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Diss. Naturwiss. Bern (kein Austausch). / Mit Sonderdrucken. Literaturverz.

Diss., Naturwissenschaften, Eidgenössische Technische Hochschule ETH Zürich, Nr. 16856, 2006.

Esta tesis presenta el diseño, desarrollo tecnológico, caracterización y aplicaciones tanto químicas como biológicas de micro- y nanodispositivos destinados a ser herramientas funcionales en biología celular. Esta línea de investigación es posible gracias a los avances obtenidos en el campo de las Micro- y Nanotecnologías, donde la aplicación de técnicas de miniaturización en la fabricación de sus dispositivos a escala celular es ya una realidad. Estas herramientas son lo suficientemente pequeñas como para etiquetar y permitir el seguimiento de embriones vivos o incluso actuar como sensores permitiendo el estudio de células vivas únicas de forma intra- y extracelular. Además, una de las características más relevantes de las micro- y nanoherramientas presentadas en esta tesis es su capacidad de suspensión, es decir, que estos dispositivos pueden ser liberados de la oblea en la que están fabricados y directamente actuar con las células en su mismo medio y en su misma escala. Estas herramientas presentan diferentes formas, tamaños, materiales y funcionalidades específicas, ya que la combinación de todas estas características o incluso la incorporación de partes nanoestructuradas en un solo dispositivo nos permite la obtención de herramientas multi-funcionales. Por todo ello, las micro- y nanoherramientas presentadas en esta tesis implican un gran número de aplicaciones como sensores y actuadores en biología celular. O incluso en el futuro estos dispositivos podrán ser aplicados en el campo de la nanomedicina como sistemas de diagnosis y drug delivery. / This thesis presents the design, technological development, characterization and chemical and biological applications of micro- and nanodevices which are focused on being functional tools for cell biology. This research is possible thanks to the recent advances in Micro- and Nanotechnologies, where the application of miniaturization techniques at cell scale is already a reality. These tools are small enough to label and track living embryos or even sense and operate in single living cells in an extra- and intracellular way. Furthermore, one of the most relevant new features of the micro- and nanotools presented in this thesis is the capability of being suspended, meaning that these devices can be released from the wafer and directly interact with cells in their same medium and at cell scale. These micro- and nanotools present different shapes, sizes, materials and specific functionalities, as the combination of these features or even the incorporation of nanostructured parts in a single device can let us obtain multi-tasking devices. Summarizing, the extensive capabilities of the presented micro- and nanotools imply a broad number of applications as sensors and actuators in cell biology. Or even in the near future, these devices can be applied in the nanomedicine field as diagnosis and drug delivery systems.

This thesis is dedicated to the study and comprehension of biological networks at the molecular level. The objectives were to analyse their topology, integrate it in a genotype-phenotype analysis, develop richer mathematical descriptions for them, study their community structure and compare different methodologies for estimating their internal fluxes. The work presented in this document moves around three main axes. The first one is the biological. Which organisms were studied in this thesis? They range from the simplest biological agents, the viruses, in this case the Potyvirus genus to prokariotes such as Escherichia coli and complex eukariotes (Arabidopsis thaliana, Nicotiana benthamiana). The second axis refers to which biological networks were studied. Those are protein-protein interaction (PPIN) and metabolic networks (MN). The final axis relates to the mathematical and modelling tools used to generate knowledge from those networks. These tools can be classify in three main branches: graph theory, constraint-based modelling and multivariate statistics. The document is structured in six parts. The first part states the justification for the thesis, exposes a general thesis roadmap and enumerates its main contributions. In the second part important literature is reviewed, summarized and integrated. From the birth and development of Systems Biology to one of its most popular branches: biological network analysis. Particular focus is put on PPIN and MN and their structure, representations and features. Finally