Tuoteryhmän kehitysprojektin optimointi

Tämä diplomityö toteutettiin Sammet Dampers Oy:ltä saatuna toimeksiantona. Yritys haluaa yhä parempia tuloksia tuoteryhmien kehitysprojekteista, jolloin se asettaa vaatimuksia kehitysprojekteissa käytettävälle kehitysprosessille. Yrityksen täytyy optimoida ja systematisoida käytettävää menetelmää, jotta näihin parempiin tuloksiin voidaan päästä. Työn ensimmäisenä tavoitteena on optimoida yrityksen käytössä oleva tuoteryhmien kehitysprojekteissa käytettävä prosessimalli. Tavoitteen mukaisesti työssä luodaan uusi optimoitu tuoteryhmien kehitysprosessimalli, joka vastaa yrityksen tarpeisiin. Tämä uusi malli kirjataan osaksi yrityksen toiminnanohjausjärjestelmää. Työn toisena tavoitteena on käyttää uutta optimoitua prosessimallia kellopeltien tuoteryhmän kehitysprojektissa. Tätä kehitysprojektia käytetään samalla uuden prosessimallin sisäänajamiseen osaksi yrityksen toimintoja.Tämän diplomityön puitteissa kellopeltien kehitysprojektista käydään läpi kehitysprojektin ensimmäinen osio eli vaatimustenmäärittelyprosessi ja esitellään sen tuloksena syntynyt toteutussuunnitelma. Työn tuloksena syntyneen uuden tuoteryhmien kehitysprojektin prosessimallin avulla voidaan saavuttaa merkittäviä parannuksia tarkasteltaessa kehitysprojektin tuloksia ajankäytön, laadun ja kustannusten suhteen.

Etiology and epidemiology of Pythium root rot in hydroponic crops: current knowledge and perspectives

The etiology and epidemiology of Pythium root rot in hydroponically-grown crops are reviewed with emphasis on knowledge and concepts considered important for managing the disease in commercial greenhouses. Pythium root rot continually threatens the productivity of numerous kinds of crops in hydroponic systems around the world including cucumber, tomato, sweet pepper, spinach, lettuce, nasturtium, arugula, rose, and chrysanthemum. Principal causal agents include Pythium aphanidermatum, Pythium dissotocum, members of Pythium group F, and Pythium ultimum var. ultimum. Perspectives are given of sources of initial inoculum of Pythium spp. in hydroponic systems, of infection and colonization of roots by the pathogens, symptom development and inoculum production in host roots, and inoculum dispersal in nutrient solutions. Recent findings that a specific elicitor produced by P. aphanidermatum may trigger necrosis (browning) of the roots and the transition from biotrophic to necrotrophic infection are considered. Effects on root rot epidemics of host factors (disease susceptibility, phenological growth stage, root exudates and phenolic substances), the root environment (rooting media, concentrations of dissolved oxygen and phenolic substances in the nutrient solution, microbial communities and temperature) and human interferences (cropping practices and control measures) are reviewed. Recent findings on predisposition of roots to Pythium attack by environmental stress factors are highlighted. The commonly minor impact on epidemics of measures to disinfest nutrient solution as it recirculates outside the crop is contrasted with the impact of treatments that suppress Pythium in the roots and root zone of the crop. New discoveries that infection of roots by P. aphanidermatum markedly slows the increase in leaf area and whole-plant carbon gain without significant effect on the efficiency of photosynthesis per unit area of leaf are noted. The platform of knowledge and understanding of the etiology and epidemiology of root rot, and its effects on the physiology of the whole plant, are discussed in relation to new research directions and development of better practices to manage the disease in hydroponic crops. Focus is on methods and technologies for tracking Pythium and root rot, and on developing, integrating, and optimizing treatments to suppress the pathogen in the root zone and progress of root rot.

Toimitusketjun hallinnan kehittäminen tekstiiliteollisuudessa

Due to the outsourcing of manufacturing, Finlayson Oy now has a need to develop its supply chain management as its new ability. This requires development of efficient and flexible procedures and models in order to efficiently manage the company’s floating assets without affecting the reliability of delivery promised for the customer. In this thesis we discuss Finlayson’s supply chain management with a focus on the operations between Finlayson and its suppliers. The aim is to develop these operations and increase the reaction speed of the supply chain in order to response to the changes in demand. In order to do this we discuss different product analysis, material and inventory management and demand forecasting. In the research part of the thesis we design strategies for different products based on product classification analysis. Market behavior of different products will be modeled with demand forecasting methods and inventory control systems will be designed for different product groups based on the nature of their supplier. We will also optimize the costs and resource needs for different suppliers’ order-deliver processes.

