Development and application of computational methodologies in qualitative modeling

La présente thèse s'intitule "Développent et Application des Méthodologies Computationnelles pour la Modélisation Qualitative". Elle comprend tous les différents projets que j'ai entrepris en tant que doctorante. Plutôt qu'une mise en oeuvre systématique d'un cadre défini a priori, cette thèse devrait être considérée comme une exploration des méthodes qui peuvent nous aider à déduire le plan de processus regulatoires et de signalisation. Cette exploration a été mue par des questions biologiques concrètes, plutôt que par des investigations théoriques. Bien que tous les projets aient inclus des systèmes divergents (réseaux régulateurs de gènes du cycle cellulaire, réseaux de signalisation de cellules pulmonaires) ainsi que des organismes (levure à fission, levure bourgeonnante, rat, humain), nos objectifs étaient complémentaires et cohérents. Le projet principal de la thèse est la modélisation du réseau de l'initiation de septation (SIN) du S.pombe. La cytokinèse dans la levure à fission est contrôlée par le SIN, un réseau signalant de protéines kinases qui utilise le corps à pôle-fuseau comme échafaudage. Afin de décrire le comportement qualitatif du système et prédire des comportements mutants inconnus, nous avons décidé d'adopter l'approche de la modélisation booléenne. Dans cette thèse, nous présentons la construction d'un modèle booléen étendu du SIN, comprenant la plupart des composantes et des régulateurs du SIN en tant que noeuds individuels et testable expérimentalement. Ce modèle utilise des niveaux d'activité du CDK comme noeuds de contrôle pour la simulation d'évènements du SIN à différents stades du cycle cellulaire. Ce modèle a été optimisé en utilisant des expériences d'un seul "knock-out" avec des effets phénotypiques connus comme set d'entraînement. Il a permis de prédire correctement un set d'évaluation de "knock-out" doubles. De plus, le modèle a fait des prédictions in silico qui ont été validées in vivo, permettant d'obtenir de nouvelles idées de la régulation et l'organisation hiérarchique du SIN. Un autre projet concernant le cycle cellulaire qui fait partie de cette thèse a été la construction d'un modèle qualitatif et minimal de la réciprocité des cyclines dans la S.cerevisiae. Les protéines Clb dans la levure bourgeonnante présentent une activation et une dégradation caractéristique et séquentielle durant le cycle cellulaire, qu'on appelle communément les vagues des Clbs. Cet évènement est coordonné avec la courbe d'activation inverse du Sic1, qui a un rôle inhibitoire dans le système. Pour l'identification des modèles qualitatifs minimaux qui peuvent expliquer ce phénomène, nous avons sélectionné des expériences bien définies et construit tous les modèles minimaux possibles qui, une fois simulés, reproduisent les résultats attendus. Les modèles ont été filtrés en utilisant des simulations ODE qualitatives et standardisées; seules celles qui reproduisaient le phénotype des vagues ont été gardées. L'ensemble des modèles minimaux peut être utilisé pour suggérer des relations regulatoires entre les molécules participant qui peuvent ensuite être testées expérimentalement. Enfin, durant mon doctorat, j'ai participé au SBV Improver Challenge. Le but était de déduire des réseaux spécifiques à des espèces (humain et rat) en utilisant des données de phosphoprotéines, d'expressions des gènes et des cytokines, ainsi qu'un réseau de référence, qui était mis à disposition comme donnée préalable. Notre solution pour ce concours a pris la troisième place. L'approche utilisée est expliquée en détail dans le dernier chapitre de la thèse. -- The present dissertation is entitled "Development and Application of Computational Methodologies in Qualitative Modeling". It encompasses the diverse projects that were undertaken during my time as a PhD student. Instead of a systematic implementation of a framework defined a priori, this thesis should be considered as an exploration of the methods that can help us infer the blueprint of regulatory and signaling processes. This exploration was driven by concrete biological questions, rather than theoretical investigation. Even though the projects involved divergent systems (gene regulatory networks of cell cycle, signaling networks in lung cells), as well as organisms (fission yeast, budding yeast, rat, human), our goals were complementary and coherent. The main project of the thesis is the modeling of the Septation Initiation Network (SIN) in S.pombe. Cytokinesis in fission yeast is controlled by the SIN, a protein kinase signaling network that uses the spindle pole body as scaffold. In order to describe the qualitative behavior of the system and predict unknown mutant behaviors we decided to adopt a Boolean modeling approach. In this thesis, we report the construction of an extended, Boolean model of the SIN, comprising most SIN components and regulators as individual, experimentally testable nodes. The model uses CDK activity levels as control nodes for the simulation of SIN related events in different stages of the cell cycle. The model was optimized using single knock-out experiments of known phenotypic effect as a training set, and was able to correctly predict a double knock-out test set. Moreover, the model has made in silico predictions that have been validated in vivo, providing new insights into the regulation and hierarchical organization of the SIN. Another cell cycle related project that is part of this thesis was to create a qualitative, minimal model of cyclin interplay in S.cerevisiae. CLB proteins in budding yeast present a characteristic, sequential activation and decay during the cell cycle, commonly referred to as Clb waves. This event is coordinated with the inverse activation curve of Sic1, which has an inhibitory role in the system. To generate minimal qualitative models that can explain this phenomenon, we selected well-defined experiments and constructed all possible minimal models that, when simulated, reproduce the expected results. The models were filtered using standardized qualitative ODE simulations; only the ones reproducing the wave-like phenotype were kept. The set of minimal models can be used to suggest regulatory relations among the participating molecules, which will subsequently be tested experimentally. Finally, during my PhD I participated in the SBV Improver Challenge. The goal was to infer species-specific (human and rat) networks, using phosphoprotein, gene expression and cytokine data and a reference network provided as prior knowledge. Our solution to the challenge was selected as in the final chapter of the thesis.