a general overview of the mathematical tools used is presented. The third, fourth and fifth parts represent the central work of this thesis. They deal respectively with genotypephenotype interaction and classical network analysis, constraint-based modelling methods comparison and modelling metabolic networks and community structure. Finally, in the sixth part the main conclusions of the thesis are summarized and enumerated. This thesis highlights the vital importance of studying biological entities as systems and how powerful and promising this integrated analysis is. Particularly, network analysis becomes a fundamental avenue of research to gain insight into those biological systems and to extract, integrate and display this new information. It generates knowledge from just data. / Esta tesis está dedicada al estudio y comprensión de redes biológicas a nivel molecular. Los objetivos fueron analizar su topología, integrar esta en un análisis de genotipo-fenotipo, desarrollar descripciones matemáticas más completas para ellas, estudiar su estructura de comunidades y comparar diferentes metodologías para estimar sus flujos internos. El trabajo presentado en este documento gira entorno a tres ejes principales. El primero es el biológico. ¿Qué organismos han sido estudiados en esta tesis? Estos van desde los agentes biológicos mas simples, los virus, en este caso el género Potyvirus, hasta procariotas como Escherichia coli y eucariotas complejos (Arabidopsis thaliana, Nicotiana benthamiana). El segundo eje hace referencia a las redes biológicas estudiadas, que fueron redes de interacción de proteínas (PPIN) y redes metabólicas (MN). El eje final es el de las herramientas matemáticas y de modelización empleadas para interrogar esas redes. Estas herramientas pueden clasificarse en tres grandes grupos: teoría de grafos, modelización basada en restricciones y estadística multivariante. Este documento está estructurado en seis partes. La primera expone la justificación para la tesis, muestra un mapa visual de la misma y enumera sus contribuciones principales. En la segunda parte, la bibliografía relevante es revisada y resumida. Desde el nacimiento y desarrollo de la Biología de Sistemas hasta una de sus ramas más populares: el análisis de redes biomoleculares. Especial interés es puesto en PPIN y MN: su estructura, representación y características. Finalmente, un resumen general de las herramientas matemáticas usadas es presentado. Los capítulos tercero, cuarto y quinto representan el cuerpo central de esta tesis. Estos tratan respectivamente sobre la interacción de genotipo-fenotipo y análisis topolólogico clásico de redes, modelos basados en restricciones y modelización de redes metabólicas y su estructura de comunidades. Finalmente, en la sexta parte las principales conclusiones de la tesis son resumidas y expuestas. Esta tesis pone énfasis en la vital importancia de estudiar los fenómenos biológicos como sistemas y en la potencia y prometedor futuro de este análisis integrativo. En concreto el análisis de redes supone un camino de investigación fundamental para obtener conocimiento sobre estos sistemas biológicos y para extraer y mostrar información sobre los mismos. Este análisis genera conocimiento partiendo únicamente desde datos. / Aquesta tesi està dedicada a l'estudi i comprensió de xarxes biològiques a nivell molecular. Els objectius van ser analitzar la seva topologia, integrar aquesta en una anàlisi de genotip-fenotip, desenvolupar descripcions matemàtiques més completes per a elles, estudiar la seva estructura de comunitats o modularitat i comparar diferents metodologies per estimar els fluxos interns. El treball presentat en aquest document gira entorn de tres eixos principals. El primer és el biològic. ¿Què organismes han estat estudiats en aquesta tesi? Aquests van des dels agents biològics mes simples, els virus, en aquest cas el gènere Potyvirus, fins procariotes com Escherichia coli i eucariotes complexos (Arabidopsis thaliana, Nicotiana benthamiana). El segon eix fa referència a les xarxes biològiques estudiades, que van ser les xarxes d'interacció de proteïnes (PPIN) i les xarxes metabòliques (MN). L'eix final és el de les eines matemàtiques i de modelització emprades per interrogar aquestes xarxes. Aquestes eines poden classificarse en tres grans grups: teoria de grafs, modelització basada en restriccions i estadística multivariant. Aquest document està estructurat en sis parts. La primera exposa la justificació per a la tesi, mostra un mapa visual de la mateixa i enumera les seves contribucions principals. A la segona part, la bibliografia rellevant és revisada