijoita. Vastaavasti strategioiden luonnintukena käytettiin asiakassuhteen osatekijöiden painoarvo- sekä asiakassuhteen ongelmat/tarpeet -mallia. Tutkimusmenetelmänä käytettiin kyselytutkimusta, jonka aineisto kerättiin sähköpostikyselyllä syksyn 2006 aikana niin asiakkailta kuin yritykseltäkin. Asiakassuhteiden havaittiin jakautuvan viidelle tasolle jakauman noudattaessa normaalijakaumaa. Asiakkaan ja myyjän näkemyksissä asiakassuhteen nykytilasta ei havaittu olevan järjestelmällistä eroa. Toisaalta myyjän havaittiin asettavan asiakassuhteen tavoitteet järjestelmällisesti asiakasta korkeammalle. Asiakassuhteiden tavoitteiden havaittiin lisäksi jakautuvan asiakassuhteen tasoittain kahteen osaan siten, että noin puolet asiakkaista halusi kehittää asiakassuhdettaan ja noin puolet oli tyytyväisiä sen nykytilaan.

The Persistence of Finnish Equity Fund Performance

Tutkimuksen tavoitteena on selvittää, esiintyykö suomeen sijoittavilla osakerahastoilla menestyksen pysyvyyttä. Tutkimusaineisto koostuu kaikista suomalaisista osakerahastoista, jotka toimivat ajanjaksolla 15.1.1998-13.1.2005. Aineisto on vapaa selviytymisvinoumasta. Suorituskyvyn mittareina käytetään CAPM-alfaa sekä kolmi- ja nelifaktori-alfaa. Empiirisessä osassa osakerahastojen menestyksen pysyvyyttä testataan Spearmanin järjestyskorrelaatiotestillä. Evidenssi menestyksen pysyvyydestä jäi vähäiseksi, vaikkakin sitä esiintyi satunnaisesti kaikilla menestysmittareilla joillakin ranking- ja sijoitusperiodin yhdistelmillä. CAPM-alfalla tarkasteltuna tilastollisesti merkitsevää menestyksen pysyvyyttä esiintyi selvästi useammin kuin muilla menestysmittareilla. Tulokset tukevat viimeaikaisia kansainvälisiä tutkimuksia, joiden mukaan menestyksen pysyvyys riippuu usein mittaustavasta. Menestysmittareina käytettyjen regressiomallien merkitsevyystestit osoittavat multifaktorimallien selittävän osakerahastojen tuottoja CAPM:a paremmin. Lisätyt muuttujat parantavat merkittävästi CAPM:n selitysvoimaa.

Kvantitatiivisen osakepisteytysmallin testaaminen Euroopan markkinoilla

Tutkielman tavoitteena on testata kvantitatiivisen osakepisteytysmallin tehokkuutta Euroopan osakemarkkinoilla. Osakepisteytysmalli järjestää osakkeet paremmuusjärjestykseen yrityskohtaisten tunnuslukujen avulla. Pisteytysmallin suositusten mukaan luodaan testisalkku ajanjaksolta 2002 2007. Testisalkun tuottoa mitataan pääomahyödykkeiden hinnoittelumallin sekä Faman ja Frenchin kolmen faktorin mallin avulla. Testisalkkua testataan markkina arvopainoisena sekä tasapainoisena. Tasapainoisessa salkussa jokaista osaketta painotetaan yhtäläisesti. Testisalkun rinnalle luodaan lisäksi vertailusalkku satunnaisista osakkeista. Tasapainotettu testisalkku tuotti tarkasteluajanjaksolla tilastollisesti merkitsevää markkinariskikorjattua ylituottoa 0,7 prosenttia kuukaudessa. Kolmen faktorin mallin avulla laskettu ylituotto ei ollut merkitsevä. Yrityskokofaktori sekä markkinatuotto näyttivät selittävän vahvasti testisalkun tuottoja. Yrityskoon vaikutus näkyi myös markkina arvopainotetussa salkussa, jonka tuotto ei päihittänyt markkinatuottoa. Vertailusalkku ei tuottanut tilastollisesti merkitsevää ylituottoa.

