Cognitive Functions After Traumatic Brain Injury. A 30-year Follow-up Study

Many cognitive deficits after TBI (traumatic brain injury) are well known, such as memory and concentration problems, as well as reduced information-processing speed. What happens to patients and cognitive functioning after immediate recovery is poorly known. Cognitive functioning is flexible and may be influenced by genetic, psychological and environmental factors decades after TBI. The general aim of this thesis was to describe the long-term cognitive course after TBI, to find variables that may contribute to it, and how the cognitive functions after TBI are associated with specific medical factors and reduced survival. The original study group consisted of 192 patients with TBI who were originally assessed with the Mild Deterioration Battery (MDB) on average two years after the injury, during the years 1966 – 1972. During a 30-year follow-up, we studied the risks for reduced survival, and the mortality of the patients was compared with the general population using the Standardized Mortality Ratio (SMR). Sixty-one patients were re-assessed during 1998-2000. These patients were evaluated with the MDB, computerized testing, and with various other neuropsychological methods for attention and executive functions. Apolipoprotein-E (ApoE) genotyping and magnetic resonance imaging (MRI) based on volumetric analysis of the hippocampus and lateral ventricles were performed. Depressive symptoms were evaluated with the short form of the Beck depression inventory. The cognitive performance at follow-up was compared with a control group that was similar to the study group in regard to age and education. The cognitive outcome of the patients with TBI varied after three decades. The majority of the patients showed a decline in their cognitive level, the rest either improved or stayed at the same level. Male gender and higher age at injury were significant risk factors for the decline. Whereas most cognitive domains declined during the follow-up, semantic memory behaved in the opposite way, showing recovery after TBI. In the follow-up assessment, the memory decline and impairments in the set-shifting domain of executive functions were associated with MRI-volumetric measures, whereas reduction in information-processing speed was not associated with the MRI measures. The presence of local contusions was only weakly associated with cognitive functions. Only few cognitive methods for attention were capable of discriminating TBI patients with and without depressive symptoms. On the other hand, most complex attentional tests were sensitive enough to discriminate TBI patients (non-depressive) from controls. This means that complex attention functions, mediated by the frontal lobes, are relatively independent of depressive symptoms post-TBI. The presence of ApoE4 was associated with different kinds of memory processes including verbal and visual episodic memory, semantic memory and verbal working memory, depending on the length of time since TBI. Many other cognitive processes were not affected by the presence of ApoE4. Age at injury and poor vocational outcome were independent risk factors for reduced survival in the multivariate analysis. Late mortality was higher among younger subjects (age < 40 years at death) compared with the general population which should be borne in mind when assessing the need for rehabilitation services and long-term follow-up after TBI.

NADPH-Dependent Thioredoxin System In Regulation of Chloroplast Functions

Photosynthesis, the process in which carbon dioxide is converted into sugars using the energy of sunlight, is vital for heterotrophic life on Earth. In plants, photosynthesis takes place in specific organelles called chloroplasts. During chloroplast biogenesis, light is a prerequisite for the development of functional photosynthetic structures. In addition to photosynthesis, a number of other metabolic processes such as nitrogen assimilation, the biosynthesis of fatty acids, amino acids, vitamins, and hormones are localized to plant chloroplasts. The biosynthetic pathways in chloroplasts are tightly regulated, and especially the reduction/oxidation (redox) signals play important roles in controlling many developmental and metabolic processes in chloroplasts. Thioredoxins are universal regulatory proteins that mediate redox signals in chloroplasts. They are able to modify the structure and function of their target proteins by reduction of disulfide bonds. Oxidized thioredoxins are restored via the action of thioredoxin reductases. Two thioredoxin reductase systems exist in plant chloroplasts, the NADPHdependent thioredoxin reductase C (NTRC) and ferredoxin-thioredoxin reductase (FTR). The ferredoxin-thioredoxin system that is linked to photosynthetic light reactions is involved in light-activation of chloroplast proteins. NADPH can be produced via both the photosynthetic electron transfer reactions in light, and in darkness via the pentose phosphate pathway. These different pathways of NADPH production enable the regulation of diverse metabolic pathways in chloroplasts by the NADPH-dependent thioredoxin system. In this thesis, the role of NADPH-dependent thioredoxin system in the redox-control of chloroplast development and metabolism was studied by characterization of Arabidopsis thaliana T-DNA insertion lines of NTRC gene (ntrc) and by identification of chloroplast proteins regulated by NTRC. The ntrc plants showed the strongest visible phenotypes when grown under short 8-h photoperiod. This indicates that i) chloroplast NADPH-dependent thioredoxin system is non-redundant to ferredoxinthioredoxin system and that ii) NTRC particularly controls the chloroplast processes that are easily imbalanced in daily light/dark rhythms with short day and long night. I identified four processes and the redox-regulated proteins therein that are potentially regulated by NTRC; i) chloroplast development, ii) starch biosynthesis, iii) aromatic amino acid biosynthesis and iv) detoxification of H₂O₂. Such regulation can be achieved directly by modulating the redox state of intramolecular or intermolecular disulfide bridges of enzymes, or by protecting enzymes from oxidation in conjunction with 2-cysteine peroxiredoxins. This thesis work also demonstrated that the enzymatic antioxidant systems in chloroplasts, ascorbate peroxidases, superoxide dismutase and NTRC-dependent 2-cysteine peroxiredoxins are tightly linked up to prevent the detrimental accumulation of reactive oxygen species in plants.

