Novel Functions of ErbB4 and NRG-1 in Development and Cancer

Cells communicate, or signal, with each other constantly to ensure proper functioning of tissues and organs. Cell signaling is often performed by interplay of receptors and ligands that bind these receptors. ErbB receptors (epidermal growth factor receptors, EGFR, HER) bind extracellular growth factors and transduce these signals inside of cells. ErbB dysfunction promotes carcinogenesis, and also results in numerous defects during normal development. This study focused on the functions of one member of the ErbB receptor family, ErbB4, and growth factor, neuregulin-1 (NRG-1), that can bind and activate ErbB4. This study aimed to find novel functions of ErbB4 and NRG-1. Hypoxia, or deficiency of oxygen, is common in cancer and ischemic conditions. One of the key findings of the work was the identification and characterization of a cross-talk between ErbB4 and Hypoxia-inducible factor 1α (HIF-1α), the central mediator of hypoxia signaling. ErbB4 activation by NRG-1 was found to increase HIF-1α activity. Interestingly, this regulation occurred in reciprocal manner as HIF-1α was also able to increase protein levels of NRG-1 and ErbB4. Moreover, expression of NRG-1 and ErbB4 was associated with HIF activity in vivo in human clinical samples and in mice. Reduction of functional ErbB4 in developing zebrafish embryos resulted in defects in development of the skeletal muscles. To study ErbB4 functions in pathological situation in humans, clinical samples of serous ovarian carcinoma were analyzed using tissue microarrays and real-time RT-PCR. A specific isoform of ErbB4, CYT-1, was associated with poor survival in serous ovarian cancer and increased anchorage independent growth of ovarian cancer cells in vitro. These observations demonstrate that ErbB4 and NRG-1 are essential regulators of cellular response to hypoxia, of development, and of ovarian carcinogenesis.

Training executive functions in the laboratory and in real life : cognitive consequences of computer-based exercises and bilingualism

The question of the trainability of executive functions and the impact of such training on related cognitive skills has stirred considerable research interest. Despite a number of studies investigating this, the question has not yet been solved. The general aim of this thesis was to investigate two very different types of training of executive functions: laboratory-based computerized training (Studies I-III) and realworld training through bilingualism (Studies IV-V). Bilingualism as a kind of training of executive functions is based on the idea that managing two languages requires executive resources, and previous studies have suggested a bilingual advantage in executive functions. Three executive functions were studied in the present thesis: updating of working memory (WM) contents, inhibition of irrelevant information, and shifting between tasks and mental sets. Studies I-III investigated the effects of computer-based training of WM updating (Study I), inhibition (Study II), and set shifting (Study III) in healthy young adults. All studies showed increased performance on the trained task. More importantly, improvement on an untrained task tapping the trained executive function (near transfer) was seen in Study I and II. None of the three studies showed improvement on untrained tasks tapping some other cognitive function (far transfer) as a result of training. Study I also used PET to investigate the effects of WM updating training on a neurotransmitter closely linked to WM, namely dopamine. The PET results revealed increased striatal dopamine release during WM updating performance as a result of training. Study IV investigated the ability to inhibit task-irrelevant stimuli in bilinguals and monolinguals by using a dichotic listening task. The results showed that the bilinguals exceeded the monolinguals in inhibiting task-irrelevant information. Study V introduced a new, complementary research approach to study the bilingual executive advantage and its underlying mechanisms. To circumvent the methodological problems related to natural groups design, this approach focuses only on bilinguals and examines whether individual differences in bilingual behavior correlate with executive task performances. Using measures that tap the three above-entioned executive functions, the results suggested that more frequent language switching was associated with better set shifting skills, and earlier acquisition of the second language was related to better inhibition skills. In conclusion, the present behavioral results showed that computer-based training of executive functions can improve performance on the trained task and on closely related tasks, but does not yield a more general improvement of cognitive skills. Moreover, the functional neuroimaging results reveal that WM training modulates striatal dopaminergic function, speaking for training-induced neural plasticity in this important neurotransmitter system. With regard to bilingualism, the results provide further support to the idea that bilingualism can enhance executive functions. In addition, the new complementary research approach proposed here provides some clues as to which aspects of everyday bilingual behavior may be related to the advantage in executive functions in bilingual individuals.