Mikroyrittäjä ja yrityksen kasvu

Tämän tutkimuksen tarkoituksena on selvittää mitkä tekijät ovat mikroyrityksen kasvun edellytyksenä ja mitkä tekijät ovat kasvun esteinä. Tutkimuksen taustalla on mikroyritysten yleisesti vähäinen kasvuhalukkuus. Tässä tutkimuksessa yrittäjien kasvuaikomuksia tarkastellaan kasvun prosessimalliin tukeutuen ja mikroyritysten kasvuun vaikuttavia tekijöitä tarkastellaan Perrenin mikroyrityksen kasvuun vaikuttavien tekijöiden mallin avulla. Tutkimuksessa on käytetty kvalitatiivista tutkimusmenetelmää. Tutkimus on toteutettu haastattelututkimuksena, jossa on haastateltu mikroyrittäjiä Päijät-Hämeessä Lahden ja Hollolan alueilla. Tämän tutkimuksen mukaan mikroyritysten kasvuun vaikuttavat yrittäjän tahtotila ja kyky yrityksen kehittämiseen sekä yrittäjän riskinottokyky että suotuisat ympäristölliset olosuhteet. Näiden tekijöiden puuttuminen estää kasvun. Yrityksen kasvua estäviä muita tekijöitä ovat tutkimuksen mukaan mikroyritysten liiallinen paikallisuus, yhteistyön vähäisyys sekä yrittäjän liiallinen kietoutuminen liiketoimintaan että toiminnan liian vähäinen strateginen suunnittelu.

Classification, comorbidity, heredity, and risk factors of female sexual dysfunctions

Female sexual dysfunctions, including desire, arousal, orgasm and pain problems, have been shown to be highly prevalent among women around the world. The etiology of these dysfunctions is unclear but associations with health, age, psychological problems, and relationship factors have been identified. Genetic effects explain individual variation in orgasm function to some extent but until now quantitative behavior genetic analyses have not been applied to other sexual functions. In addition, behavior genetics can be applied to exploring the cause of any observed comorbidity between the dysfunctions. Discovering more about the etiology of the dysfunctions may further improve the classification systems which are currently under intense debate. The aims of the present thesis were to evaluate the psychometric properties of a Finnish-language version of a commonly used questionnaire for measuring female sexual function, the Female Sexual Function Index (FSFI), in order to investigate prevalence, comorbidity, and classification, and to explore the balance of genetic and environmental factors in the etiology as well as the associations of a number of biopsychosocial factors with female sexual functions. Female sexual functions were studied through survey methods in a population based sample of Finnish twins and their female siblings. There were two waves of data collection. The first data collection targeted 5,000 female twins aged 33–43 years and the second 7,680 female twins aged 18–33 and their over 18–year-old female siblings (n = 3,983). There was no overlap between the data collections. The combined overall response rate for both data collections was 53% (n = 8,868), with a better response rate in the second (57%) compared to the first (45%). In order to measure female sexual function, the FSFI was used. It includes 19 items which measure female sexual function during the previous four weeks in six subdomains; desire, subjective arousal, lubrication, orgasm, sexual satisfaction, and pain. In line with earlier research in clinical populations, a six factor solution of the Finnish-language version of the FSFI received supported. The internal consistencies of the scales were good to excellent. Some questions about how to avoid overestimating the prevalence of extreme dysfunctions due to women being allocated the score of zero if they had had no sexual activity during the preceding four weeks were raised. The prevalence of female sexual dysfunctions per se ranged from 11% for lubrication dysfunction to 55% for desire dysfunction. The prevalence rates for sexual dysfunction with concomitant sexual distress, in other words, sexual disorders were notably lower ranging from 7% for lubrication disorder to 23% for desire disorder. The comorbidity between the dysfunctions was substantial most notably between arousal and lubrication dysfunction even if these two dysfunctions showed distinct patterns of associations with the other dysfunctions. Genetic influences on individual variation in the six subdomains of FSFI were modest but significant ranging from 3–11% for additive genetic effects and 5–18% for nonadditive genetic effects. The rest of the variation in sexual functions was explained by nonshared environmental influences. A correlated factor model, including additive and nonadditive genetic effects and nonshared environmental effects had the best fit. All in all, every correlation between the genetic factors was significant except between lubrication and pain. All correlations between the nonshared environment factors were significant showing that there is a substantial overlap in genetic and nonshared environmental influences between the dysfunctions. In general, psychological problems, poor satisfaction with the relationship, sexual distress, and poor partner compatibility were associated with more sexual dysfunctions. Age was confounded with relationship length but had over and above relationship length a negative effect on desire and sexual satisfaction and a positive effect on orgasm and pain functions. Alcohol consumption in general was associated with better desire, arousal, lubrication, and orgasm function. Women pregnant with their first child had fewer pain problems than nulliparous nonpregnant women. Multiparous pregnant women had more orgasm problems compared to multiparous nonpregnant women. Having children was associated with less orgasm and pain problems. The conclusions were that desire, subjective arousal, lubrication, orgasm, sexual satisfaction, and pain are separate entities that have distinct associations with a number of different biopsychosocial factors. However, there is also considerable comorbidity between the dysfunctions which are explained by overlap in additive genetic, nonadditive genetic and nonshared environmental influences. Sexual dysfunctions are highly prevalent and are not always associated with sexual distress and this relationship might be moderated by a good relationship and compatibility with partner. Regarding classification, the results supports separate diagnoses for subjective arousal and genital arousal as well as the inclusion of pain under sexual dysfunctions.