Rukoile ja työtä tee. Onni Puhakan kehitys innovaattorista oman tien kulkijaksi

Pray and work. The development of Onni Puhakka: from innovator to nonconformist This ethnological biographical study examines the modernization which began in the mid-1800s, continued into the mid-1900s, and has changed Finnish society in many ways. This era has been studied on a general level quite extensively, but this work explores the life and everyday experiences of Onni Puhakka (1870−1955), a farmer who spent most of his life in the town of Liperi. The goal is to find new perspectives on the development of the modernization process in society through the experiences of an individual. In this study, a central theme is the rural co-operative movement represented in Finland by Pellervo as well as its development in this country and as a significant undertaking in Onni Puhakka’s life. The co-operative movement was one of the most significant sectors affecting modernization in rural communities. The main character in the study is the grandfather of the present author, and thus this research belongs to the newly accepted ethnological research tradition of studying one’s own community. Written documents, mainly collected and preserved by Onni Puhakka himself during his lifetime, form the research material. The material consists mainly of Puhakka’s extensive correspondence, personal notes and diaries, documents related to his farm, and photographs taken by him. Earlier research and other written material examining the general development of the period were used to provide a background for the study. The co-operative movement formed a comprehensive ideology for Onni Puhakka, in which the possibilities for the development of both individuals and the community were combined. His life was based on a religious conviction, and he felt that the co-operative movement was the application of Christian love for one’s neighbour in practice. At the beginning of his active working career, Puhakka was an innovator, a reformer at the forefront of progress, but quite soon he became a sworn critic of the development of the co-operative movement in particular. One of Puhakka’s criticisms of the co-operative movement was the shifting of decision-making power to professional managers and central organizations, far from the reach of local actors. A fundamental reason for his dissatisfaction was the development within the co-operative movement in which the ideological background was forgotten, and economic goals and making a profit took an excessive significance. This assessment of the co-operative movement made by Onni Puhakka and his predictions about its development were not unfounded. This has been shown by several studies examining the development of both the Pellervo and working class cooperative movements. The professionalization of management, managerialism, as well as the direct links between professional managers of local co-operatives and central organizations have lead to the situation in which fewer and fewer people make the decisions, and management has as its goal economic success and growth. Co-operative enterprises that have grown in size have become estranged from the everyday life of their members. Instead of taking care of relations with the membership of the co-op, competitive ability and the market share have become the most important concerns of the management. As the membership has become alienated, their interest in large-scale co-ops has also become largely economic. A significant change among the membership of the Pellervo movement occurred at the stage when the co-operative movement shifted from rural areas to urban centres. This meant that the commitment of the membership became much looser than it had been in the farmers’ production and consumer co-ops. From the point of view of its members, the nature of the co-operative movement has become diametrically opposed to its point of departure: the active members who previously formed the subject of the co-operative movement have become the object of the economic activities of that same movement. The co-operative movement has been transformed from the progressive agent of change of its early years into a business activity which no longer has any significant task as a social reformer. This study confirms the observations of the latest research on modernization which states that modernization has not been a straightforward and inevitable development that has lead to the present situation. For example, the criticism directed by Puhakka toward the co-operative movement includes information that shows that a few others who were initially actively involved also criticized the development of the movement. Despite his occasional frustration, Onni Puhakka continued his criticism and attempts to get the co-operative movement to change its course and return to its ‘roots’. In the early years of the cooperative movement he probably did not differ much from the other pioneers in the sense that many of them had adopted and internalized the same values and motive for being involved that he had. However, Puhakka differed from his colleagues in the sense that he was able to believe in what he called the “fundamental values” of the co-operative movement longer than many of them.