Cost-effectiveness analysis in South Karelia Central Hospital

The target organization of this study, otherwise South-Karelia Social and Health Care District (Eksote) provides health, senior, family and social welfare services. South Karelia Central Hospital provides special health care and offers health services from all of the most important medical specialties. Eksote has in use 15D instrument to measure the health-related quality of life (HRQoL) of their patients before and after their interventions for observing the health effects of the medical care. Furthermore, 15D allows measuring the effectiveness and cost-effectiveness of health care when comparing these before and after results of the 15D measurements and adding the costs of the interventions into this research. The main purposes of this study were to analyze the effectiveness and cost-effectiveness of medical care in South Karelia Central Hospital by using the gathered 15D data to calculate effectiveness and cost-effectiveness ratios and to analyze the reliability and availability of the data. Study has been conducted using literature review and quantitative research methods. The results indicate that from the patients within the eight units selected to this study the 15D change information was available from the 52 %, the 15D change and the cost information from 38 % and the information of quality-adjusted life years (QALYs) produced and the cost information from 35 %. The effectiveness and cost-effectiveness of medical care were greatest at the units of Pain Outpatient Clinic and Rheumatic Diseases Outpatient Clinic. The most effective medical care is given in the unit where the average price of one produced QALY is the highest (Orthopedics). However, the calculated standard deviations pointed out that there are great variances in the effectiveness and cost-effectiveness within the units also.

Effects of fasting and refeeding on the metabolic functions of the turtle Kinosternon scorpioides (Linnaeus, 1766) raised in captivity

The metabolic responses of adult and young freshwater Kinosternon scorpioides turtles raised in captivity were evaluated. Two experiments were performed: a) blood metabolite changes caused by food deprivation, and b) liver and muscle glycogen and total lipid differences after fasting and refeeding. Blood glucose concentration of young animals was susceptible to food deprivation. In both groups this metabolite decreased after 30 days of fasting. Feeding for 15 days did not recover blood glucose. Total seric proteins were not affected by food deprivation. Fasting decreased blood urea nitrogen and the highest difference was found around 30 days. Uric acid increased in young animals after 60 days of fasting. Triacylglicerol decreased after 15 days of fasting and refeeding for 15 days recovered the pre-fasting levels. Free fatty acid plasma tended to increase around 15 days of fasting. Liver glycogen decreased at day 15 of fasting, being stable thereafter while muscle glycogen decreased at a slower rate. Total liver lipid stabilized after 30 days and then decreased 70% after 60 days of fasting. Muscle lipids remained stable throughout fasting. It could be concluded that fasting of Kinosternon scorpioides led to metabolic adaptations similar to the one reported from reptiles and fish.

Regulation of self-renewal and detection of karyotypic changes of pluripotent human embryonic stem cells

