Methods for construction and analysis of computational models in systems biology : applications to the modelling of the heat shock response and the self-assembly of intermediate filaments

Systems biology is a new, emerging and rapidly developing, multidisciplinary research field that aims to study biochemical and biological systems from a holistic perspective, with the goal of providing a comprehensive, system- level understanding of cellular behaviour. In this way, it addresses one of the greatest challenges faced by contemporary biology, which is to compre- hend the function of complex biological systems. Systems biology combines various methods that originate from scientific disciplines such as molecu- lar biology, chemistry, engineering sciences, mathematics, computer science and systems theory. Systems biology, unlike “traditional” biology, focuses on high-level concepts such as: network, component, robustness, efficiency, control, regulation, hierarchical design, synchronization, concurrency, and many others. The very terminology of systems biology is “foreign” to “tra- ditional” biology, marks its drastic shift in the research paradigm and it indicates close linkage of systems biology to computer science. One of the basic tools utilized in systems biology is the mathematical modelling of life processes tightly linked to experimental practice. The stud- ies contained in this thesis revolve around a number of challenges commonly encountered in the computational modelling in systems biology. The re- search comprises of the development and application of a broad range of methods originating in the fields of computer science and mathematics for construction and analysis of computational models in systems biology. In particular, the performed research is setup in the context of two biolog- ical phenomena chosen as modelling case studies: 1) the eukaryotic heat shock response and 2) the in vitro self-assembly of intermediate filaments, one of the main constituents of the cytoskeleton. The range of presented approaches spans from heuristic, through numerical and statistical to ana- lytical methods applied in the effort to formally describe and analyse the two biological processes. We notice however, that although applied to cer- tain case studies, the presented methods are not limited to them and can be utilized in the analysis of other biological mechanisms as well as com- plex systems in general. The full range of developed and applied modelling techniques as well as model analysis methodologies constitutes a rich mod- elling framework. Moreover, the presentation of the developed methods, their application to the two case studies and the discussions concerning their potentials and limitations point to the difficulties and challenges one encounters in computational modelling of biological systems. The problems of model identifiability, model comparison, model refinement, model inte- gration and extension, choice of the proper modelling framework and level of abstraction, or the choice of the proper scope of the model run through this thesis.

Mapping of QTLs related with wood quality and developmental characteristics in hybrids (Eucalyptus grandis x Eucalyptus urophylla)

The present work aimed to characterize and identify QTLs for wood quality and growth traits in E. grandis x E. urophylla hybrids. For this purpose a RAPD linkage map was developed for the hybrids (LOD=3 and r=0.40) containing 52 markers and 12 linkage groups. Traits related to wood quality and growth were evaluated in the QTL analyses. QTL analyses were performed using chi-square tests, single-marker, interval mapping and composite interval mapping analyses. All approaches led to the identification of similar QTLs associated with wood density, cellulose pulp yield and percentage of extractives, which were detected and confirmed by both the interval mapping and composite interval mapping methodologies. Some QTLs regions were confirmed only by the composite interval mapping methodology: percentage of soluble lignin, percentage of insoluble lignin, CBH and total height. Overlapping QTLs regions were detected, and these, can be the result of major genes involved in the regulation and control of the growth traits by epistatic interactions. In order to evaluate the effect of early selection using RAPD molecular data, molecular markers adjacent to QTLs were used genotype selection. The analysis of selection differential values suggests that for all the traits the phenotypic selection at seven years should generate larger genetic gains than early selection assisted by molecular markers and the combination of the strategies should elevate the selection efficiency.

Multivariate statistical analysis to support the minimum streamflow regionalization

ABSTRACT This study aimed to develop a methodology based on multivariate statistical analysis of principal components and cluster analysis, in order to identify the most representative variables in studies of minimum streamflow regionalization, and to optimize the identification of the hydrologically homogeneous regions for the Doce river basin. Ten variables were used, referring to the river basin climatic and morphometric characteristics. These variables were individualized for each of the 61 gauging stations. Three dependent variables that are indicative of minimum streamflow (Q7,10, Q90 and Q95). And seven independent variables that concern to climatic and morphometric characteristics of the basin (total annual rainfall – Pa; total semiannual rainfall of the dry and of the rainy season – Pss and Psc; watershed drainage area – Ad; length of the main river – Lp; total length of the rivers – Lt; and average watershed slope – SL). The results of the principal component analysis pointed out that the variable SL was the least representative for the study, and so it was discarded. The most representative independent variables were Ad and Psc. The best divisions of hydrologically homogeneous regions for the three studied flow characteristics were obtained using the Mahalanobis similarity matrix and the complete linkage clustering method. The cluster analysis enabled the identification of four hydrologically homogeneous regions in the Doce river basin.