Chasing performance persistence of hedge funds

The thesis examines the performance persistence of hedge funds using complement methodologies (namely cross-sectional regressions, quantile portfolio analysis and Spearman rank correlation test). In addition, six performance ranking metrics and six different combinations of selection and holding periods are compared. The data is gathered from HFI and Tremont databases covering over 14,000 hedge funds and time horizon is set from January 1996 to December 2007. The results suggest that there definitely exists performance persistence among hedge funds and the strength and existence of persistence vary among fund styles. The persistence depends on the metrics and combination of selection and prediction period applied. According to the results, the combination of 36-month selection and holding period outperforms other five period combinations in capturing performance persistence within the sample. Furthermore, model-free performance metrics capture persistence more sensitively than model-specific metrics. The study is the first one ever to use MVR as a performance ranking metric, and surprisingly MVR is more sensitive to detect persistence than other performance metrics employed.

Yrityksen koko ja book-to-market ilmiöt Yhdysvaltojen osakemarkkinoilla

Tämä kandidaatintutkielma käsittelee yrityksen kokoon ja book-to-market arvoon perustuvia anomalioita Yhdysvaltojen osakemarkkinoilla. Tutkimuksen kohteena on epänormaalien tuottojen saavuttaminen kyseisten anomalioiden kautta erityisesti finanssikriisin aikana. Osakeportfolioiden analysointi tapahtuu pääasiassa Fama-French kolmifaktorimallin avulla.

Kvantitatiivisten arvostrategioiden menestyminen Frankfurtin pörssissä

Tutkimuksessa tarkastellaan voidaanko Piotroskin (2000) kehittämää F-scorea käyttämällä saada arvostrategiaa parempia tuottoja Frankfurtin pörssissä 1998 – 2012. Arvostrategiaa määrittävinä tunnuslukuina käytetään P/E- ja P/B-lukujen käänteislukuja sekä niistä muodostettua yhdistelmätunnuslukua. Tunnusluvuille luodaan yhden, kahden ja kolmen vuoden sijoitusstrategiat, joiden menestymistä verrataan toisiinsa. Tuloksien perusteella voidaan todeta F-scoren olevan hyödyllisin P/B-lukuun yhdistettynä ja P/E-lukuun sovellettuna hyödytön. P/B-luvun kohdalla F-scoren ylituotto arvostrategiaan nähden on 9,60 prosenttiyksikköä. Vuotuinen tuotto P/B-luvun F-scoren strategialle on 23,16 %. Paras riskiin suhteutettu (oikaistu Sharpe) tulos on P/B-luvun yhden vuoden F-scoren strategialla (0,3414). Kolmifaktorimallin estimoimien ylituottojen erot ovat marginaalisen pieniä F-scoren ja arvostrategian välillä. Sijoitushorisontin osalta yhden vuoden pitoaika on menestyksekkäin kaikkien tutkimuksessa käytettyjen tunnuslukujen mukaan.