Human embryonic stem cells are pluripotent cells capable of renewing themselves and differentiating to specialized cell types. Because of their unique regenerative potential, pluripotent cells offer new opportunities for disease modeling, development of regenerative therapies, and treating diseases. Before pluripotent cells can be used in any therapeutic applications, there are numerous challenges to overcome. For instance, the key regulators of pluripotency need to be clarified. In addition, long term culture of pluripotent cells is associated with the accumulation of karyotypic abnormalities, which is a concern regarding the safe use of the cells for therapeutic purposes. The goal of the work presented in this thesis was to identify new factors involved in the maintenance of pluripotency, and to further characterize molecular mechanisms of selected candidate genes. Furthermore, we aimed to set up a new method for analyzing genomic integrity of pluripotent cells. The experimental design applied in this study involved a wide range of molecular biology, genome-wide, and computational techniques to study the pluripotency of stem cells and the functions of the target genes. In collaboration with instrument and reagent company Perkin Elmer, KaryoliteTM BoBsTM was implemented for detecting karyotypic changes of pluripotent cells. Novel genes were identified that are highly and specifically expressed in hES cells. Of these genes, L1TD1 and POLR3G were chosen for further investigation. The results revealed that both of these factors are vital for the maintenance of pluripotency and self-renewal of the hESCs. KaryoliteTM BoBsTM was validated as a novel method to detect karyotypic abnormalities in pluripotent stem cells. The results presented in this thesis offer significant new information on the regulatory networks associated with pluripotency. The results will facilitate in understanding developmental and cancer biology, as well as creating stem cell based applications. KaryoliteTM BoBsTM provides rapid, high-throughput, and cost-efficient tool for screening of human pluripotent cell cultures.

Long term dietary deficiency in steers: vital functions and T3 and IGF-1 relationships

To evaluate the influence of diets with different degrees of energy deficiency on the hormonal profile and vital functions, 12 steers were randomly distributed into 3 groups of 4 animals. For 140 days, each group received (G1) a diet to promote a weight gain of 900gr/day (17.7 Mcal/d DE and 13% CP), (G2) 80% of the maintenance requirements (5.8 Mcal/d DE and 7% CP), or (G3) 60% of the maintenance requirements (4.7 Mcal/d DE and 5% CP). In G2 and G3, the energy deficit caused a marked decrease in the heart rate and respiratory rate and a reduction in the blood levels of Insulin like growth factor-1 (IGF-1) and triiodothyronine (T3). The decrease in heart rate, respiratory movement and, to a lesser extent, reduction of the rectal temperature, reflected the low status of energy and was negatively impacted by the low levels of T3. There was a strong correlation between the hormones T3 and IGF-1 (r=0.833). There were also strong correlations between T3 and HR (r=0.701), T3 and RR (r=0.632), IGF-1 and HR (r=0.731), and IGF-1 and RR (r=0.679). There were intermediate correlations between T3 and TºC (r=0.484), T3 and insulin (r=0.506), IGF-1 and insulin (r=0.517), and IGF-1 and TºC (r=0.548). This study showed the influence of a long period of providing an energy-deficient diet on animal performance, correlating hormonal status and vital functions in growing cattle. The results indicated that the evaluated parameters represent an important tool for the early detection of dietary deficiency.

A quality and cost approach for welding process selection

The aim of this work was to propose, apply and evaluate a methodical approach to select welding processes in a productive environment based on market requirements of Quality and Costs. A case study was used. The welds were carried out in laboratory, simulating the joint conditions of a manufacturer and using several welding processes: SMAW, GTAW, pulsed GTAW, GMAW with CO2 and Ar based shielding gases and pulsed GMAW. For Quality analysis geometrical aspects of the beads were considered and for Cost analysis, welding parameters and consumable prices. Quantitative indices were proposed and evaluated. After that, evaluation of both Quality and Costs was done, showing to be possible to select the most suitable welding process to a specific application, taking into account the market conditions of a company.