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.

Development of the Simulation Environment for the Mobile Phone User Interfaces

Diplomityössä käsitellään Nokia Mobile Phonesin matkapuhelimien käyttöliittymäohjelmistojen suunnittelu-ja testausympäristön kehitystä. Ympäristöön lisättiin kaksi ohjelmistomodulia avustamaan simulointia ja versionhallintaa. Visualisointityökalulla matkapuhelimen toiminta voidaan jäljittää suunnittelu- kaavioihin tilasiirtyminä, kun taas vertailusovelluksella kaavioiden väliset erot nähdään graafisesti. Kehitetyt sovellukset parantavat käyttöliittymien suunnitteluprosessia tehostaen virheiden etsintää, optimointia ja versionhallintaa. Visualisointityökalun edut ovat merkittävät, koska käyttöliittymäsovellusten toiminta on havaittavissa suunnittelu- kaavioista reaaliaikaisen simuloinnin yhteydessä. Näin virheet ovat välittömästi paikannettavissa. Lisäksi työkalua voidaan hyödyntää kaavioita optimoitaessa, jolloin sovellusten kokoja muistintarve pienenee. Graafinen vertailutyökalu tuo edun rinnakkaiseen ohjelmistosuunnitteluun. Eri versioisten suunnittelukaavioiden erot ovat nähtävissä suoraan kaaviosta manuaalisen vertailun sijaan. Molemmat työkalut otettiin onnistuneesti käyttöön NMP:llä vuoden 2001 alussa.

Mobile technology, gender and development in Africa, India and Bangladesh

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Drivers and barriers of mobile travel and tourism service adoption : a study of individual perceptions and business model development in a travel and tourism context