i resumida. Des del naixement i desenvolupament de la Biologia de Sistemes fins a una de les seves branques més populars: l'anàlisi de xarxes moleculars. Especial interès és posat en PPIN i MN: la seva estructura, representació i característiques. Finalment, un resum general de les eines matemàtiques utilitzades és presentat. Els capítols tercer, quart i cinquè representen el cos central d'aquesta tesi. Aquests tracten respectivament sobre la interacció de genotip-fenotip i anàlisi topolólogico clàssic de xarxes, models basats en restriccions i modelització de xarxes metabòliques i la seva estructura de comunitats. Finalment, en la sisena part les principals conclusions de la tesi són resumides i exposades. Aquesta tesi posa èmfasi en la vital importància d'estudiar els fenòmens biològics com sistemes i en la potència i prometedor futur d'aquesta anàlisi integratiu. En concret l'anàlisi de xarxes suposa un camí d'investigació fonamental per obtenir coneixement sobre aquests sistemes biològics i per extreure i mostrar informació sobre els mateixos. Aquest anàlisi genera coneixement partint únicament des de dades. / Bosque Chacón, G. (2017). Network Analysis and Modeling in Systems Biology [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/79082

Gli obbiettivi di questa tesi di dottorato erano: i) valutare l’effetto di differenti condizioni ambientali sulla biologia ed epidemiologia di isolati di B. cinerea appartenenti alle sub-popolazioni transposa e vacuma, e ii) sviluppare un nuovo modello previsionale per predire il rischio di muffa grigia nei vigneti tra le fasi fenologiche di sviluppo delle infiorescenze e maturazione dei grappoli. Gli effetti della temperatura, durata di bagnatura e umidità relativa sulle infezioni di infiorescenze e bacche di Vitis vinifera sono stati valutati con inoculazioni artificiali di isolati di B. cinerea. Gli effetti della temperatura, attività dell’acqua, umidità relativa e composizione delle bacche di uva sulla germinazione dei conidi, crescita miceliale e produzione di conidi sono stati valutati su substrati artificiali. I risultati evidenziano che la capacità di causare infezioni varia con gli isolati indipendentemente dall’appartenenza alle sub-popolazioni transposa o vacuma. Inoltre, le risposte dei differenti isolati al variare delle condizioni ambientali risultano essere simili. Basandosi sui risultati ottenuti sono state sviluppate equazioni matematiche per spiegare l’effetto dei fattori ambientali sull’incidenza delle infezioni di infiorescenze e bacche, germinazione dei conidi, crescita miceliale e produzione di conidi. Un nuovo modello previsionale è stato sviluppato per predire le infezioni di Botrytis cinerea nei vigneti utilizzando le equazioni sviluppate e seguendo un approccio meccanicistico. Il modello è stato validato per 6 anni (2009-2014) in 13 vigneti localizzati in Italia e Francia. Il nuovo modello risulta essere più completo di quelli proposti finora in letteratura e può essere utilizzato per migliorare le strategie di controllo della muffa grigia nei vigneti. / The aims of this Doctoral work were: i) to investigate the effect of different environmental conditions on biology and epidemiology of B. cinerea strains belonging the two transposon types vacuma and transposa, and ii) develop a new weather-driven mechanistic model in order to predict risk of grey mould in vineyards from early growth of inflorescences to berry ripening. The effect of temperature, wetness duration and relative humidity on infection of Vitis vinifera inflorescences and berries was investigated by artificial inoculation of B. cinerea strains. The effect of temperature, water activity, relative humidity and grape berry composition on conidia germination, colony growth and conidial production was investigated in agar-medium. The results showed that the ability to cause infection was a strain rather than a transposon genotype attribute. Moreover, the general response to different environmental conditions is similar among different B. cinerea strains. Based on these data, equations were developed to account the combined effects of environmental factors on infection incidence, conidia germination, colony growth and conidial production. A new previsional model for Botrytis cinerea infections on grapevine was elaborated using the equations developed and following a mechanistic approach. The model was validated over a 6-year period (2009 to 2014) in 13 vineyards located in different grape-growing areas of Italy and France. The model is more complete than the others proposed in literature and represents an improvement to control grey mould in vineyards.