Innovaatioprosessin alkupään toimintamalli ja päätöksenteko

Työn tavoitteena oli tutkia innovaatioita ja organisaation innovaatiokyvykkyyttä, innovaatiokyvykkyyden taustatekijöitä sekä innovaatioprosessin alkupään (Fuzzy Front End, FFE) sekä siinä tapahtuvan päätöksenteon johtamista. Lisäksi tavoitteena oli suunnitella innovaatioprosessin alkupään toimintamalli selkeyttämään toimintaa prosessin alkupäässä sekä antaa toimenpide-ehdotuksia ja suosituksia. Tutkimuksen teoriaosuus tehtiin kirjallisuustutkimuksena. Tutkimuksen empiirinen osuus suoritettiin case -analyysinä yrityksen henkilöhaastattelu- ja toimintatutkimuksen muodossa. Innovaatioprosessin alkupäähän on tunnistettu toimintamalleja, joilla selkeytetään ja tehostetaan prosessin alkupään vaiheita. Vaiheet ovat mahdollisuuksien tunnistaminen, mahdollisuuksien analysointi, ideointi, ideoiden valitseminen ja konsepti- ja teknologiakehitys. Innovaatioprosessin rinnalla kulkee päätöksenteon prosessi, jonka suhteen tunnistetaan selkeät päätöksentekokohdat ja kriteerit prosessissa etenemiselle. Innovaatio- ja päätöksentekoprosessiin osallistuu eri vaiheissa sekä yrityksen sisäiset, kuten henkilöstö, että ulkoiset, kuten asiakkaat, toimittajat ja verkostokumppanit, sidosryhmät. Lisäksi innovaatioprosessin toimintaan vaikuttavat johdon tuki ja sitoutuminen, osallistujien kyky luovuuteen sekä muut innovaatiokyvykkyyden taustatekijät. Kaikki nämä tekijät tulee huomioida innovaatioprosessin alkupään mallia suunniteltaessa. Tutkimus tehtiin tietoliikennealan yrityksen tarpeisiin. Yrityksessä on käytössä aloitetoimintaa, mutta sen ei koeta tarjoavan riittävästi ideoita yrityksen tuotekehityksen tarpeisiin. Yrityksen henkilöstön innovaatiopotentiaali on suuri, mikä halutaan hyödyntää paremmin suunnittelemalla yrityksen käyttöön soveltuva, innovaatioprosessin alkupään toimintaan ohjaava, vakioitu ja henkilöstöä ja muita yhteistyötahoja, kuten asiakkaita, osallistava toimintamalli. Toimenpide-ehdotuksina ja suosituksina esitetään innovaatioprosessin alkupään johtamisen toimintamallia. Esitetyssä mallissa määritellään vaiheet, menetelmät, päätöksenteko ja vastuut. Toimintamalli esitetään soveltuen yhdistettäväksi yrityksessä käytössä olevaan innovaatioprosessin loppupään, tuotekehitysprojektien läpiviemisen, malliin.

Essays on Business and Leadership Ethics

As this is a dissertation, an academic thesis, it is important to define the objectives of my research, even if ex post facto, explicitly: - To define, develop and study the concept of business and leadership ethics. - To empirically study the phenomena associated with business and leadership from an ethical perspective. - To create a new framework for the development of responsible business. - To create an “acid test” for my body of works, i.e. a test and an evaluation on how well my research and ideas hold up under academic philosophical reflection. The utilitarian reasoning had the most support when the actors justified their actions regarding economic benefit. (=instrumental good). Duty and benefit were often mixed up in people’s speech. Their meaning contents were blurred and the argumentation lines created by the actors were broken. This can be interpreted in a way that supports Frankena’s mixed deontological philosophy as a frame of reference. Deontologica reasoning was used e.g. in describing the personnel management processes of a company. Virtue ethics is a favourable starting point for studying management and leadership ethics. All the actors studied could name virtues for their operations, towards which to aspire to. They also named professional practices already in use that they considered to be virtuous. Finally, I wish to state that normative ethics is an important branch of philosophical ethics, if also very important in applied ethics especially. From the normative standpoint, the results of this dissertation want to lead nations, communities and individuals towards the virtues of democratic leadership and sustainable economic development.

Mobile learning and video experience in delivering digital content

In recent years, the worldwide distribution of smartphone devices has been growing rapidly. Mobile technologies are evolving fast, a situation which provides new possibilities for mobile learning applications. Along with new delivery methods, this development enables new concepts for learning. This study focuses on the effectiveness and experience of a mobile learning video promoting the key features of a specific device. Through relevant learning theories, mobile technologies and empirical findings, the thesis presents the key elements for a mobile learning video that are essential for effective learning. This study also explores how previous experience with mobile services and knowledge of a mobile handset relate to final learning results. Moreover, this study discusses the optimal delivery mechanisms for a mobile video. The target group for the study consists of twenty employees of a Sanoma Company. The main findings show that the individual experience of learning and the actual learning results may differ and that the design for certain video elements, such as sound and the presentation of technical features, can have an impact on the experience and effectiveness of a mobile learning video. Moreover, a video delivery method based on cloud technologies and HTML5 is suggested to be used in parallel with standalone applications.