Preferred Offer as a Method in Competitive Bidding

The objective of this master’s thesis was to find means and measures by which an industrial manufacturing company could find cost-competitive solutions in a price-driven market situation. Initially, it was essential to find individual high customer value spots from the offering. The study addressed this in an innovative way by providing the desired information for the entire range of offering. The research was carried out using the constructivist approach method. Firstly, the project and solution marketing literature was reviewed in order to establish an overview of the processes and strategies involved. This information was then used in conjunction with the company’s specific offering data to conduct a construction. This construction can be used in various functions within the target company to streamline and optimize the specifications into so-called “preferred offers”. The study also presents channels and methods with which to exploit the construction in practice in the target company. The study aimed to bring concrete improvements in competitiveness and profitability. One result of this study was the creation of a training material for internal use. This material is now used in several countries to inform and present to the staff the cost-competitive aspects of the target company’s offering.

Information exchange and disruption risk in multimodal maritime supply chains

Supply chains are becoming increasingly dependent on information ex-change in today’s world, and any disruption can cause severe repercus-sions to the flow of materials in the chain. The speed, accuracy and amount of information are key factors. The aim in this thesis is to address a gap in the research by focusing on information exchange and the risks related to it in a multimodal wood supply chain operating between the Baltic States and Finland. The study involved interviewing people engaged in logistics management in the supply chain in question. The main risk the interviewees identified arose from the sea logistics system, which held a lot of different kinds of information. The threat of breakdown in the Internet connection was also found to hinder the operations significantly. A vulnerability analysis was carried out in order to identify the main actors and channels of infor-mation flow in the supply chain. The analysis revealed that the most important and therefore most vulnerable information-exchange channels were those linking the terminal superintendent, the operative managers and the mill managers. The study gives a holistic picture of the investigated supply chain. Information-exchange-related risks varied greatly. One of the most frequently mentioned was the risk of information inaccuracy, which was usually due to the fact that those in charge of the various functions did not fully understand the consequences for the entire chain.