Diagnóstico e manejo do câncer gástrico familiar

Embora a neoplasia gástrica maligna constitua-se numa das principais causas de mortalidade por câncer, as bases moleculares desta enfermidade permanecem ainda pouco compreendidas. Recentemente, a identificação de lesões gástricas difusas ocorrendo em famílias com padrão de transmissão tipicamente mendeliano, resultou no achado de um evento molecular único: mutações no gene da caderina-E. Esta entidade foi denominada câncer gástrico hereditário. Apesar de rara, a sua identificação deve ser suspeitada na prática clínica, já que é possível detectar-se casos precoces de câncer nestas famílias em alto risco. Como a análise mutacional do gene da caderina-E só é realizada em pouquíssimos centros no mundo, é importante tentar identificar estas famílias por meio de critérios de fácil acesso para qualquer profissional de saúde. Este trabalho comenta os critérios sugeridos pelo International Gastric Cancer Linkage Consortium (IGCLC), propostos em 1999, além de tentar estabelecer algumas diretrizes para o rastreamento das pessoas em risco.

Baixo peso ao nascer em coorte de recém-nascidos em Goiânia-Brasil no ano de 2000

OBJETIVO: analisar o peso ao nascer da coorte de recém-nascidos do ano 2000, em Goiânia, pela determinação do coeficiente de mortalidade e probabilidade de sobrevivência neonatal, estratificados por categorias de peso ao nascer e, ainda, pela identificação dos fatores associados ao baixo peso ao nascer (BPN). MÉTODOS: estudo de coorte retrospectivo, constituído por linkage dos arquivos do SIM (Sistema de Informações de Mortalidade) e do SINASC (Sistema de Informações de Nascimentos). Foram calculados coeficientes de mortalidade neonatal para as categorias de peso ao nascer e construído um gráfico de probabilidades de sobrevivência neonatal por meio de análise de regressão linear. Foram identificados fatores de risco para o BPN mediante análise univariada (RR) e regressão logística, considerando-se nível de significância de 5%. RESULTADOS: a incidência de BPN foi de 6,9%, sendo que 140 (66,8%) óbitos neonatais ocorreram nesse grupo. Trinta por cento dos óbitos se deram na categoria de peso entre 1.500-2.500 g. Os fatores identificados como de risco para o BPN foram: prematuridade, presença de malformações congênitas, mães com idade em extremos reprodutivos, residência na região noroeste do município, baixo número de consultas no pré-natal, parto em hospital público e sexo feminino. CONCLUSÃO: a incidência de BPN foi semelhante aos países desenvolvidos e os coeficientes de mortalidade neonatal, por categoria de peso, aquém dos encontrados naqueles países. Os resultados encontrados orientam atenção para: prematuridade, hospitais públicos e região noroeste de Goiânia.

Acquisition target selection of a serial acquirer : case KONE Oyj

Acquisitions are a way for a company to grow, enter new geographical areas, buy out competition or diversify. Acquisitions have recently grown in both size and value. Despite of this, only approximately 25 percent of acquisitions reach their targets and goals. Companies making serial acquisitions seem to be exceptionally successful and succeed in the majority of their acquisitions. The main research question this study aims to answer is: “What issues impact the selection of acquired companies from the point of view of a serial acquirer? The main research question is answered through three sub questions: “What is a buying process for a serial acquirer like?”, “What are the motives for a serial acquirer to buy companies?” and “What is the connection between company strategy and serial acquisitions?”. The case company KONE is a globally operating company which mainly produces and maintains elevators and escalators. Its headquarter is located in Helsinki, Finland. The company has a long history of making acquisitions and does 20- 30 acquisitions a year. By a key person interview, the acquisition process of the case company is compared with the literature about successful serial acquirers. The acquisition motives in this case are reflected upon three of the acquisition motive theories by Trautwein: efficiency theory, monopoly theory and valuation theory. The linkage between serial acquisitions and company strategy is studied through the key person interview. The main research findings are that the acquisition process of KONE is compatible with a successful acquisition process recognized in literature (RAID). This study confirms the efficiency theory as an acquisition motive and more closely the operational synergies. The monopoly theory can only vaguely be supported by this study, but cannot be totally rejected because of the structure of the industry. The valuation theory does not get any support in this study and can therefore be rejected. The linkage between company strategy and serial acquisitions is obvious and making acquisitions can be seen as growth strategy and a part of other company strategies.