The Travel and Tourism field is undergoing changes due to the rapid development of information technology and digital services. Online travel has profoundly changed the way travel and tourism organizations interact with their customers. Mobile technology such as mobile services for pocket devices (e.g. mobile phones) has the potential to take this development even further. Nevertheless, many issues have been highlighted since the early days of mobile services development (e.g. the lack of relevance, ease of use of many services). However, the wide adoption of smartphones and the mobile Internet in many countries as well as the formation of so-called ecosystems between vendors of mobile technology indicate that many of these issues have been overcome. Also when looking at the numbers of downloaded applications related to travel in application stores like Google Play, it seems obvious that mobile travel and tourism services are adopted and used by many individuals. However, as business is expected to start booming in the mobile era, many issues have a tendency to be overlooked. Travelers are generally on the go and thus services that work effectively in mobile settings (e.g. during a trip) are essential. Hence, the individuals’ perceived drivers and barriers to use mobile travel and tourism services in on-site or during trip settings seem particularly valuable to understand; thus this is one primary aim of the thesis. We are, however, also interested in understanding different types of mobile travel service users. Individuals may indeed be very different in their propensity to adopt and use technology based innovations (services). Research is also switching more from investigating issues of mobile service development to understanding individuals’ usage patterns of mobile services. But designing new mobile services may be a complex matter from a service provider perspective. Hence, our secondary aim is to provide insights into drivers and barriers of mobile travel and tourism service development from a holistic business model perspective. To accomplish the research objectives seven different studies have been conducted over a time period from 2002 – 2013. The studies are founded on and contribute to theories within diffusion of innovations, technology acceptance, value creation, user experience and business model development. Several different research methods are utilized: surveys, field and laboratory experiments and action research. The findings suggest that a successful mobile travel and tourism service is a service which supports one or several mobile motives (needs) of individuals such as spontaneous needs, time-critical arrangements, efficiency ambitions, mobility related needs (location features) and entertainment needs. The service could be customized to support travelers’ style of traveling (e.g. organized travel or independent travel) and should be easy to use, especially easy to take into use (access, install and learn) during a trip, without causing security concerns and/or financial risks for the user. In fact, the findings suggest that the most prominent barrier to the use of mobile travel and tourism services during a trip is an individual’s perceived financial cost (entry costs and usage costs). It should, however, be noted that regulations are put in place in the EU regarding data roaming prices between European countries and national telecom operators are starting to see ‘international data subscriptions’ as a sales advantage (e.g. Finnish Sonera provides a data subscription in the Baltic and Nordic region at the same price as in Finland), which will enhance the adoption of mobile travel and tourism services also in international contexts. In order to speed up the adoption rate travel service providers could consider e.g. more local initiatives of free Wi-Fi networks, development of services that can be used, at least to some extent, in an offline mode (do not require costly network access during a trip) and cooperation with telecom operators (e.g. lower usage costs for travelers who use specific mobile services or travel with specific vendors). Furthermore, based on a developed framework for user experience of mobile trip arrangements, the results show that a well-designed mobile site and/or native application, which preferably supports integration with other mobile services, is a must for true mobile presence. In fact, travel service providers who want to build a relationship with their customers need to consider a downloadable native application, but in order to be found through the mobile channel and make contact with potential new customers, a mobile website should be available. Moreover, we have made a first attempt with cluster analysis to identify user categories of mobile services in a travel and tourism context. The following four categories were identified: info-seekers, checkers, bookers and all-rounders. For example “all-rounders”, represented primarily by individuals who use their pocket device for almost any of the investigated mobile travel services, constituted primarily of 23 to 50 year old males with high travel frequency and great online experience. The results also indicate that travel service providers will increasingly become multi-channel providers. To manage multiple online channels, closely integrated and hybrid online platforms for different devices, supporting all steps in a traveler process should be considered. It could be useful for travel service providers to focus more on developing browser-based mobile services (HTML5-solutions) than native applications that work only with specific operating systems and for specific devices. Based on an action research study and utilizing a holistic business model framework called STOF we found that HTML5 as an emerging platform, at least for now, has some limitations regarding the development of the user experience and monetizing the application. In fact, a native application store (e.g. Google Play) may be a key mediator in the adoption of mobile travel and tourism services both from a traveler and a service provider perspective. Moreover, it must be remembered that many device and mobile operating system developers want service providers to specifically create services for their platforms and see native applications as a strategic advantage to sell more devices of a certain kind. The mobile telecom industry has moved into a battle of ecosystems where device makers, developers of operating systems and service developers are to some extent forced to choose their development platforms.