Paperikoneen toimituskonseptin muutos strategisena kilpailutekijänä

2000-luvulla paperikoneiden kustannuskilpailukykyä on parannettu jatkuvasti, mutta se ei ole ollut riittävää. Tarve muutoksiin havaitaan kilpailukyvyn puutteena vuosina 2007–2008. Eräänä hankkeena on paperikoneen suunnitteleminen ja valmistaminen kopiokonseptikoneena, jossa toimitusmoduulina on paperikone perälaatikolta rullaimelle. Moduulikonsepti on toimintatapa, jossa paperikone tuotteistetaan rakenneryhmien ja laitteiden osalta tietyn ominaisuuden mukaan koko paperikonelinjassa. Paperikone rakentuisi sovituista moduulipalikoista. Moduulikonseptitavassa paperikone suunnitellaan ja toteutetaan aina malliaineiston pohjalta kaikissa rakenneryhmissä. Työssä on tarkoitus vertailla kopiokonsepti- ja moduulikonseptimallia. Kaksi tutkimustyön pääkysymystä käsittelee ulkoista kilpailukykyä ja yrityksen sisäistä tehokkuutta valmistaa paperi- ja kartonkikoneita kopiokonsepti- tai moduulikonseptimallilla näkökulmana pitkäaikainen kilpailuetu. Tutkimustulokset selvitettiin Kamenskyn kehittämällä yrityksen strategisen arkkitehtuurin mallilla. Sisäiset ja ulkoiset toiminnot analysoitiin. Ulkoisen ja sisäisen analyysin pohjalta muodostettiin yhdistetty näkemys, synteesianalyysi, joka vastaa työn tavoitteisiin, kahteen pääkysymykseen sekä alakysymyksiin. Kopiokonsepti ei ole ratkaisu pitkäaikaiseen kilpailukykyyn, koska jokainen paperilaji ja konekoko tarvitsevat oman kopiomallinsa. Nykyiset henkilöresurssit eivät tule riittämään näihin koneisiin tarvittavien dokumenttien luomiseen ja ylläpitoon. Suunnittelun perustehtävä muuttuisi projektisuunnittelusta kopiomallien suunnitteluksi. Moduulikonseptilla saavutetaan kaikki ne edut, joita kopiokonseptilla on tavoiteltu, mukaan lukien nimikkeiden uudelleenkäyttö. Moduulikonseptilla voidaan toteuttaa kaikki nykyiset ja tulevat paperikoneet ja paperilajit. Vuosittain saatavissa oleva määrä on 1,5–2,5 kopiokonseptipaperikonetta. Moduulikonseptimallia on saatavissa sama määrä.

Creating possibilities for collective creativity : Brokerage Functions in Practice-Based Innovation

In the network era, creative achievements like innovations are more and more often created in interaction among different actors. The complexity of today‘s problems transcends the individual human mind, requiring not only individual but also collective creativity. In collective creativity, it is impossible to trace the source of new ideas to an individual. Instead, creative activity emerges from the collaboration and contribution of many individuals, thereby blurring the contribution of specific individuals in creating ideas. Collective creativity is often associated with diversity of knowledge, skills, experiences and perspectives. Collaboration between diverse actors thus triggers creativity and gives possibilities for collective creativity. This dissertation investigates collective creativity in the context of practice-based innovation. Practice-based innovation processes are triggered by problem setting in a practical context and conducted in non-linear processes utilising scientific and practical knowledge production and creation in cross-disciplinary innovation networks. In these networks diversity or distances between innovation actors are essential. Innovation potential may be found in exploiting different kinds of distances. This dissertation presents different kinds of distances, such as cognitive, functional and organisational which could be considered as sources of creativity and thus innovation. However, formation and functioning of these kinds of innovation networks can be problematic. Distances between innovating actors may be so great that a special interpretation function is needed – that is, brokerage. This dissertation defines factors that enhance collective creativity in practice-based innovation and especially in the fuzzy front end phase of innovation processes. The first objective of this dissertation is to study individual and collective creativity at the employee level and identify those factors that support individual and collective creativity in the organisation. The second objective is to study how organisations use external knowledge to support collective creativity in their innovation processes in open multi-actor innovation. The third objective is to define how brokerage functions create possibilities for collective creativity especially in the context of practice-based innovation. The research objectives have been studied through five substudies using a case-study strategy. Each substudy highlights various aspects of creativity and collective creativity. The empirical data consist of materials from innovation projects arranged in the Lahti region, Finland, or materials from the development of innovation methods in the Lahti region. The Lahti region has been chosen as the research context because the innovation policy of the region emphasises especially the promotion of practice-based innovations. The results of this dissertation indicate that all possibilities of collective creativity are not utilised in internal operations of organisations. The dissertation introduces several factors that could support collective creativity in organisations. However, creativity as a social construct is understood and experienced differently in different organisations, and these differences should be taken into account when supporting creativity in organisations. The increasing complexity of most potential innovations requires collaborative creative efforts that often exceed the boundaries of the organisation and call for the involvement of external expertise. In practice-based innovation different distances are considered as sources of creativity. This dissertation gives practical implications on how it is possible to exploit different kinds of distances knowingly. It underlines especially the importance of brokerage functions in open, practice-based innovation in order to create possibilities for collective creativity. As a contribution of this dissertation, a model of brokerage functions in practice-based innovation is formulated. According to the model, the results and success of brokerage functions are based on the context of brokerage as well as the roles, tasks, skills and capabilities of brokers. The brokerage functions in practice-based innovation are also possible to divide into social and cognitive brokerage.