Laser-TIG hybrid welding process

Joining processes and techniques need to meet the trend of new applications and the development of new materials. The application in connection with thick and thin plates in industrial fields is wide and the joining technology is in very urgent need. The laser-TIG hybrid welding technology can play the respective advantages of both of them. One major advantage of the hybrid laser-TIG welding technology is its efficient use of laser energy. Additionally, it can develop into a high and new advanced welding technology and become a hot spot in both the application and research area. This thesis investigated laser –TIG hybrid welding with the aim of enlightening the reader on its advantages, disadvantages and future areas of improvement. The main objective is to investigate laser-TIG hybrid on the welding of various metals (steels, magnesium, aluminium etc.). In addition, it elaborates on various possible combinations on hybrid laser-TIG welding technology and their benefits. The possibility of using laser-TIG hybrid in welding of thick materials was investigated. The method applied in carrying out this research is by using literature review. The results showed that hybrid laser-TIG is applicable to almost all weldable metals. Also it proves to be effective in welding refractive metals. The possibility of welding with or without filler materials is of economic advantage especially in welding of materials with no filler material. Thick plate’s hybrid laser-TIG welding is showing great prospects although it normally finds its used in welding thin materials in the range of 0.4 to 0.8 mm. The findings show that laser-TIG hybrid welding can be a versatile welding process and therefore will be increasingly used industrially due to its numerous advantages and the development of new TIG arc that enhances its capabilities.

Gene Regulation in The Human Immune System. Gene Expression Signatures of Th2 Cell Differentiation, Type 1 Diabetes, and Intrauterine Immune Adaptation

The human immune system is constantly interacting with the surrounding stimuli and microorganisms. However, when directed against self or harmless antigens, these vital defense mechanisms can cause great damage. In addition, the understanding the underlying mechanism of several human diseases caused by aberrant immune cell functions, for instance type 1 diabetes and allergies, remains far from being complete. In this Ph.D. study these questions were addressed using genome-wide transcriptomic analyses. Asthma and allergies are characterized by a hyperactive response of the T helper 2 (Th2) immune cells. In this study, the target genes of the STAT6 transcription factor in naïve human T cells were identified with RNAi for the first time. STAT6 was shown to act as a central activator of the genes expression upon IL-4 signaling, with both direct and indirect effects on Th2 cell transcriptome. The core transcription factor network induced by IL-4 was identified from a kinetic analysis of the transcriptome. Type 1 diabetes is an autoimmune disease influenced by both the genetic susceptibility of an individual and the disease-triggering environmental factors. To improve understanding of the autoimmune processes driving pathogenesis in the prediabetic phase in humans, a unique series of prospective whole-blood RNA samples collected from HLA-susceptible children in the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study was studied. Changes in different timewindows of the pathogenesis process were identified, and especially the type 1 interferon response was activated early and throughout the preclinical T1D. The hygiene hypothesis states that allergic diseases, and lately also autoimmune diseases, could be prevented by infections and other microbial contacts acquired in early childhood, or even prenatally. To study the effects of the standard of hygiene on the development of neonatal immune system, cord blood samples from children born in Finland (high standard of living), Estonia (rapid economic growth) and Russian Karelia (low standard of living) were compared. Children born in Russian Karelia deviated from Finnish and Estonian children in many aspects of the neonatal immune system, which was developmentally more mature in Karelia, resembling that of older infants. The results of this thesis offer significant new information on the regulatory networks associated with immune-mediated diseases in human. The results will facilitate understanding and further research on the role of the identified target genes and mechanisms driving the allergic inflammation and type 1 diabetes, hopefully leading to a new era of drug development.

Perehdyttäminen osana strategista osaamisen kehittämistä - Uusien esimiesten perehdyttäminen kuntaorganisaatiossa