Tietoperusteinen päätöksenteon prosessi

Yhteiskunnan tietovaltaistumisen seurauksena ovat julkisten organisaati-oiden toimintaympäristöt monimutkaistuneet ja luoneet haasteita tiedon käyttämiselle päätöksenteon prosessissa sekä sen tukena. Tämän tutki-muksen aiheena oleva tietoon perustuva päätöksenteon prosessi sekä sen vaiheiden sujuvuus ovat strategisesti merkittäviä kaikessa päätöksen-teossa. Tutkimus toteutettiin kvalitatiivisena tutkimuksena, jonka empiirinen osuus suoritettiin tapaustutkimuksena kunnallisessa organisaatiossa. Haastatteluaineisto kerättiin kunnallisen päätöksenteon ylintä päätäntävaltaa käyttäviltä kaupunginvaltuutetuilta. Tutkimuksen mukaan tietoperusteisen päätöksenteon prosessin vaiheita ovat tavoitteen ja päämäärän asettaminen, vaihtoehtojen asettaminen, vaihtoehtojen ja niiden vaikutuksien arvioiminen, päätöksen tekeminen sekä päätöksen vaikutuksien arvioiminen. Tiedon käyttäminen keskittyy vaihtoehtojen asettamiseen sekä vaihtoehtojen ja niiden vaikutuksien arvioimiseen tiedon hankkimisen ja hyödyntämisen kautta. Monitahoisuus ja -ulotteisuus sekä subjektiivisuus ja kontekstisidonnaisuus vaikuttavat merkittävästi tietoperusteisen päätöksenteon prosessin vaiheisiin.

The genetics of behaviour and other adaptive traits in nine-spined sticklebacks (Pungitius pungitius)

One of the main goals in current evolutionary biology research is to identify genes behind adaptive phenotypic variations. The advances in genomic technologies have made it possible to identify genetic loci behind these variations, also concerning non-model species. This thesis investigates the genetics of the behaviour and other adaptive traits of the nine-spined stickleback (Pungitius pungitius) through the application of different genetic approaches. Fennoscandian nine-spined stickleback populations express large phenotypical differences especially in behaviour, life –history traits and morphology. However the underlying genetic bases for these phenotypical differences have not been studied in detail. The results of the project will lay the foundation for further genetics studies and provide valuable information for our understanding of the genetics of the adaptive divergence of the nine-spined stickleback. A candidate gene approach was used to develop microsatellite markers situating close to candidate genes for behaviour in the nine-spined stickleback. Altogether 13 markers were developed and these markers were used in the subsequent studies with the anonymous random markers and physiologically important gene markers which are already currently available for nine-spined sticklebacks. It was shown that heterozygosity correlated with behaviour in one of the marine nine-spined stickleback populations but with contrasting effects: correlations with behaviour were negative when using physiological gene markers and positive with random markers. No correlation was found between behavioural markers and behaviour. From the physiological gene markers, a strong correlation was found between osmoregulation-related gene markers and behaviour. These results indicate that both local (physiological) and general (random) effects are important in the shaping of behaviour and that heterozygosity– behaviour correlations are population dependent. In this thesis a second linkage map for nine-spined sticklebacks was constructed. Compared to the earlier nine-spined stickleback linkage map, genomic rearrangements were observed between autosomal (LG7) and sex-determing (LG12) linkage groups. This newly constructed map was used in QTL mapping studies in order to locate genomic regions associated with pelvic structures, behaviour and body size/growth. One major QTL was found for pelvic structures and Pitx1 gene was related to these traits as was predicted from three-spined stickleback studies, but this was in contrast to earlier nine-spined stickleback study. The QTL studies also revealed that behaviour and body size/growth were genetically more complex by having more QTL than pelvic traits. However, in many cases, pelvic structure, body size/growth and behaviour were linked to similar map locations indicating possible pleiotropic effects of genes locating in these QTL regions. Many of the gene related markers resided in the QTL area. In the future, studying these possible candidate genes in depth might reveal the underlying mechanism behind the measured traits.