The Forms and Functions of Multilingual Practices in Early Modern School Drama from the King‟s School, Canterbury

Käsittelen tutkimuksessani monikielisyyden ilmenemistä Canterburyn katedraalikoulun oppilaiden 1600-luvun loppupuoliskolla esittämissä näytelmissä, jotka löytyvät käsikirjoituksesta Lit.Ms.E41 (Canterburyn katedraalin arkisto). Tämä käsikirjoitus sisältää puheita ja näytelmiä, joiden kielinä ovat englanti, latina ja vähemmissä määrin myös kreikka. Useissa näytelmissä esiintyy koodinvaihtoa näiden kielten välillä, ja tutkielmassani selvitän, millaisia syntaktisia ilmenemismuotoja ja pragmaattisia merkityksiä koodinvaihdolla on. Teoreettinen viitekehykseni on yhdistelmä filologista ja lingvististä lähestymistapaa. Olen sisällyttänyt tutkielmaani aiemman koodinvaihdon tutkimuksen lisäksi Brownin ja Levinsonin kohteliaisuusteorian, jonka avulla erityisesti puhujien välisiin sosiaalisiin suhteisiin liittyviä koodinvaihdon funktioita voidaan luokitella. Koska historiallinen koodinvaihto on tutkimusaiheena vielä melko tuore, käsittelen perusteellisesti erilaisia metodologisia ratkaisuja. Valitsemani metodi yhdistää perinteisen filologisen lähiluvun pragmaattiseen analyysiin, jonka kautta työssäni vaikuttavat muun muassa rationaalisuuden ja empatian käsitteet. Analyysini perusteella kävi ilmi, että erityisen yleinen koodinvaihdon funktio on mahdollistaa intertekstuaalisuus, jolla edelleen voidaan ilmaista esimerkiksi solidaarisuutta eli sosiaalista läheisyyttä tai loukata puhuteltavaa. Solidaarisuus oli myös ilman intertekstuaalisuutta yleinen koodinvaihdon funktio. Näiden lisäksi koodinvaihdon funktioita olivat muun muassa kasvoja uhkaavat teot, eufemismit, stilistiset efektit sekä diskurssin avustaminen. Syntaktisten ilmenemismuotojen osalta keskeisin havainto oli, että koodinvaihdon ja lainaamisen erottaminen ei ole tarpeellista tai edes kannattavaa kaikissa tilanteissa. Lisäksi voitiin todeta, että valittu metodi soveltui hyvin aineiston analysoimiseen, ja sitä tulisi soveltaa mahdollisuuksien mukaan laajempaan materiaaliin sekä muiden pragmaattisten ilmiöiden tutkimiseen.