Torque vibration model of axial-flux surface-mounted permanent magnet synchronous machine

In order that the radius and thus ununiform structure of the teeth and otherelectrical and magnetic parts of the machine may be taken into consideration the calculation of an axial flux permanent magnet machine is, conventionally, doneby means of 3D FEM-methods. This calculation procedure, however, requires a lotof time and computer recourses. This study proves that also analytical methods can be applied to perform the calculation successfully. The procedure of the analytical calculation can be summarized into following steps: first the magnet is divided into slices, which makes the calculation for each section individually, and then the parts are submitted to calculation of the final results. It is obvious that using this method can save a lot of designing and calculating time. Thecalculation program is designed to model the magnetic and electrical circuits of surface mounted axial flux permanent magnet synchronous machines in such a way, that it takes into account possible magnetic saturation of the iron parts. Theresult of the calculation is the torque of the motor including the vibrations. The motor geometry and the materials and either the torque or pole angle are defined and the motor can be fed with an arbitrary shape and amplitude of three-phase currents. There are no limits for the size and number of the pole pairs nor for many other factors. The calculation steps and the number of different sections of the magnet are selectable, but the calculation time is strongly depending on this. The results are compared to the measurements of real prototypes. The permanent magnet creates part of the flux in the magnetic circuit. The form and amplitude of the flux density in the air-gap depends on the geometry and material of the magnetic circuit, on the length of the air-gap and remanence flux density of the magnet. Slotting is taken into account by using the Carter factor in the slot opening area. The calculation is simple and fast if the shape of the magnetis a square and has no skew in relation to the stator slots. With a more complicated magnet shape the calculation has to be done in several sections. It is clear that according to the increasing number of sections also the result will become more accurate. In a radial flux motor all sections of the magnets create force with a same radius. In the case of an axial flux motor, each radial section creates force with a different radius and the torque is the sum of these. The magnetic circuit of the motor, consisting of the stator iron, rotor iron, air-gap, magnet and the slot, is modelled with a reluctance net, which considers the saturation of the iron. This means, that several iterations, in which the permeability is updated, has to be done in order to get final results. The motor torque is calculated using the instantaneous linkage flux and stator currents. Flux linkage is called the part of the flux that is created by the permanent magnets and the stator currents passing through the coils in stator teeth. The angle between this flux and the phase currents define the torque created by the magnetic circuit. Due to the winding structure of the stator and in order to limit the leakage flux the slot openings of the stator are normally not made of ferromagnetic material even though, in some cases, semimagnetic slot wedges are used. In the slot opening faces the flux enters the iron almost normally (tangentially with respect to the rotor flux) creating tangential forces in the rotor. This phenomenon iscalled cogging. The flux in the slot opening area on the different sides of theopening and in the different slot openings is not equal and so these forces do not compensate each other. In the calculation it is assumed that the flux entering the left side of the opening is the component left from the geometrical centre of the slot. This torque component together with the torque component calculated using the Lorenz force make the total torque of the motor. It is easy to assume that when all the magnet edges, where the derivative component of the magnet flux density is at its highest, enter the slot openings at the same time, this will have as a result a considerable cogging torque. To reduce the cogging torquethe magnet edges can be shaped so that they are not parallel to the stator slots, which is the common way to solve the problem. In doing so, the edge may be spread along the whole slot pitch and thus also the high derivative component willbe spread to occur equally along the rotation. Besides forming the magnets theymay also be placed somewhat asymmetric on the rotor surface. The asymmetric distribution can be made in many different ways. All the magnets may have a different deflection of the symmetrical centre point or they can be for example shiftedin pairs. There are some factors that limit the deflection. The first is that the magnets cannot overlap. The magnet shape and the relative width compared to the pole define the deflection in this case. The other factor is that a shifting of the poles limits the maximum torque of the motor. If the edges of adjacent magnets are very close to each other the leakage flux from one pole to the other increases reducing thus the air-gap magnetization. The asymmetric model needs some assumptions and simplifications in order to limit the size of the model and calculation time. The reluctance net is made for symmetric distribution. If the magnets are distributed asymmetrically the flux in the different pole pairs will not be exactly the same. Therefore, the assumption that the flux flows from the edges of the model to the next pole pairs, in the calculation model from one edgeto the other, is not correct. If it were wished for that this fact should be considered in multi-pole pair machines, this would mean that all the poles, in other words the whole machine, should be modelled in reluctance net. The error resulting from this wrong assumption is, nevertheless, irrelevant.