Perehdyttäminen ja osaamisen kehittäminen ovat koko ajan entistä keskeisempiä tekijöitä yritysten menestymisessä entistä nopeammin muuttuvassa maailmassa. Tässä Pro gradu-tutkielmassa tutkitaan uusien esimiesten perehdyttämistä. Tavoitteena on selvittää esimiesten perehdyttämisen toteuttaminen, keskeiset kehittämiskohteet sekä henkilöstöhallinnossa kartoitettujen esimiestyön osaamisvaatimusten näkyminen kohdeorganisaation perehdytysprosessissa. Tutkimuksessa tarkastellaan perehdyttämisen ja osaamisen kehittämisen tieteellistä viitekehystä. Tutkimuksessa on yhdistetty laadullisen ja määrällisen tutkimuksen menetelmiä. Tutkimus on toteutettu sähköisenä lomakekyselynä. Uusien esimiesten perehdyttämisen toteuttamisessa oli havaittavissa eroja kohdeorganisaation uusien esimiesten välillä. Pääasiallisena perehdyttäjänä oli toiminut oma esimies. Suuri osa esimiehistä oli melko tyytyväisiä omaan perehdyttämiseensä ja heillä oli positiivisia kehittymisnäkymiä osaamisensa kasvamisesta seuraavan vuoden aikana. Keskeisinä kehittämiskohteina esille nousivat epäyhteneväisyydet perehdyttämisessä, joidenkin uusien esimiesten yksin jääminen sekä perehdyttämisen tukimateriaalien tarve. Esimiestyön osaamisvaatimuksia ei ollut tuotu aktiivisesti esiin prosessin aikana.

Managing Customer Co-creation: Empirical Evidence from Finnish High-tech SMEs

The purpose of this thesis is to find out how customer co-creation activities are managed in Finnish high-tech SMEs by understanding managers’ views on relevant issues. According to theory, issues such as firm size, customer knowledge implementation, lead customers, the fuzzy front-end of product/service development as well as the reluctance to engage in customer co-creation are some of the field’s focal issues. The views of 145 Finnish SME managers on these issues were gathered as empirical evidence through an online questionnaire and analyzed with SPSS statistics software. The results show, firstly, that Finnish SME managers are aware of the issues associated with customer co-creation and are able to actively manage them. Additionally, managers performed well in regards to collaborating with lead customers and implemented customer knowledge evenly in various stages of their new product and service development processes. Intellectual property rights emerged as an obstacle deterring managers from engaging in co-creation. The results suggest that in practice managers would do well by looking for more opportunities to implement customer knowledge in the early and late stages of new product and service development, as well as by actively searching for lead customers.

El éxito del Mercosur posible

The success of the possible Mercosur. Mercosur can be observed from two different perspectives. One from an ideal integration project, whose reference is the European Union. The other, based in the profound prevailing asymmetries within the region and the progress achieved since the founding bilateral agreements of presidents Alfonsin and Sarney, in 1985. From the first perspective, Mercosur in a failure; from the second, it has achieved considerable success. The integration process is displayed in three levels: the national density prevailing in the member countries, the rules of the game of the system and the common standings vis a vis the rest of the world. The future of Mercosur depends on progress achieved in these three levels and the opening of new possibilities of national development for each member country in a regional framework.

Valmentamisen hyödyntäminen työntekijöiden motivoinnissa

Tutkimuksen tavoitteena on tutkia voidaanko työntekijöitä motivoida valmentamisen avulla sekä löytää keinoja ja uusia työkaluja kohdeorganisaation työntekijöiden valmentamisen kehittämiseen. Tutkimuskysymys on ”Kuinka työmotivaatioon voidaan vaikuttaa henkilökohtaisen valmentamisen avulla?”. Tämä tapaustutkimus toteutettiin finanssialan yritykselle laadullisena tutkimuksena ja aineisto kerättiin haastattelemalla puolistrukturoidusti neljää kohdeorganisaation työntekijää. Aineisto analysoitiin sisällönanalyysimenetelmää hyödyntäen. Tutkimustulosten mukaan valmentamisen avulla pystytään vaikuttamaan henkilöstön työmotivaatioon, kun työntekijä on itse siihen asenteiltaan sekä mieleltään vastaanottavainen. Motivaatio jakautuu sisäiseen ja ulkoiseen motivaatioon, joista sisäiseen motivaatioon pystytään vaikuttamaan esimerkiksi mielenkiintoisen työn voimin ja ulkoiseen esimerkiksi palkkauksen avulla. Asiantuntijaorganisaation henkilöstön motivaatiolla on suora vaikutus organisaation suorituskykyyn sekä työyhteisön ilmapiiriin. Tulevaisuudessa kohdeorganisaation tulee panostaa erityisesti yksilölliseen valmentamiseen sekä palautemyönteiseen työilmapiiriin. Uudeksi motivointikeinoksi kohdeorganisaatiolle ehdotetaan ryhmävalmennusta, joka tukee palautteenantamisen kulttuuria sekä motivoi ja sparraa työyhteisöä

Le financement de la haute technologie dans le système de santé : le cas de la pharmacogénomique