Overview on the Cost-effectiveness of Maritime Safety Policy Instruments

Maritime safety is an issue that has gained a lot of attention in the Baltic Sea area due to the dense maritime traffic and transportation of oil in the area. Lots of effort has been paid to enhance maritime safety in the area. The risk exists that excessive legislation and other requirements mean more costs for limited benefit. In order to utilize both public and private resources efficiently, awareness is required of what kind of costs maritime safety policy instruments cause and whether the costs are in relation to benefits. The aim of this report is to present an overview of the cost-effectiveness of maritime safety policy instruments focusing on the cost aspect: what kind of costs maritime safety policy causes, to whom, what affects the cost-effectiveness and how cost-effectiveness is studied. The study is based on a literature review and on the interviews of Finnish maritime experts. The results of this study imply that cost-effectiveness is a complicated issue to evaluate. There are no uniform practices for which costs and benefits should be included in the evaluation and how they should be valued. One of the challenges is how to measure costs and benefits during the course of a longer time period. Often a lack of data erodes the reliability of evaluation. In the prevention of maritime accidents, costs typically include investments in ship structures or equipment, as well as maintenance and labor costs. Also large investments may be justifiable if they respectively provide significant improvements to maritime safety. Measures are cost-effective only if they are implemented properly. Costeffectiveness is decreased if a measure causes overlapping or repetitious work. Costeffectiveness is also decreased if the technology isn’t user-friendly or if it is soon replaced with a new technology or another new appliance. In future studies on the cost-effectiveness of maritime safety policy, it is important to acknowledge the dependency between different policy instruments and the uncertainty of the factors affecting cost-effectiveness. The costs of a single measure are rarely relatively significant and the effect of each measure on safety tends to be positive. The challenge is to rank the measures and to find the most effective combination of different policy instruments. The greatest potential offered for the analysis of cost-effectiveness of individual measures is their implementation in clearly defined risk situations, in which different measures are truly alternative to each other. Overall, maritime safety measures do not seem to be considered burdening for the shipping industry in Finland at the moment. Generally actors in the Finnish shipping industry seem to find maintaining a high safety level important and act accordingly.

CTQ process flow development and the impact for cost of quality

Tämä työ tehtiin Kone Industrial Oy:lle Major Projects yksikköön, laatuosastolle. Kone Major Projects yksikkö keskittyy erikoisiin ja suuriin hissi- ja liukuporras projekteihin. Työn tavoitteena oli luoda harmonisoitu prosessi hissikomponenttien laaduntarkkailua varten sekä tarkastella ja vertailla kustannussäästöjä, jota tällä uudella prosessilla voidaan saavuttaa. Tavoitteena oli saavuttaa 80-prosentin kustannussäästöt laatukustannuksissa uuden laatuprosessin avulla. Työn taustana ja tutkimusongelmana ovat lisääntyneet erikoisprojektit ja niiden myötä lisääntynyt laaduntarkkailun tarve. Ongelmana laaduntarkkailussa voitiin pitää harmonisoidun ja selkeän prosessin puuttumista C-prosessikomponenttien valmistuksessa. Lisäksi kehitysprosessin aikana luotiin vanhojen työkalujen pohjalta keskeinen laaduntarkkailutyökalu, CTQ-työkalu. Työssä käsitellään ensin Konetta yhtiönä ja selvitetään Koneen keskeisimmät prosessit työn taustaksi. Teoria osuudessa käsitellään prosessin kehitykseen liittyviä teorioita sekä yleisiä laatukäsitteitä ja esitetään teorioita laadun asemasta nykypäivänä. Lopuksi käsitellään COQ eli laatukustannusten teoriaa ja esitellään teoria PAF-analyysille, jota käytetään työssä laatukustannusten vertailuun case esimerkin avulla. Työssä kuvataan CTQ prosessin luominen alusta loppuun ja case esimerkin avulla testataan uutta CTQ prosessia pilottihankkeessa. Tässä case esimerkissä projektin bracket eli johdekiinnitysklipsi tuotetaan uuden laatuprosessin avulla sekä tehdään kustannusvertailu saman projektin toisen bracketin kanssa, joka on tuotettu ennen uuden laatuprosessin implementoimista. Työn lopputuloksena CTQ prosessi saatiin luotua ja sitä pystyttiin testaamaan käytännössä case esimerkin avulla. Tulosten perusteella voidaan sanoa, että CTQ prosessin käyttö vähentää laatukustannuksia huomattavasti ja helpottaa laadunhallintaa C-prosessikomponenttien tuotannossa.