Development of a Business Model that Supports Mobile Value-Added Services Market Creation in Emerging Countries

Tutkielman tavoitteena on luoda liiketoimintamalli, joka tukee langattomien matkaviestintäpalveluiden markkinoiden luomista kehittyvillä markkinoilla. Teoreettinen osa tarkastelee langattomien matkaviestintäpalveluiden liiketoimintamallin kehittämisen tärkeimpiä elementtejä CIS maissa. Teoreettisen kappaleen tuloksena saadaan puitteet, jonka avulla liiketoimintamalli matkaviestintäpalveluille voidaan kehittää. Tutkielman empiirinen osa on toteutettu case tutkimuksena, jonka tavoitteena on ollut langattomien matkaviestintäpalvelujen markkinoiden luominen CIS maissa. Pääasiallinen empiirisen tiedon lähde on ollut teemahaastattelut. Tuloksena saatuja empiirisen osan tietoja verrataan teoriakappaleen vastaaviin tuloksiin Tulokset osoittavat, että radikaalin korkean teknologian innovaation markkinoiden luominen on hidas prosessi, joka vaatii kärsivällisyyttä yritykseltä. Markkinoiden, teknologian ja strategian epävarmuustekijät tuovat epävarmuutta kehittyvälle toimialalle ja markkinoille, joka vaikeuttaa liiketoimintamallin kehittämistä. Tärkein tekijä on palvelujen markkinointi ennemmin kuin teknologian. Avain kyvykkyys markkinoiden luomisessa on oppiminen, ei tietäminen.

Organisaation strategian mukainen uudistumiskyky case: KM-factor -mittaus Itäisessä tullipiirissä

Tutkielman tarkoituksena on tutkia case-organisaationa toimivan Itäisen tullipiirin strategista uudistumiskykyä. Minkälaiset lähtökohdat organisaatiolla on kohdata tulevaisuuden haasteet omassa toimintaympäristössään ja minkälaisia esteitä uudistumiselle löytyy? Pärjätäkseen kiristyvässä kilpailussa on uudistumiseen vaikuttavien tekijöiden, kuten osaamisen, tiedon kulun, johtamisen ja suhteiden tunnistaminen ja hyödyntäminen ensiarvoisen tärkeää myös julkishallinnon organisaatioille. Tässä tutkielmassa uudistumiskykyä tarkastellaan kolmiulotteisen organisaatiomallin (mekaaninen, orgaaninen ja dynaaminen) valossa ja kehittämistoimien lähtökohtana pidetään organisaation omaa strategista fokusta. Tutkimus- ja tiedonkeruumenetelminä käytetään kvantitatiiviseksi luokiteltavaa, sähköisessä muodossa tehtävää KM-factor -kyselyä ja kvalitatiivista teemahaastattelua. Tutkimustulokset antavat strategisesti tärkeää tietoa case-organisaation nykytilasta; sen heikkouksista ja vahvuuksista. Tulosten perusteella organisaation toimintatapa on melko yhtenäinen ja strategisen fokuksensa, eli orgaanisen toimintaympäristön vaatimusten mukainen. Kehittämistoimia tulee kuitenkin kohdentaa erityisesti henkilöstön strategian mukaisen osaamisen ja esimiesten tiedon kulun lisäämiseen sekä yleisesti työmotivaatiotason nostamiseen koko kohdeorganisaatiossa. Organisaatiossa on luotava käytäntöjä, jotka tukevat avoimen tiedon kulun ilmapiiriä ja dialogimaista kommunikointia, jotta organisaation uudistumiskyky yhtenäisenä systeeminä parantuisi entisestään.