L’exercice d’allocation de ressources en santé, relevant du Ministère de la santé, se voit fortement influencé autant par les besoins variés de la population que par les exigences des intervenants en santé. Quel rôle ces différents intérêts peuvent-ils jouer dans l’intégration de nouvelles technologies dans la distribution des soins de santé ? La pharmacogénomique, branche émergente de la pharmacologie intégrant les données issues du projet génome humain au processus de développement du médicament, est perçue comme une technologie qui permettrait de personnaliser la médecine. Son intégration aux processus de développement ou de prescription de médicaments promet de minimiser l’apparition d’effets secondaires néfastes découlant de la prise de médicaments. Serait-il alors judicieux pour le gouvernement du Québec, considérant la conjoncture actuelle d’allocation de ressources, d’investir dans la pharmacogénomique en tant que nouvel outil de développement du médicament ou nouveau mode pronostic de médication pour sa population ? Nous aborderons cette question à l’aide de critères de sélection dictés par Caulfield et ses collaborateurs (2001)[1] pour évaluer la pertinence de l’investissement public dans la mise sur pied d’un test génétique, soit l’acceptabilité, l’utilité, la non-malfaisance et la présence d’un bénéfice clair – à coût raisonnable – pour la population. La génomique avoisinant la génétique, ces facteurs s’avèrent applicables dans notre discussion.

Mutagénèse semi-aléatoire au site actif de la DHFR humaine : création et caractérisation de variantes hautement résistantes au MTX.

La dihydrofolate réductase humaine (DHFRh) est une enzyme essentielle à la prolifération cellulaire. Elle réduit le dihydrofolate en tétrahydrofolate, un co-facteur impliqué dans la biosynthèse des purines et du thymidylate. La DHFRh est une cible de choix pour des agents de chimiothérapie comme le méthotrexate (MTX), inhibant spécifiquement l’enzyme ce qui mène à un arrêt de la prolifération et ultimement à la mort cellulaire. Le MTX est utilisé pour le traitement de plusieurs maladies prolifératives, incluant le cancer. La grande utilisation du MTX dans le milieu clinique a mené au développement de mécanismes de résistance, qui réduisent l’efficacité de traitement. La présente étude se penche sur l’un des mécanismes de résistance, soit des mutations dans la DHFRh qui réduisent son affinité pour le MTX, dans le but de mieux comprendre les éléments moléculaires requis pour la reconnaissance de l’inhibiteur au site actif de l’enzyme. En parallèle, nous visons à identifier des variantes plus résistantes au MTX pour leur utilisation en tant que marqueurs de sélection en culture cellulaire pour des systèmes particuliers, tel que la culture de cellules hématopoïétiques souches (CHS), qui offrent des possibilités intéressantes dans le domaine de la thérapie cellulaire. Pour étudier le rôle des différentes régions du site actif, et pour vérifier la présence d’une corrélation entre des mutations à ces régions et une augmentation de la résistance au MTX, une stratégie combinatoire a été dévelopée pour la création de plusieurs banques de variantes à des résidus du site actif à proximité du MTX lié. Les banques ont été sélectionnées in vivo dans un système bactérien en utilisant des milieux de croissance contenant des hautes concentrations de MTX. La banque DHFRh 31/34/35 généra un nombre considérable de variantes combinatoires de la DHFRh hautement résistantes au MTX. Les variantes les plus intéressantes ont été testées pour leur potentiel en tant que marqueur de sélection dans plusieurs lignées cellulaires, dont les cellules hématopoïétiques transduites. Une protection complète contre les effets cytotoxiques du MTX a été observée chez ces cellules suite à leur infection avec les variantes combinatoires. Pour mieux comprendre les causes moléculaires reliées à la résistance au MTX, des études de structure tridimensionnelle de variantes liées au MTX ont été entreprises. La résolution de la structure de la double variante F31R/Q35E lié au MTX a révélé que le phénotype de résistance était attribuable à d’importantes différences entre le site actif de la double variante et de l’enzyme native, possiblement dû à un phénomème dynamique. Une compréhension plus générale de la reconnaissance et la résistance aux antifolates a été réalisée en comparant des séquences et des structures de variantes de la DHFR résistants aux antifolates et provenant de différentes espèces. En somme, ces travaux apportent de nouveaux éléments pour la comprehension des intéractions importantes entre une enzyme et un ligand, pouvant aider au développement de nouveaux antifolates plus efficaces pour le traitement de diverses maladies. De plus, ces travaux ont généré de nouveaux gènes de résistance pouvant être utilisés en tant que marqueurs de sélection en biologie cellulaire.