Abstract Lymphomas are a heterogeneous group of malignancies that arise from lymphatic tissues. Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma sub-type. It is an aggressive malignancy with an increasing incidence. The prognosis of DLBCL has improved significantly, but problems also remain. The clinical significance of central nervous system (CNS) relapses has become increasingly important. As secondary CNSL (sCNSL) and primary CNS lymphoma (PCNSL) are known to have poor prognoses; the prevention of sCNSL is of crucial importance. Peripheral T-cell lymphomas (PTCL) are rare neoplasms and include several lymphoma subtypes that possess complex and also overlapping morphological and immunophenotypic characteristics. The identification of different entities has improved, but the biological knowledge remains scarce when compared to DLBCL. The optimal treatment schemas for PTCLs are still lacking and they have long been treated with the same therapies as B-cell lymphomas, mainly with suboptimal treatment results. The aim of this study was to identify poor prognostic markers in DLBCL and PTCLs and potential biological markers for the prediction of DLBCL CNS relapse. The study material included patients with systemic DLBCL without CNS affision (sDLBCL), sCNSL, PCNSL and PTCLs. The expression of epithelial-mesenchymal transition (EMT) transcription factors (TFs), chemokines and their receptors and adhesion-, migration- and inflammatory responses-associated molecules were studied by means of immunohistochemistry. IEM was used to verify the specific subcellular location of the studied molecules. GEP was performed on 12 PTCL samples in order to compare the poor prognosis group with the good prognosis group and on one sDLBCL and one sCNSL sample from the time of primary diagnosis. The EMT TFs were found to be expressed in both DLBCL and PTCLs, where they ultimately proved to have prognostic relevance as well. In PTCLs, these TFs were able to delineate a disease group with a specific gene-expression profile. CXCR4, CXCR5, ITGA10, PTEN and CD44 were found to be differently expressed between DLBCL cases with CNS affision when compared to those without CNS disease. These molecules seem to play a role in the development of CNS relapse and hopefully, if further verified, will lead towards the identification of biological markers for CNS relapse prediction. / Tiivistelmä Lymfoomat ovat heterogeeninen ryhmä imukudossyöpiä, joista diffuusi suurisoluinen B-solulymfooma (DLBCL) on yleisin alatyyppi. Se on aggressiivinen maligniteetti, jonka insidenssi on noussut viime vuosina. DLBCL potilaiden ennuste on parantunut merkittävästi, mutta yhä osa potilaista menehtyy tautiinsa. DLBCL:n keskushermostorelapsin kliininen merkitys on tänä päivänä aiempaa suurempi. Sekundaarisen keskushermostolymfooman (sCNSL) ja primaarin aivolymfooman (PCNSL) ennusteet ovat nykyhoidoilla huonoja, joten keskushermostorelapsin ennaltaehkäiseminen on tärkeää. Perifeeriset T-solulymfoomat (PTCLs) ovat ryhmä harvinaisia neoplasioita, joka sisältää useita eri alatyyppejä, joiden morfologiset ja immunofenotyyppiset ominaisuudet ovat monimuotoisia ja osin päällekkäisiä. Eri entiteettien indentifiointi on parantunut, mutta PTCL:ien biologinen tietämys on yhä DLBCL:aa heikompaa. PTCL:ien optimaalinen hoito ei ole selvillä ja tätä tautiryhmää on pitkään hoidettu samoilla hoidoilla kuin DLBCL:aa, mutta huonommilla hoitotuloksilla. Tutkimuksen tavoitteena oli löytää huonon ennusteen markkereita, joilla myös pystyttäisiin ennustamaan DLBCL:n keskushermostorelapsia. Aineisto koostui DLBCL, sCNSL, PCNSL ja PTCL näytteistä. Immunohistokemiallisilla värjäyksillä tutkittiin epiteliaalis-mesenkymaalisen transition (EMT) transkriptiotekijöitä (TF), kemokiinireseptoreita sekä adheesioon-, migraatioon ja inflammaatioon assosioituja molekyylejä. Immunoelektronimikroskopialla varmennettiin molekyylien lokalisaatio soluissa. Geeniekspressioprofiloinnilla (GEP) verrattiin kahdentoista hyvän ja huonon ennusteen ryhmään kuuluvan PTCL näytteen välisiä geeniekspressioeroja sekä kahden DLBCL potilaan näytteitä, joista toiselle kehittyi keskushermostorelapsi. EMT TF:ien ekspressiota nähtiin DLBCL ja PTCL näytteissä, joissa niillä myös todettiin olevan ennusteellista merkitystä. PTCL:ssa TF:t pystyivät erottelemaan tautiryhmän, jolla oli oma spesifinen geeniekspressioprofiilinsa. CXCR4, CXCR5, ITGA10, PTEN ja CD44 ekspressio oli erilaista systeemisissä DLBCL tapauksissa verrattuna sCNSL tapauksiin. Edellä mainituilla molekyyleillä näyttää olevan oma roolinsa keskushermostotaudin kehittymisessä ja jos nämä tulokset pystytään vahvistamaan tulevissa tutkimuksissa, johtavat ne toivottavasti kohti keskushermostorelapsiriskin tarkempaa tunnistamista.