Model-based study of a chemical-looping combustion process

Chemical-looping combustion (CLC) is a novel combustion technology with inherent separation of the greenhouse gas CO2. The technique typically employs a dual fluidized bed system where a metal oxide is used as a solid oxygen carrier that transfers the oxygen from combustion air to the fuel. The oxygen carrier is looping between the air reactor, where it is oxidized by the air, and the fuel reactor, where it is reduced by the fuel. Hence, air is not mixed with the fuel, and outgoing CO2 does not become diluted by the nitrogen, which gives a possibility to collect the CO2 from the flue gases after the water vapor is condensed. CLC is being proposed as a promising and energy efficient carbon capture technology, since it can achieve both an increase in power station efficiency simultaneously with low energy penalty from the carbon capture. The outcome of a comprehensive literature study concerning the current status of CLC development is presented in this thesis. Also, a steady state model of the CLC process, based on the conservation equations of mass and energy, was developed. The model was used to determine the process conditions and to calculate the reactor dimensions of a 100 MWth CLC system with bunsenite (NiO) as oxygen carrier and methane (CH4) as fuel. This study has been made in Oxygen Carriers and Their Industrial Applications research project (2008 – 2011), funded by the Tekes – Functional Material program. I would like to acknowledge Tekes and participating companies for funding and all project partners for good and comfortable cooperation.

Competitors' Financial Performance Monitoring Model

The objective of the thesis was to develop a competitors’ financial performance monitoring model for management reporting. The research consisted of the selections of the comparison group and the performance meters as well as the actual creation of the model. A brief analysis of the current situation was also made. The aim of the results was to improve the financial reporting quality in the case organization by adding external business environment observation to the management reports. The comparison group for the case company was selected to include five companies that were all involved in power equipment engineering and project type business. The most limiting factor related to the comparison group selection was the availability of quarterly financial reporting. The most suitable performance meters were defined to be the developments of revenue, order backlog and EBITDA. These meters should be monitored systematically on quarterly basis and reported to the company management in a brief and informative way. The monitoring model was based on spreadsheet construction with key characteristics being usability, flexibility and simplicity. The model acts as a centered storage for financial competitor information as well as a reporting tool. The current market situation is strongly affected by the economic boom in the recent years and future challenges can be clearly seen in declining order backlogs. The case company has succeeded well related to its comparison group during the observation period since its business volume and profitability have developed in the best way.