Tooth-Coil Permanent Magnet Synchronous Machine Design for Special Applications

This doctoral thesis presents a study on the design of tooth-coil permanent magnet synchronous machines. The electromagnetic properties of concentrated non-overlapping winding permanent magnet synchronous machines, or simply tooth-coil permanent magnet synchronous machines (TC-PMSMs), are studied in details. It is shown that current linkage harmonics play the deterministic role in the behavior of this type of machines. Important contributions are presented as regards of calculation of parameters of TC-PMSMs,particularly the estimation of inductances. The current linkage harmonics essentially define the air-gap harmonic leakage inductance, rotor losses and localized temporal inductance variation. It is proven by FEM analysis that inductance variation caused by the local temporal harmonic saturation results in considerable torque ripple, and can influence on sensorless control capabilities. Example case studies an integrated application of TC-IPMSMs in hybrid off-highway working vehicles. A methodology for increasing the efficiency of working vehicles is introduced. It comprises several approaches – hybridization, working operations optimization, component optimization and integration. As a result of component optimization and integration, a novel integrated electro-hydraulic energy converter (IEHEC) for off-highway working vehicles is designed. The IEHEC can considerably increase the operational efficiency of a hybrid working vehicle. The energy converter consists of an axial-piston hydraulic machine and an integrated TCIPMSM being built on the same shaft. The compact assembly of the electrical and hydraulic machines enhances the ability to find applications for such a device in the mobile environment of working vehicles.Usage of hydraulic fluid, typically used in working actuators, enables direct-immersion oil cooling of designed electrical machine, and further increases the torque- and power- densities of the whole device.

Escape in a nonideal electro-mechanical system

In this work a particular system is investigated consisting of a pendulum whose point of support is vibrated along a horizontal guide by a two bar linkage driven from a DC motor, considered as a limited power source. This system is nonideal since the oscillatory motion of the pendulum influences the speed of the motor and vice-versa, reflecting in a more complicated dynamical process. This work comprises the investigation of the phenomena that appear when the frequency of the pendulum draws near a secondary resonance region, due to the existing nonlinear interactions in the system. Also in this domain due to the power limitation of the motor, the frequency of the pendulum can be captured at resonance modifying completely the final response of the system. This behavior is known as Sommerfeld effect and it will be studied here for a nonlinear system.

Design and testing of an armature-reaction-compensated permanent magnet synchronous generator for island operation

At present, permanent magnet synchronous generators (PMSGs) are of great interest. Since they do not have electrical excitation losses, the highly efficient, lightweight and compact PMSGs equipped with damper windings work perfectly when connected to a network. However, in island operation, the generator (or parallel generators) alone is responsible for the building up of the network and maintaining its voltage and reactive power level. Thus, in island operation, a PMSG faces very tight constraints, which are difficult to meet, because the flux produced by the permanent magnets (PMs) is constant and the voltage of the generator cannot be controlled. Traditional electrically excited synchronous generators (EESGs) can easily meet these constraints, because the field winding current is controllable. The main drawback of the conventional EESG is the relatively high excitation loss. This doctoral thesis presents a study of an alternative solution termed as a hybrid excitation synchronous generator (HESG). HESGs are a special class of electrical machines, where the total rotor current linkage is produced by the simultaneous action of two different excitation sources: the electrical and permanent magnet (PM) excitation. An overview of the existing HESGs is given. Several HESGs are introduced and compared with the conventional EESG from technical and economic points of view. In the study, the armature-reaction-compensated permanent magnet synchronous generator with alternated current linkages (ARC-PMSG with ACL) showed a better performance than the other options. Therefore, this machine type is studied in more detail. An electromagnetic design and a thermal analysis are presented. To verify the operation principle and the electromagnetic design, a down-sized prototype of 69 kVA apparent power was built. The experimental results are demonstrated and compared with the predicted ones. A prerequisite for an ARC-PMSG with ACL is an even number of pole pairs (p = 2, 4, 6, …) in the machine. Naturally, the HESG technology is not limited to even-pole-pair machines. However, the analysis of machines with p = 3, 5, 7, … becomes more complicated, especially if analytical tools are used, and is outside the scope of this thesis. The contribution of this study is to propose a solution where an ARC-PMSG replaces an EESG in electrical power generation while meeting all the requirements set for generators given for instance by ship classification societies, particularly as regards island operation. The maximum power level when applying the technology studied here is mainly limited by the economy of the machine. The larger the machine is, the smaller is the efficiency benefit. However, it seems that machines up to ten megawatts of power could benefit from the technology. However, in low-power applications, for instance in the 500 kW range, the efficiency increase can be significant.