TR(i)P, TR(i)P, hooray : new functions for TRPC2 and TRPC3

Kalciumjonen påverkar många aspekter av cellbiologi, från fertiliseringen av äggcellen till tillväxt och differentiering av alla typer av celler. Störningar i hur kalciumjonerna transporteras in och friges i cellerna kan ha stor betydelse för hur sjukdomar framskrider. På grund av detta är det viktigt att studera hur kalciumtransportörer såsom kalciumkanaler fungerar och hur de påverkar cellernas funktioner. I avhandlingen har klassiska transient receptorpotential (TRPC) katjonkanaler studerats. Dessa kanaler är permeabla för kalcium och aktiveras nedströms av G-proteinkopplade receptorer. Resultaten som presenteras i avhandlingen visar på nya funktioner för TRPC2- och TRPC3-kanalerna. Utöver TRPC3-kanalens roll i plasmamembranen, där den medverkar i receptorreglerat kalciuminflöde, tyder våra resultat på att TRPC3 har en potentiell intracellulär roll. Vid överuttryck av kanalen lokaliserade kanalen till endoplasmatiska nätverket där kanalen friger intracellulärt kalcium. TRPC2 har en viktig funktion i möss där kanalen reglerar hur djuret reagerar på feromoner. Våra resultat tyder på att TRPC2 är involverad i autokrin sfingosin-1-fosfat (S1P)-signalering. S1P som produceras i cellerna transporterades ut från cellerna varpå det aktiverade S1P2-receptorer på plasmamembranen. Diacylglycerol som bildas som en följd av aktivering av S1P2-receptorn aktiverade i sin tur inflöde av extracellulärt kalcium. Våra resultat indikerar att TRPC2 är kanalen som förmedlar detta kalciuminflöde. I sköldkörtelceller studerades nedströms effekter för TRPC2. Kanalen reglerade negativt cAMP-produktionen i cellerna vilket hämmar extracellulärt signalreglerat kinas 1/2 (ERK1/2). När uttrycket för TRPC2 minskades i cellerna, ökades produktionen av cAMP och fosforyleringen av ERK1/2, vilket resulterade i ökat uttryck för receptorn för sköldkörtelstimulerande hormon. Slutligen, presenterar vi resultat som tyder på att TRPC2 är viktigt för sekretion av prekursorn till sköldkörtelhormon.

Integration in project business : mechanisms for integrating customers and the project network during the life-cycle of industrial projects

This thesis focuses on integration in project business, i.e. how projectbased companies organize their product and process structures when they deliver industrial solutions to their customers. The customers that invest in these solutions run their businesses in different geographical, political and economical environments, which should be acknowledged by the supplier when providing solutions comprising of larger and more complex scopes than previously supplied to these customers. This means that the suppliers are increasing their supply range by taking over some of the activities in the value chain that have traditionally been handled by the customer. In order to be able to provide the functioning solutions, including more engineering hours, technical equipment and a wider project network, a change is needed in the mindset in order to be able to carry out and take the required responsibility that these new approaches bring. For the supplier it is important to be able to integrate technical products, systems and services, but the supplier also needs to have the capabilities to integrate the cross-functional organizations and departments in the project network, the knowledge and information between and within these organizations and departments, along with inputs from the customer into the product and process structures during the lifecycle of the project under development. Hence, the main objective of this thesis is to explore the challenges of integration that industrial projects meet, and based on that, to suggest a concept of how to manage integration in project business by making use of integration mechanisms. Integration is considered the essential process for accomplishing an industrial project, whereas the accomplishment of the industrial project is considered to be the result of the integration. The thesis consists of an extended summary and four papers, that are based on three studies in which integration mechanisms for value creation in industrial project networks and the management of integration in project business have been explored. The research is based on an inductive approach where in particular the design, commissioning and operations functions of industrial projects have been studied, addressing entire project life-cycles. The studies have been conducted in the shipbuilding and power generation industries where the scopes of supply consist of stand-alone equipment, equipment and engineering, and turnkey solutions. These industrial solutions include demanding efforts in engineering and organization. Addressing the calls for more studies on the evolving value chains of integrated solutions, mechanisms for inter- and intra-organizational integration and subsequent value creation in project networks have been explored. The research results in thirteen integration mechanisms and a typology for integration is proposed. Managing integration consists of integrating the project network (the supplier and the sub-suppliers) and the customer (the customer’s business purpose, operations environment and the end-user) into the project by making use of integration mechanisms. The findings bring new insight into research on industrial project business by proposing integration of technology and engineering related elements with elements related to customer oriented business performance in contemporary project environments. Thirteen mechanisms for combining products and the processes needed to deliver projects are described and categorized according to the impact that they have on the management of knowledge and information. These mechanisms directly relate to the performance of the supplier, and consequently to the functioning of the solution that the project provides. This thesis offers ways to promote integration of knowledge and information during the lifecycle of industrial projects, enhancing the development towards innovative solutions in project business.