Development of Generic Simulation Model for Mobile Working Machines

This master’s thesis has been done for Drive! –project in which a new electric motor solution for mobile working machines is developed. Generic simulation model will be used as marketing and development tool. It can be used to model a wide variety of different vehicles with and without electric motor and to show customer the difference between traditionally build vehicles and those with new electric motor solution. Customers can also use simulation model to research different solutions for their own vehicles. At the start of the project it was decided that MeVEA software would be used as main simulation program and Simulink will only be used to simulate the operation of electrical components. Development of the generic model started with the research of these two software applications, simulation models which are made with them and how these simulation models can be build faster. Best results were used for building of generic simulation model. Finished generic model can be used to produce new tractor models for real-time simulations in short notice. All information about model is collected to one datasheet which can be easily filled by the user. After datasheet is filled a script will automatically build new simulation model in seconds. At the moment generic model is capable of building simulation models for wide variety of different tractors but it can be easily altered for other vehicle types too which would also benefit greatly from electric drive solution. Those could be for example wheel loaders and harvesters.

Development of a Control System for a Tele Operated Mobile Robot

Mobile robots are capable of performing spatial displacement motions in different environments. This motions can be calculated based on sensorial data (autonomous robot) or given by an operator (tele operated robot). This thesis is focused on the latter providing the control architecture which bridges the tele operator and the robot’s locomotion system and end effectors. Such a task might prove overwhelming in cases where the robot comprises a wide variety of sensors and actuators hence a relatively new option was selected: Robot Operating System (ROS). The control system of a new robot will be sketched and tested in a simulation model using ROS together with Gazebo in order to determine the viability of such a system. The simulated model will be based on the projected shape and main features of the real machine. A stability analysis will be performed first theoretically and afterwards using the developed model. This thesis concluded that both the physical properties and the control architecture are feasible and stable settling up the ground for further work with the same robot.

Adherence to Treatment in Psychotic Disorders - Development of user-centered mobile health intervention

The aim of this study was to explore adherence to treatment among people with psychotic disorders through the development of user-centered mobile technology (mHealth) intervention. More specifically, this study investigates treatment adherence as well as mHealth intervention and the factors related to its possible usability. The data were collected from 2010 to 2013. First, patients’ and professionals’ perceptions of adherence management and restrictive factors of adherence were described (n = 61). Second, objectives and methods of the intervention were defined based on focus group interviews and previously used methods. Third, views of patients and professionals about barriers and requirements of the intervention were described (n = 61). Fourth, mHealth intervention was evaluated based on a literature review (n = 2) and patients preferences regarding the intervention (n = 562). Adherence management required support in everyday activities, social networks and maintaining a positive outlook. The factors restricting adherence were related to illness, behavior and the environment. The objective of the intervention was to support the intention to follow the treatment guidelines and recommendations with mHealth technology. The barriers and requirements for the use of the mHealth were related to technology, organizational issues and the users themselves. During the course of the intervention, 33 (6%) out of 562 participants wanted to edit the content, timing or amount of the mHealth tool, and 23 (4%) quit the intervention or study before its conclusion. According to the review, mHealth interventions were ineffective in promoting adherence. Prior to the intervention, participants perceived that adherence could be supported, and the use of mHealth as a part of treatment was seen as an acceptable and efficient method for doing so. In conclusion, the use of mHealth may be feasible among people with psychotic disorders. However, clear evidence for its effectiveness in regards to adherence is still currently inconclusive.

Development and Investigations of Mobile Antennas for less Radiation Hazards

Antennas, the key element in wireless communication devices had undergone amazing developments especially in the direction of compactness and safety aspects. In the last two decades, the use of the cellular phones has become the most popular mode of communication across the globe. At the same time, the concerns about the radiation effects have increased in the general public. The main concern of this thesis is to develop a mobile antenna which gives reduced RF interference to the user. The reduction of the power absorbed by the user can tremendously avoid any possible health hazards. The radiation characteristic of a monopole antenna is modified with good radiation characteristics suitable for a mobile handset. The modification is implemented by using different resonating structures which provides reduced radiation along one direction. The direction of less radiation can be changed by modifying the planar antenna structure to a ground folded antenna. This modified structure with excellent radiation characteristic is suitable for modern wireless handheld devices with less user RF interference. Specific Absorption Rate (SAR) is an important parameter for mobile handset. The SAR is estimated for the newly developed antenna for different conditions and discussed in this thesis.