Internationalization of small and medium-sized enterprises and impact of institutions on international entrepreneurship in emerging economies: the case of Russia

The doctoral study presents a comprehensive analysis of the impact of the institutional environment on the internationalization-based growth strategic choices of small and mediumsized enterprises (SMEs) in emerging economies. In responding to the calls for more research on institutions and international entrepreneurship, this dissertation extends the linkages between the two to the context of emerging economies. The study presents a comprehensive analysis of institutional challenges and their impact on the internationalization of SMEs in emerging economies, particularly in Russia. The research contributes to the adoption of the institution-based view in international entrepreneurship. The dissertation is presented through five research papers. Based on primary and secondary data, the study categorizes the possible sources of institutional influences on internationalization and empirically tests their impact by applying a method triangulation research design. The result of the conducted research is a proposed theoretical model of the institutional impact on the internationalization of SMEs in emerging economies. The model is specifically focused on the growth stage of the entrepreneurial process and considers only its internationalization facet. The research identifies and provides empirical support for the existence of a positive influence of a transparent and supportive regulatory environment, an institutionalized pool of general business knowledge, and collectivistic value orientation on the proclivity of SMEs to internationalize. A level of appreciation of entrepreneurial initiatives in home country and a greater positive institutional gap provide a positive impact on the international performance of SMEs. The research provides contextualized knowledge of the institutional impact on the internationalization of SMEs in Russia. The obtained results present theoretical value in terms of showing how the environmental conditions effect the entrepreneurial internationalization-based growth in emerging economies, providing the methodological insights into the measurement of the institutional effects, and empirically contextualizing the linkage between institutions and internationalization in the Russian business environment. The research also provides value for the business and policy making stakeholders by identifying ways of utilizing the conditions in the external institutional environment.

Budgeting decision-making in Finnish municipalities

This master’s thesis examines budgeting decision-making in Finnish municipalities; an issue that has not received a lot of attention in the academic literature. Furthermore, this thesis investigates whether the current budgeting decision-making practices could be improved by using a new kind of budget decision-making tool that is based on presenting multiple investment or divestment alternatives simultaneously to the decision makers as a frontier, rather than one by one. In the empirical part of the thesis, the results from three case interviews are introduced in order to answer the research questions of the study. The empirical evidence of this thesis suggests that there is a need for the presented budgeting decision-making tool in Finnish municipalities. The current routine is seen as good even though the interviewees would warmly welcome the alternative method that would function as a linkage be-tween strategy and the budget. The results also indicate that even though municipalities are left with a lot of room in their budgeting decision-making routine, the routine closely, though not always purposely, follows given guidelines and legislation. The major problem in the current practices seems to be the lack of understanding, as the decision-makers find it hard fully to understand the multiplicative effects of the budget-related decisions.

Software and Code Finder: making research outputs visible

Poster at Open Repositories 2014, Helsinki, Finland, June 9-13, 2014

Comparative analysis of leaf cell-wall polysaccharides of Dialypetalanthus fuscescens and Bathysa meridionalis: evidence of biochemical similarities between Dialypetalanthaceae and Rubiaceae-Cinchonoideae

Dialypetalanthus fuscescens is an Amazonian endemic species with problematic taxonomic position. This neotropical rainforest tree belongs to the monospecific Dialypetalanthaceae. In the present work, we analysed the leaf cell-wall polysaccharide composition of Dialypetalanthus fuscescens and compared it to that of Bathysa meridionalis (Rubiaceae-Cinchonoideae). Glycosyl composition and glycosyl-linkage analysis indicated that both species have similar cell wall composition. Arabinogalactans were the major component of the pectic polysaccharides and xylans, although being reported in minor amounts in dicots, were found to be the predominant hemicellulosic polysaccharide in cell walls of both species. These findings are in agreement with previous data on cell wall composition reported for Rubiaceae and corroborate the current suggestion of the possible link between this family and Dialypetalanthaceae.