Influence of distal ileum exclusion on hepatic and renal functions in presence of extrahepatic cholestasis

OBJECTIVE: To verify whether the ileal exclusion interferes with liver and kidney functional changes secondary to extrahepatic cholestasis.METHODS: We studied 24 rats, divided into three groups with eight individuals each: Group 1 (control), Group 2 (ligation of the hepatic duct combined with internal biliary drainage), and Group 3 (bile duct ligation combined with internal biliary drainage and exclusion of the terminal ileum). Animals in Group 1 (control) underwent sham laparotomy. The animals of groups 2 and 3 underwent ligation and section of the hepatic duct and were kept in cholestasis for four weeks. Next, they underwent an internal biliary bypass. In Group 3, besides the biliary-enteric bypass, we associated the exclusion of the last ten centimeters of the terminal ileum and carried out an ileocolic anastomosis. After four weeks of monitoring, blood was collected from all animals of the three groups for liver and kidney biochemical evaluation (albumin, ALT, AST, direct and indirect bilirubin, alkaline phosphatase, cGT, creatinine and urea).RESULTS: there were increased values of ALT, AST, direct bilirubin, cGT, creatinine and urea in rats from Group 3 (p < 0.05).CONCLUSION: ileal exclusion worsened liver and kidney functions in the murine model of extrahepatic cholestasis, being disadvantageous as therapeutic procedure for cholestatic disorders.

Localization, Frequency, and Functions of Filled Pauses: Five American Politicians’ Use of er and erm in the Talk Show Larry King Live

Tämän pro gradu– tutkielman tavoitteena oli testata täytettyjen taukojen (er ja erm) esiintymistiheyttä, sijaintia kieliopillisessa rakenteessa sekä funktioita Kjellmerin (2003) korpus-tutkimuksessa. Materiaalina käytin viiden yhdysvaltalaisen poliitikon puhetta keskusteluohjelmasta Larry King Live. Tutkimuksessani sovelsin Kjellmerin tutkimusmenetelmiä, joita muokkasin huomattavasti suppeampaan materiaaliini sopiviksi. Lähestymistapani oli täten induktiivinen toisin kuin testatussa tutkimuksessa. Materiaalini oli tarkoituksellisesti rajattu, sillä halusin selvittää, kuvaavatko Kjellmerin laajaan materiaaliin perustuvat tutkimustulokset myös täytettyjen taukojen käyttöä suppeammassa materiaalissa. Materiaalini (kokonaisuudessaan 101 minuuttia) transkriboin ortografisesti. Analyysissäni arvioin täytettyjen taukojen esiintymistiheyden puhujakohtaisesti ja koko ryhmälle suhteuttamalla täytettyjen taukojen lukumäärän kokonaissanamäärään. Tämän jälkeen tein perinteisen kielioppianalyysin rakenteista, joita edeltää tai joissa esiintyy täytetty tauko, ja täytettyjen taukojen sijainnin perusteella luokittelin ne sana-, lauseke-, ja lausetasolle. Lopuksi analysoin täytettyjen taukojen käyttöä soveltaen Kjellmerin ehdottamia funktioita (hesitaatio, vuorottelujäsennyksen merkitseminen, huomion herättäminen ja kontaktin luominen, korostus ja korjaus) ja niiden piirteitä omaan materiaaliini. Tutkimukseni perusteella täytetyt tauot esiintyvät tutkitun viiden poliitikon puheessa suhteellisen usein. Puhujakohtaiset eroavaisuudet olivat kuitenkin huomattavat. Kieliopillisen luokitteluni mukaan sana-, lauseke- ja lausetasot eivät täysin kuvaa täytettyjen taukojen sijoittumista, sillä täytetyt tauot edelsivät mm. määre-lauseita, jotka eivät vastaa lausetasoa englannin kielessä. Materiaalini funktioanalyysi osoitti, että täytetyt tauot yleensä vastaavat yhtä tai useampaa Kjellmerin ehdottamaa funktioita. Lisäksi tutkimukseni mukaan täytetyillä tauoilla on ainakin yksi rakenteellinen funktio. Analyysini perusteella Kjellmerin tutkimustulokset ovat siis pääosin sovellettavissa suppeampaan materiaaliin. Puutteiksi hänen tutkimuksessaan osoittautuivat funktioanalyysille tärkeän kontekstuaalisen informaation puute sekä keskittyminen täytettyihin taukoihin, jotka esiintyvät vain tietyissä kielioppirakenteissa. Yleisesti voin tutkimukseni pohjalta todeta, että täytetyt tauot ovat vielä vajaasti tunnettuja ja että kieliopillisen sijoituksen ja funktioiden lisätutkimus on tarpeellista.

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.

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.

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.