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Development of new methodologies for entry to targets of therapeutic interest

This Account provides an overview of strategies that have been reported from our laboratories for the synthesis of targets of therapeutic interest, namely carbohydrates, and prodrugs for the treatment of melanoma. These programmes have involved the development of new synthetic methodologies including the regio- and stereoselective synthesis of specific carbohydrate isomers, and new protecting group methodologies. This review provides an insight into the progress of these research themes, and suggests some applications for the targets that are currently being explored.

Ability of students to recognize the relationship between using mobile apps for learning during fieldwork and the development of graduate attributes

The increasing importance of employability in Higher Education curricula and the prevalence of using mobile devices for fieldbased learning prompted an investigation into student awareness of the relationship between the use of mobile apps for learning and the development of graduate attributes (GAs) (and the link to employability). The results from post-fieldwork focus groups from four field courses indicated that students could make clear links between the use of a variety of mobile apps and graduate attribute development. The study suggests a number of mobile apps can align simultaneously with more than one graduate attribute. Furthermore, prior experience and the context of use can influence students’ perceptions of an app and its link with different GAs.

Development of a novel microextraction by packed sorbent-based approach followed by ultrahigh pressure liquid chromatography as a powerful technique for quantification phenolic constituents of biological interest in wines

A novel analytical approach, based on a miniaturized extraction technique, the microextraction by packed sorbent (MEPS), followed by ultrahigh pressure liquid chromatography (UHPLC) separation combined with a photodiode array (PDA) detection, has been developed and validated for the quantitative determination of sixteen biologically active phenolic constituents of wine. In addition to performing routine experiments to establish the validity of the assay to internationally accepted criteria (linearity, sensitivity, selectivity, precision, accuracy), experiments are included to assess the effect of the important experimental parameters on the MEPS performance such as the type of sorbent material (C2, C8, C18, SIL, and M1), number of extraction cycles (extract-discard), elution volume, sample volume, and ethanol content, were studied. The optimal conditions of MEPS extraction were obtained using C8 sorbent and small sample volumes (250 μL) in five extraction cycle and in a short time period (about 5 min for the entire sample preparation step). The wine bioactive phenolics were eluted by 250 μL of the mixture containing 95% methanol and 5% water, and the separation was carried out on a HSS T3 analytical column (100 mm × 2.1 mm, 1.8 μm particle size) using a binary mobile phase composed of aqueous 0.1% formic acid (eluent A) and methanol (eluent B) in the gradient elution mode (10 min of total analysis). The method gave satisfactory results in terms of linearity with r2-values > 0.9986 within the established concentration range. The LOD varied from 85 ng mL−1 (ferulic acid) to 0.32 μg mL−1 ((+)-catechin), whereas the LOQ values from 0.028 μg mL−1 (ferulic acid) to 1.08 μg mL−1 ((+)-catechin). Typical recoveries ranged between 81.1 and 99.6% for red wines and between 77.1 and 99.3% for white wines, with relative standard deviations (RSD) no larger than 10%. The extraction yields of the MEPSC8/UHPLC–PDA methodology were found between 78.1 (syringic acid) and 99.6% (o-coumaric acid) for red wines and between 76.2 and 99.1% for white wines. The inter-day precision, expressed as the relative standard deviation (RSD%), varied between 0.2% (p-coumaric and o-coumaric acids) and 7.5% (gentisic acid) while the intra-day precision between 0.2% (o-coumaric and cinnamic acids) and 4.7% (gallic acid and (−)-epicatechin). On the basis of analytical validation, it is shown that the MEPSC8/UHPLC–PDA methodology proves to be an improved, reliable, and ultra-fast approach for wine bioactive phenolics analysis, because of its capability for determining simultaneously in a single chromatographic run several bioactive metabolites with high sensitivity, selectivity and resolving power within only 10 min. Preliminary studies have been carried out on 34 real whole wine samples, in order to assess the performance of the described procedure. The new approach offers decreased sample preparation and analysis time, and moreover is cheaper, more environmentally friendly and easier to perform as compared to traditional methodologies.