A territorial approach to R&D subsidies: Empirical evidence for Catalonian firms

Using a database of 2,263 responses to R&D public calls in Catalonia, during the period 2007–2010, this paper proceeds to analyse the potential interaction of the territorial and policy dimensions with the propensity to apply for, and be awarded, a public R&D subsidy. Controlling for characteristics at the firm and project level, we estimate models using a twostep procedure. In the first step, our results suggest that large firms which export and which belong to high-tech manufactures are more likely to participate in a public R&D call. Furthermore, both urban location and past experience of such calls have a positive effect. Our territorial proxy of information spillovers shows a positive sign, but this is only significant at intra-industry level. Membership of one of the sectors prioritized by the Catalan government, perhaps surprisingly, does not have a significant impact. In the second step, our results show that cooperative projects, SMEs or old firms shows a positive effect on the probability of obtaining a public subsidy. Finally, the cluster policy does not show a clear relationship with the public R&D call, suggesting that cluster policies and R&D subsidies follow different goals. Our results are in line with previous results in the literature, but they highlight the unequal territorial distribution of the firms which apply and the fact that policymakers should interlink the decision criteria for their public call with other policies.

Dynamic Capabilities and Real Options

Tutkielman tavoitteena oli selvittää dynaamisten kyvykkyyksien teorian kehittymistä ja nykytilaa. Työssä tarkastellaan myös mahdollisuuksia yhdistää reaalioptioajattelua ja dynaamisten kyvykkyyksien teoriaa. Tutkielma on toteutettu teoreettisena kirjallisuuskatsauksena. Dynaamisten kyvykkyyksien teorian mukaan muuttuvassa toimintaympäristössä yritysten kilpailuetu perustuu kykyyn rakentaa, yhdistää ja muokata resursseja ja kyvykkyyksiä. Yritysten täytyy pystyä löytämään, sulauttamaan ja muuntamaan tietoa voidakseen tunnistaa uusia mahdollisuuksia ja pystyäkseen reagoimaan niihin. Tutkielma tuo esille uusia yhteyksiä dynaamisten kyvykkyyksien teorian ja yritysten käyttäytymisen välillä. Reaalioptioajattelu auttaa tunnistamaan yrityksen rajojen määrittämiseen vaikuttavia tekijöitä. Työssä tehdään ehdotuksia dynaamisten kyvykkyyksien teorian jatkotutkimusta varten.

Corporate political activity and firm outcomes: A meta-analysis

Using meta-analytic methods on a sample of 74 studies, we explore the links between CPA and public policy outcomes, and between CPA and firm outcomes. We find that CPA has at best a weak effect and that it appears to be better at maintaining public policy than changing them.

International Expansion, Diversification and Regulated Firm Nonmarket Strategy

Previous studies have shown that regulated firms diversify for reasons that are different than for unregulated firms. We explore some of these differences by providing a theoretical model that starts by considering the firm-regulator relationship as an incomplete information issue, in which a regulated incumbent has knowledge that the regulator does not have, but the firm cannot convey hard information about this knowledge. The incumbent faces both market and nonmarket competition from a new entrant. In that context, we show that when the firm faces tough nonmarket competition domestically, going abroad can create a mechanism that makes information transmission to the regulator more credible. International expansion can thus be a way to solve domestic nonmarket issues in addition to being a catalyst for growth.

Diversidade genética intra e interespecífica de pitaya com base nas características físico-químicas de frutos

Neste trabalho, objetivou-se avaliar a diversidade genética intra e interespecífica de 21 acessos de duas espécies de pitaya, Hylocereus undatus (Haw) Britton & Rose e Selenicereus setaceus Salm-Dyck. A. Bereger ex Werderm., com base nas características físico-químicas dos frutos. Foram avaliadas as características: comprimento, diâmetro, sólidos solúveis, massa total da casca e da polpa dos frutos. Com base na média das características físico-químicas de cada acesso, foram calculados índices de distância genética entre cada par de acessos com base na distância euclidiana média padronizada. A partir da matriz de distâncias genéticas, realizaram-se análises de agrupamento por meio de dendograma e dispersão gráfica baseada em escalas multidimensionais. As variáveis analisadas apresentaram diferentes contribuições relativas para a diversidade genética. O diâmetro do fruto foi a variável que teve maior contribuição no índice de diversidade genética (27,45 %), seguido pela massa total do fruto (25,43 %) e pela massa da polpa do fruto (24,67 %). As distâncias genéticas entre os 21 acessos de pitaya variaram entre 2,2 e 540,1. A análise de agrupamento permitiu subdividir os 21 acessos em dois grupos de similaridade genética, Hylocereus e Selenicereus, a uma distância genética relativa de 100. As características físico-químicas dos frutos evidenciaram alta diversidade genética entre os acessos das espécies H. undatus e S. setaceus.