Validation and Selection of Transportation Cost Drivers with Advanced Methods

In today's logistics environment, there is a tremendous need for accurate cost information and cost allocation. Companies searching for the proper solution often come across with activity-based costing (ABC) or one of its variations which utilizes cost drivers to allocate the costs of activities to cost objects. In order to allocate the costs accurately and reliably, the selection of appropriate cost drivers is essential in order to get the benefits of the costing system. The purpose of this study is to validate the transportation cost drivers of a Finnish wholesaler company and ultimately select the best possible driver alternatives for the company. The use of cost driver combinations as an alternative is also studied. The study is conducted as a part of case company's applied ABC-project using the statistical research as the main research method supported by a theoretical, literature based method. The main research tools featured in the study include simple and multiple regression analyses, which together with the literature and observations based practicality analysis forms the basis for the advanced methods. The results suggest that the most appropriate cost driver alternatives are the delivery drops and internal delivery weight. The possibility of using cost driver combinations is not suggested as their use doesn't provide substantially better results while increasing the measurement costs, complexity and load of use at the same time. The use of internal freight cost drivers is also questionable as the results indicate weakening trend in the cost allocation capabilities towards the end of the period. Therefore more research towards internal freight cost drivers should be conducted before taking them in use.

Ison tuuligeneraattorin roottorin ja staattorin rakennetarkastelu

Maailmanlaajuinen ilmastopolitiikka asettaa vaativia tavoitteita hiilidioksidipäästöjen vähentämiselle. Suurin haaste on tuottaa energiaa mahdollisimman alhaisin kustannuksin käyttäen uusiutuvia ja ympäristöä säästäviä energiamuotoja. Tuulivoimasta on tullut nopeimmin kehittyvä sähköntuotantotapa, ja tuuliturbiinien koon kasvun myötä on myös generaattorien koko kasvanut merkittävästi 1990-luvulta lähtien. Generaattorin massiivisuus suoravetoisessa tuuliturbiinin voimansiirrossa vaatii tarkkoja kuormitustarkasteluja, jotta rakenne kestäisi tuuliturbiinin eliniän. Tuuliturbiinin kuormitukset ovat stokastisia ja toisinaan erittäin suuria, mikä vaikeuttaa kuormitusten määrittämistä. Tuulen kuormitusten lisäksi generaattori altistuu eri toimintojen kautta muillekin kuormituksille, ja tästä syystä on otettava huomioon jarrutuksen, dynaamisen tasapainon ja ohjauksen sekä verkkovikojen aiheuttamat rasitukset tuuliturbiinin voimansiirrolle. Edellisten lisäksi työssä on tarkasteltu erilaisia rakenneratkaisuja sekä pyritty kiinnittämään huomio niiden kuormankantokykyyn ja jäykkyyteen sekä generaattorin keventämismahdollisuuksiin verrattuna perinteisiin radiaalivuogeneraattoreihin. Työssä on pyritty selvittämään rakenteen kuormitukset siten, että pystyttäisiin optimoimaan mahdollisimman kevyt rakenne. Optimoinnin kohteena on pinnarakenteisen generaattorin rakenteen massa puolien, puolan kulmien sekä tukirenkaan ja niistä aiheutuvien erilaisten rakenneyhdistelmien suhteen tarkasteltuna.

Neurocognitive changes in early-stage Parkinson's disease : functional and structural brain correlates of memory and verbal functions