Thesis (MEd)--Stellenbosch University, 2013. / Bibliography / ENGLISH ABSTRACT: The focus of this study is on Biology teachers in selected Namibian schools. The researcher seeks to understand how Biology teachers implement Environmental Education (EE) as part of the Biology curriculum as is mandated in the curriculum policy. Literature indicates that the EE curriculum and the science curriculum are underpinned by different philosophical and pedagogical perspectives. This prompts the research questions, and the subsequent research reported on in this thesis. During a case study guided by a qualitative interpretive paradigm, Biology teachers and Biology advisory teachers are interviewed about their experiences and actions and invited to make suggestions. In addition curriculum document analysis and observation are used. The data point to the aspects that can facilitate the implementation of EE in the curriculum, However the implementation of EE is associated with many obstacles and challenges. Teachers struggle to implement EE because of an inadequate understanding of EE and its underlying philosophy. Further enhancement of EE will also require the reduction of tensions between policy and practice, logistic barriers, and the gap between EE and science, while increasing the involvement of teachers in curriculum development, collegiality among teachers and principals, teachers and advisory teachers’ knowledge of EE, teachers and advisory teachers’ curriculum understanding and professional support. Teachers cannot achieve the objectives of EE unaided; therefore the establishment of EE co-coordinators in schools is suggested, since schools have failed to implement EE without such support. In addition, it is suggested that activity systems be studied in totality and that boundaries be crossed to enrich the outcome of EE. . Subject advisors are mandated by the government to support teachers experiencing problems, and it is suggested that ideas linked to the activity systems and activity theory be investigated and implemented to solve the problems. This should improve the implementation of EE as part of science teaching in the schools where the study was conducted and in other schools. / AFRIKAANSE OPSOMMING: Die fokus van hierdie studie was op biologie-onderwysers in geselekteerde Namibiese skole. Die navorser probeer om te verstaan hoe biologie-onderwysers Environmental Education (EE) implementeer as deel van die biologie van die kurrikulum wat in die kurrikulum beleid mandaat. Literatuur dui daarop dat die EE kurrikulum en die wetenskap kurrikulum word ondersteun deur "anders" filosofiese en pedagogiese perspektiewe wat die navorsing vrae gevra, en die daaropvolgende projek berig in hierdie tesis. Het egter Biologie-onderwysers se pre-diens onderwys sluit nie EE. Tydens 'n gevallestudie gelei deur 'n kwalitatiewe interpretatiewe paradigma, is biologie-onderwysers en biologie raadgewende onderwysers ondervra oor hul ervarings, aksies en voorstelle. Kurrikulum dokumente is ontleed en waarnemings van onderwysers in klaskamers in Benewens onderhoude en dokument-analise is gebruik. Data dui daarop dat die implementering word omring deur baie struikelblokke en uitdagings. EE is beperk tot opvoeding oor die omgewing en word gelei deur wetenskapsfilosofie. Dit lyk asof daar 'n gebrek aan begrip van EE en sy onderliggende filosofie deur onderwysers. Die meeste onderwysers noem baie struikelblokke as struikelblokke tot die implementering en dit sluit in logistieke hindernisse, en die gaping tussen EE en wetenskap, 'n gebrek van die betrokkenheid van onderwysers in kurrikulumontwikkeling, 'n gebrek van kollegialiteit onder onderwysers en skoolhoofde, gebrek aan onderwysers en raadgewende onderwysers se kurrikulum begrip en professionele ondersteuning. Terwyl, dokument-analise het gewys op die spanning tussen beleid en praktyk. Verdere data wys na die aspekte wat kan ondersteun as die inlywing van EE in die kurrikulum EE implementering, Biologie word gesien as 'n goeie voertuig vir EE, onderwysers benaderings is kennis van leerder, onderwysers se houding teenoor die implementering is positief. Advisory onderwysers kennis van hul algemene verantwoordelikhede, maar hulle lyk nie te verstaan hoe dit is van toepassing in EE weens gebrek aan EE kennis. Onderwysers kan nie die doel bereik sonder hulp, dus die vestiging van EE mede-koördineerders in skole word voorgestel, aangesien skole het misluk EE te implementeer sonder ondersteuning. Daarbenewens word dit voorgestel dat die aktiwiteit stelsels in totaliteit bestudeer word en dat die grense oorgesteek om die uitkoms te verryk. In hierdie verband, vakadviseurs mandaat deur die regering om onderwysers te ondersteun wat hindernisse ervaar, en daar word voorgestel dat die idees gekoppel aan die aktiwiteit en aktiwiteit-teorie ondersoek word en geïmplementeer word om die hindernisse aan te pak. Dit moet EE implementering te verbeter as deel van die wetenskap-onderrig in die skole waar die studie gedoen is.

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