Optimising approaches to active immunotherapy of cancer

The design of therapeutic cancer vaccines is aimed at inducing high numbers and potent T cells that are able to target and eradicate malignant cells. This calls for close collaboration between cells of the innate immune system, in particular dendritic cells (DCs), and cells of the adaptive immune system, notably CD4+ helper T cells and CD8+ cytotoxic T cells. Therapeutic vaccines are aided by adjuvants, which can be, for example, Toll¬like Receptor agonists or agents promoting the cytosolic delivery of antigens, among others. Vaccination with long synthetic peptides (LSPs) is a promising strategy, as the requirement for their intracellular processing will mainly target LSPs to professional antigen presenting cells (APCs), hence avoiding the immune tolerance elicited by the presentation of antigens by non-professional APCs. The unique property of antigen cross-processing and cross-presentation activity by DCs plays an important role in eliciting antitumour immunity given that antigens from engulfed dead tumour cells require this distinct biological process to be processed and presented to CD8+T cells in the context of MHC class I molecules. DCs expressing the XCR1 chemokine receptor are characterised by their superior capability of antigen cross- presentation and priming of highly cytotoxic T lymphocyte (CTL) responses. Recently, XCR1 was found to be also expressed in tissue-residents DCs in humans, with a simitar transcriptional profile to that of cross- presenting murine DCs. This shed light into the value of harnessing this subtype of XCR1+ cross-presenting DCs for therapeutic vaccination of cancer. In this study, we explored ways of adjuvanting and optimising LSP therapeutic vaccinations by the use, in Part I, of the XCLl chemokine that selectively binds to the XCR1 receptor, as a mean to target antigen to the cross-presenting XCR1+ DCs; and in Part II, by the inclusion of Q.S21 in the LSP vaccine formulation, a saponin with adjuvant activity, as well as the ability to promote cytosolic delivery of LSP antigens due to its intrinsic cell membrane insertion activity. In Part I, we designed and produced XCLl-(OVA LSP)-Fc fusion proteins, and showed that their binding to XCR1+ DCs mediate their chemoattraction. In addition, therapeutic vaccinations adjuvanted with XCLl-(OVA LSP)-Fc fusion proteins significantly enhanced the OVA-specific CD8+ T cell response, and led to complete tumour regression in the EL4-OVA model, and significant control of tumour growth in the B16.0VA tumour model. With the aim to optimise the co-delivery of LSP antigen and XCLl to skin-draining lymph nodes we also tested immunisations using nanoparticle (NP)-conjugated OVA LSP in the presence or absence of XCLl chemokine. The NP-mediated delivery of LSP potentiated the CTL response seen in the blood of vaccinated mice, and NP-OVA LSP vaccine in the presence of XCLl led to higher blood frequencies of OVA-specific memory-precursor effector cells. Nevertheless, in these settings, the addition XCLl to NP-OVA LSP vaccine formulation did not increase its antitumour therapeutic effect. In the Part II, we assessed in HLA-A2/DR1 mice the immunogenicity of the Melan-AA27L LSP or the Melan-A26. 35 AA27l short synthetic peptide (SSP) used in conjunction with the saponin adjuvant QS21, aiming to identify a potent adjuvant formulation that elicits a quantitatively and qualitatively strong immune response to tumour antigens. We showed a high CTL immune response elicited by the use of Melan-A LSP or SSP with QS21, which both exerted similar killing capacity upon in vivo transfer of target cells expressing the Melan-A peptide in the context of HLA-A2 molecules. However, the response generated by the LSP immunisation comprised higher percentages of CD8+T cells of the central memory phenotype (CD44hl CD62L+ and CCR7+ CD62L+) than those of SSP immunisation, and most importantly, the strong LSP+QS21 response was strictly CD4+T cell-dependent, as shown upon CD4 T cell depletion. Altogether, these results suggest that both XCLl and QS21 may enhance the ability of LSP to