Resultaten påvisade små, men mätbara försämringar i minnes- och verbal förmåga hos personer som haft Parkinsons sjukdom under tre år. Jämfört med en kontrollgrupp uppvisade Parkinsonpatienter avvikande responser i hjärnans elektriska aktivitet under en korttidsminnesuppgift, och de presterade även sämre i olika typer av andra minnesuppgifter. Försämring i en specifik typ av minnesuppgift korrelerade med förminskad volym i höger hjärnhalva. Samband hittades också mellan sämre verbal förmåga och förminskad volym i djupa hjärnstrukturer. Förminskad hjärnvolym har tidigare påvisats hos dementa patienter i senare sjukdomsstadier. Forskningsresultaten bidrar med ny kunskap om kognitiva symptom och deras neurala bakgrund vid Parkinsons sjukdom. De tyder också på att tidig kognitiv funktionsnedsättning kan identifieras, vilket kan bidra till utvecklingen av sjukdomens behandling. Parkinsons sjukdom är den näst vanligaste neurogeriatriska sjukdomen efter Alzheimers sjukdom. Symptomen uppstår som följd av förminskad produktion av hjärnans transmittorämne dopamin. Parkinsons sjukdom har traditionellt betraktats som en progressiv motorisk sjukdom. Ny forskning tyder på att multipla hjärnsystem skadas, vilket resulterar i att även tankeprocesser påverkas. 75-80% uppskattas insjukna i demens 10-15 år efter diagnos, men det kognitiva sjukdomsförloppet och orsaken till demenssymptomen är tillsvidare okänd. I Finland uppskattas ca 10-12 000 personer ha Parkinsons sjukdom, varav ca 3 000 uppskattas ha demens. ----------------------------------------------------------------------------------------------------------------------------------------------------- Tutkimuksessa todettiin lieviä muutoksia muisti- ja kielellisissä toiminnoissa alle kolme vuotta sairastaneilla Parkinson-potilailla. Potilailla havaittiin poikkeavia aivosähkötoiminnan vasteita lyhytkestoista muistia mittaavan tehtävän aikana. Potilaat suoriutuivat myös verrokkiryhmää heikommin useissa muistitehtävissä. Heikentynyt tahaton muisti liittyi pienempään aivokuoren harmaan aineen paikalliseen tilavuuteen. Heikompi kielellinen suoriutuminen liittyi pienempään harmaan aineen tilavuuteen aivojen syvissä rakenteissa. Pienentyneitä aivorakenteiden tilavuuksia on aiemmin todettu dementoituneilla Parkinson-potilailla sairauden myöhemmissä vaiheissa. Tutkimustulokset tuovat uutta tietoa Parkinsonin taudin kognitiivisista oireista ja niiden aivoperäisestä taustasta. Tulosten perusteella on mahdollista tunnistaa jo varhaisia kognitiivisia muutoksia, mikä voi mahdollistaa tehokkaamman hoidon kohdentamisen. Parkinsonin tauti on Alzheimerin taudin jälkeen toiseksi yleisin neurogeriatrinen sairaus. Oirekuva liittyy aivojen dopaminergisen järjestelmän rappeutumiseen. Perinteisesti liikehäiriösairaudeksi luokiteltu sairaus vaurioittaa lukuisia muita aivojärjestelmiä aiheuttaen muutoksia myös mm. ajattelutoiminnoissa. Pitkään sairastaneista 75–80 prosentilla esiintyy dementiaoireita, mutta oireiden syy ja kehityskaari tunnetaan toistaiseksi huonosti. Suomessa on arviolta 10–12 000 Parkinson-potilasta, joista noin 3 000 arvioidaan kärsivän dementiaoireista.

Excessive functions, Appell polynomials and optimal stopping

The main topic of the thesis is optimal stopping. This is treated in two research articles. In the first article we introduce a new approach to optimal stopping of general strong Markov processes. The approach is based on the representation of excessive functions as expected suprema. We present a variety of examples, in particular, the Novikov-Shiryaev problem for Lévy processes. In the second article on optimal stopping we focus on differentiability of excessive functions of diffusions and apply these results to study the validity of the principle of smooth fit. As an example we discuss optimal stopping of sticky Brownian motion. The third research article offers a survey like discussion on Appell polynomials. The crucial role of Appell polynomials in optimal stopping of Lévy processes was noticed by Novikov and Shiryaev. They described the optimal rule in a large class of problems via these polynomials. We exploit the probabilistic approach to Appell polynomials and show that many classical results are obtained with ease in this framework. In the fourth article we derive a new relationship between the generalized Bernoulli polynomials and the generalized Euler polynomials.