Role and regulatory mechanisms of heat shock factor 2

Protein homeostasis is essential for cells to prosper and survive. Various forms of stress, such as elevated temperatures, oxidative stress, heavy metals or bacterial infections cause protein damage, which might lead to improper folding and formation of toxic protein aggregates. Protein aggregation is associated with serious pathological conditions such as Alzheimer’s and Huntington’s disease. The heat shock response is a defense mechanism that protects the cell against protein-damaging stress. Its ancient origin and high conservation among eukaryotes suggest that the response is crucial for survival. The main regulator of the heat shock response is the transcription factor heat shock factor 1 (HSF1), which induces transcription of genes encoding protective molecular chaperones. In vertebrates, a family of four HSFs exists (HSF1-4), with versatile functions not only in coping with acute stress, but also in development, longevity and cancer. Thus, knowledge of the HSFs will aid in our understanding on how cells survive suboptimal circumstances, but will also provide insights into normal physiological processes as well as diseaseassociated conditions. In this study, the function and regulation of HSF2 have been investigated. Earlier gene inactivation experiments in mice have revealed roles for HSF2 in development, particularly in corticogenesis and spermatogenesis. Here, we demonstrate that HSF2 holds a role also in the heat shock response and influences stress-induced expression of heat shock proteins. Intriguingly, DNA-binding activity of HSF2 upon stress was dependent on the presence of intact HSF1, suggesting functional interplay between HSF1 and HSF2. The underlying mechanism for this phenomenon could be configuration of heterotrimers between the two factors, a possibility that was experimentally verified. By changing the levels of HSF2, the expression of HSF1-HSF2 heterotrimer target genes was altered, implementing HSF2 as a modulator of HSF-mediated transcription. The results further indicate that HSF2 activity is dependent on its concentration, which led us to ask the question of how accurate HSF2 levels are achieved. Using mouse spermatogenesis as a model system, HSF2 was found to be under direct control of miR-18, a miRNA belonging to the miR-17~92 cluster/Oncomir-1 and whose physiological function had remained unclear. Investigations on spermatogenesis are severely hampered by the lack of cell systems that would mimic the complex differentiation processes that constitute male germ cell development. Therefore, to verify that HSF2 is regulated by miR-18 in spermatogenesis, a novel method named T-GIST (Transfection of Germ cells in Intact Seminiferous Tubules) was developed. Employing this method, the functional consequences of miR-18-mediated regulation in vivo were demonstrated; inhibition of miR- 18 led to increased expression of HSF2 and altered the expression of HSF2 target genes Ssty2 and Speer4a. Consequently, the results link miR-18 to HSF2-mediated processes such as germ cell maturation and quality control and provide miR-18 with a physiological role in gene expression during spermatogenesis.Taken together, this study presents compelling evidence that HSF2 is a transcriptional regulator in the heat shock response and establishes the concept of physical interplay between HSF2 and HSF1 and functional consequences thereof. This is also the first study describing miRNA-mediated regulation of an HSF.

The Dual Role of HIF Hydroxylase PHD3 in Cancer Cell Survival

Most advanced tumours face periods of reduced oxygen availability i.e. hypoxia. During these periods tumour cells undergo adaptive changes enabling their survival under adverse conditions. In cancer hypoxia-induced cellular changes cause tumour progression, hinder cancer treatment and are indicative of poor prognosis. Within cells the main regulator of hypoxic responses is the hypoxia-inducible factor (HIF). HIF governs the expression of over a hundred hypoxia-inducible genes that regulate a number of cellular functions such as angiogenesis, glucose metabolism and cell migration. Therefore the activity of HIF must be tightly governed. HIF is regulated by a family of prolyl hydroxylase enzymes, PHDs, which mark HIF for destruction in normoxia. Under hypoxic conditions PHDs lose much of their enzymatic activity as they need molecular oxygen as a cofactor. Out of the three PHDs (PHD1, 2 and 3) PHD2 has been considered to be the main HIF-1 regulator in normoxic conditions. PHD3 on the other hand shows the most robust induction in response to oxygen deprivation and it has been implied as the main HIF-1 regulator under prolonged hypoxia. SQSTM1/p62 (p62) is an adaptor protein that functions through its binding motifs to bring together proteins in order to regulate signal transduction. In non-stressed situations p62 levels are kept low but its expression has been reported to be upregulated in many cancers. It has a definitive role as an autophagy receptor and as such it serves a key function in cancer cell survival decisions. In my thesis work I evaluated the significance of PHD3 in cancer cell and tumour biology. My results revealed that PHD3 has a dual role in cancer cell fate. First, I demonstrated that PHD3 forms subcellular protein aggregates in oxygenated carcinoma cells and that this aggregation promotes apoptosis induction in a subset of cancer cells. In these aggregates an adaptor protein SQSTM1/p62 interacts with PHD3 and in so doing regulates PHD3 expression. SQSTM1/p62 expression is needed to keep PHD3 levels low in normoxic conditions. Its levels rapidly decrease in response to hypoxia allowing PHD3 protein levels to be upregulated and the protein to be diffusely expressed throughout the cell. The interaction between PHD3 and SQSTM1/p62 limits the ability of PHD3 to function on its hydroxylation target protein HIF-1alpha. Second, the results indicate that when PHD3 is upregulated under hypoxia it protects cancer cells by allowing cell cycle to proceed from G1 to S-phase. My data demonstrates that PHD3 may either cause cell death or protect the cells depending on its expression pattern and the oxygen availability of tumours.