prime CD8 specific T cell responses, and promote a long-term memory response. Therefore, these observations may have important implications for the design of protein or LSP-based cancer vaccines for specific immunotherapy of cancer -- Les vacans thérapeutiques contre le cancer visent à induire une forte et durable réponse immunitaire contre des cellules cancéreuses résiduelles. Cette réponse requiert la collaboration entre le système immunitaire inné, en particulier les cellules dendrites (DCs), et le système immunitaire adaptatif, en l'occurrence les lymphocytes TCD4 hdper et CD8 cytotoxiques. La mise au point d'adjuvants et de molécules mimant un agent pathogène tels les ligands TLRs ou d'autres agents facilitant l'internalisation d'antigènes, est essentielle pour casser la tolérance du système immunitaire contre les cellules cancéreuses afin de générer une réponse effectrice et mémoire contre la tumeur. L'utilisation de longs peptides synthétiques (LSPs) est une approche prometteuse du fait que leur présentation en tant qu'antigénes requiert leur internalisation et leur transformation par les cellules dendrites (DCs, qui sont les mieux à même d'éviter la tolérance immunitaire. Récemment une sous-population de DCs exprimant le récepteur XCR1 a été décrite comme ayant une capacité supérieure dans la cross-présentation d'antigènes, d'où un intérêt à développer des vaccins ciblant les DCs exprimant le XCR1. Durant ma thèse de doctorat, j'ai exploré différentes approches pour optimiser les vaccins avec LSPs. La première partie visait à cibler les XCR1-DCs à l'aide de la chemokine XCL1 spécifique du récepteur XCR1, soit sou s la forme de protéine de fusion XCL1-OVA LSP-Fc, soit associée à des nanoparticules. La deuxième partie a consisté à tester l'association des LSPs avec I adjuvant QS21 dérivant d'une saponine dans le but d'optimiser l'internalisation cytosolique des longs peptides. Les protéines de fusion XCLl-OVA-Fc développées dans la première partie de mon travail, ont démontré leur capacité de liaison spécifique sur les XCRl-DCs associée à leur capacité de chemo-attractio. Lorsque inclues dans une mmunisation de souris porteuse de tumeurs établies, ces protéines de fusion XCL1-0VA LSP-Fc et XCLl-Fc plus OVA LSP ont induites une forte réponse CDS OVA spécifique permettant la complète régression des tumeurs de modèle EL4- 0VA et un retard de croissance significatif de tumeurs de type B16-0VA. Dans le but d'optimiser le drainage des LSPs vers es noyaux lymphatiques, nous avons également testé les LSPs fixés de manière covalente à des nanoparticules co- injectees ou non avec la chemokine XCL1. Cette formulation a également permis une forte réponse CD8 accompagnée d'un effet thérapeutique significatif, mais l'addition de la chemokine XCL1 n'a pas ajouté d'effet anti-tumeur supplémentaire. Dans la deuxième partie de ma thèse, j'ai comparé l'immunogénicité de l'antigène humain Melan A soit sous la forme d un LSP incluant un épitope CD4 et CD8 ou sous la forme d'un peptide ne contenant que l'épitope CD8 (SSP) Les peptides ont été formulés avec l'adjuvant QS21 et testés dans un modèle de souris transgéniques pour les MHC let II humains, respectivement le HLA-A2 et DR1. Les deux peptides LSP et SSP ont généré une forte réponse CD8 similaire assoc.ee a une capacité cytotoxique équivalente lors du transfert in vivo de cellules cibles présentant le peptide SSP' Cependant les souris immunisées avec le Melan A LSP présentaient un pourcentage plus élevé de CD8 ayant un Phénotype «centra, memory» (CD44h' CD62L+ and CCR7+ CD62L+) que les souris immunisées avec le SSP, même dix mois après I'immunisation. Par ailleurs, la réponse CD8 au Melan A LSP était strictement dépendante des lymphocytes CD4, contrairement à l'immunisation par le Melan A SSP qui n'était pas affectée. Dans l'ensemble ces résultats suggèrent que la chemokine XCL1 et l'adjuvant QS21 améliorent la réponse CD8 à un long peptide synthétique, favorisant ainsi le développement d'une réponse anti-tumeur mémoire durable. Ces observations pourraient être utiles au développement de nouveau vaccins thérapeutiques contre les tumeurs.