Bioanalytical applications of multicolour bioluminescence imaging: new tools for drug discovery and development

The subject of this thesis is multicolour bioluminescence analysis and how it can provide new tools for drug discovery and development.The mechanism of color tuning in bioluminescent reactions is not fully understood yet but it is object of intense research and several hypothesis have been generated. In the past decade key residues of the active site of the enzyme or in the surface surrounding the active site have been identified as responsible of different color emission. Anyway since bioluminescence reaction is strictly dependent from the interaction between the enzyme and its substrate D-luciferin, modification of the substrate can lead to a different emission spectrum too. In the recent years firefly luciferase and other luciferases underwent mutagenesis in order to obtain mutants with different emission characteristics. Thanks to these new discoveries in the bioluminescence field multicolour luciferases can be nowadays employed in bioanalysis for assay developments and imaging purposes. The use of multicolor bioluminescent enzymes expanded the potential of a range of application in vitro and in vivo. Multiple analysis and more information can be obtained from the same analytical session saving cost and time. This thesis focuses on several application of multicolour bioluminescence for high-throughput screening and in vivo imaging. Multicolor luciferases can be employed as new tools for drug discovery and developments and some examples are provided in the different chapters. New red codon optimized luciferase have been demonstrated to be improved tools for bioluminescence imaging in small animal and the possibility to combine red and green luciferases for BLI has been achieved even if some aspects of the methodology remain challenging and need further improvement. In vivo Bioluminescence imaging has known a rapid progress since its first application no more than 15 years ago. It is becoming an indispensable tool in pharmacological research. At the same time the development of more sensitive and implemented microscopes and low-light imager for a better visualization and quantification of multicolor signals would boost the research and the discoveries in life sciences in general and in drug discovery and development in particular.

Technology acquisition through licensing. Implications for firm strategy

Nowadays licensing practices have increased in importance and relevance driving the widespread diffusion of markets for technologies. Firms are shifting from a tactical to a strategic attitude towards licensing, addressing both business and corporate level objectives. The Open Innovation Paradigm has been embraced. Firms rely more and more on collaboration and external sourcing of knowledge. This new model of innovation requires firms to leverage on external technologies to unlock the potential of firms’ internal innovative efforts. In this context, firms’ competitive advantage depends both on their ability to recognize available opportunities inside and outside their boundaries and on their readiness to exploit them in order to fuel their innovation process dynamically. Licensing is one of the ways available to firm to ripe the advantages associated to an open attitude in technology strategy. From the licensee’s point view this implies challenging the so-called not-invented-here syndrome, affecting the more traditional firms that emphasize the myth of internal research and development supremacy. This also entails understanding the so-called cognitive constraints affecting the perfect functioning of markets for technologies that are associated to the costs for the assimilation, integration and exploitation of external knowledge by recipient firms. My thesis aimed at shedding light on new interesting issues associated to in-licensing activities that have been neglected by the literature on licensing and markets for technologies. The reason for this gap is associated to the “perspective bias” affecting the works within this stream of research. With very few notable exceptions, they have been generally concerned with the investigation of the so-called licensing dilemma of the licensor – whether to license out or to internally exploit the in-house developed technologies, while neglecting the licensee’s perspective. In my opinion, this has left rooms for improving the understanding of the determinants and conditions affecting licensing-in practices. From the licensee’s viewpoint, the licensing strategy deals with the search, integration, assimilation, exploitation of external technologies. As such it lies at the very hearth of firm’s technology strategy. Improving our understanding of this strategy is thus required to assess the full implications of in-licensing decisions as they shape firms’ innovation patterns and technological capabilities evolution. It also allow for understanding the so-called cognitive constraints associated to the not-invented-here syndrome. In recognition of that, the aim of my work is to contribute to the theoretical and empirical literature explaining the determinants of the licensee’s behavior, by providing a comprehensive theoretical framework as well as ad-hoc conceptual tools to understand and overcome frictions and to ease the achievement of satisfactory technology transfer agreements in the marketplace. Aiming at this, I investigate licensing-in in three different fashions developed in three research papers. In the first work, I investigate the links between licensing and the patterns of firms’ technological search diversification according to the framework of references of the Search literature, Resource-based Theory and the theory of general purpose technologies. In the second paper - that continues where the first one left off – I analyze the new concept of learning-bylicensing, in terms of development of new knowledge inside the licensee firms (e.g. new patents) some years after the acquisition of the license, according to the Dynamic Capabilities perspective. Finally, in the third study, Ideal with the determinants of the remuneration structure of patent licenses (form and amount), and in particular on the role of the upfront fee from the licensee’s perspective. Aiming at this, I combine the insights of two theoretical approaches: agency and real options theory.

Il processo migratorio come determinante della salute mentale: l'esperienza del Centro di Consultazione Socio-Culturale nel Distretto di Pianura Est, AUSL di Bologna.

La ricerca in oggetto ha analizzato le relazioni tra migrazione e salute mentale nel Distretto di Pianura Est dell'AUSL di Bologna. Attraverso un dispositivo d’indagine multi-disciplinare basato sui quadri teorici dell'Antropologia Medica Critica, della Salute Pubblica e della Psichiatria, la ricerca si è inserita nell’ampio contesto di sperimentazione di un innovativo modello di assistenza per pazienti migranti, denominato Centro di Consultazione Socio- Culturale. L'architettura dello studio si rifà a un modello di Ricerca-Azione Partecipata e Multi-Situata fondato su un approccio analitico e auto-riflessivo, il quale ha consentito di problematizzare, oltre alle azioni e alle traiettorie dei vari soggetti che operano nel campo della ricerca, anche le categorie oggetto della ricerca stessa. L'analisi, profondamente radicata nel dato empirico, è stata condotta a partire dall'esperienza degli attori sociali coinvolti. Le esperienze, le informazioni e le rappresentazioni reciproche sono state co-costruite in forma partecipativa attraverso l'uso combinato di metodologie quali-quantitative proprie sia delle discipline sanitarie sia di quelle sociali. Come materiali della ricerca sono stati utilizzati: dati primari e secondari prodotti dalle istituzioni e dalle organizzazioni del territorio stesso; informazioni provenienti dall'osservazione partecipante; colloqui con informatori-chiave; interviste semi-strutturate con decisori politici, amministratori, organizzazioni del territorio, operatori dei servizi, cittadini e pazienti. La ricerca ha dimostrato la validità delle prospettive teoriche utilizzate e delle strategie di lavoro proposte. Il modello di lavoro multi-disciplinare e multi-metodologico si è rivelato produttivo nell'indagare congiuntamente le prospettive degli attori coinvolti insieme alle loro traiettorie, alle reciproche interconnessioni e alle relazioni tra processi locali e globali. L’analisi auto-riflessiva ha consentito di analizzare le attività del Centro di Consultazione evidenziandone vantaggi e limiti. Infine, la collaborazione tra Salute Pubblica e Antropologia Medica Critica ha dimostrato una grande potenzialità e produttività sia sul versante della ricerca scientifica sia su quello dell'assistenza sanitaria.