<p>The purpose of this Master's Thesis is to investigate the outlooks for a seed stage venture capital fund investing in biotechnology-related spinouts from public research to be established in Mecklenburg-Western Pomerania, Germany. Recommendations on how to improve any discovered deficits of the fund's prerequisites are also to be presented. </p><p>Analyses showed that the spinout potential of the research in the region is weak. The entrepreneurial prerequisites of the researchers, in terms of previous experience, business knowledge and a track record that would vouch for them being suitable entrepreneurs, are generally poor. Nor is there sufficient industry in the region to facilitate the establishment of and subsequent businesses for the spinouts. The seed fund must therefore provide any future portfolio ventures with a substantial amount of Hands-on Management. </p><p>To improve the prerequisites for the seed fund, PVA-MV must influence the researchers'attitude towards spinouts and make the monetary gains more visible. The researchers must be imbued with a business approach in their research and PVA-MV must market its services as being the intermediary of government, universities and industry and as being able to create opportunities for researchers as well as for industry. PVA-MV should also focus on the few institutes and individual researchers that do have some favourable entrepreneurial characteristics, in order to evoke professional entrepreneurs with a forming track record. To cope with the deficient prerequisites of the fund, PVA-MV must expand the competence of its own work force and focus on the rate of return rather than on building regional infrastructure pro bono as a governmental agency.</p>

<p>In spite of Sweden´s lack of formal regions, the country is evolving towards regional administrations. The regional level are to a growing extent viewed as important bases for economic growth and development. The concept of the triple helix implies that interaction between the public sector, the industry and universities is a source to economic and social development. Research has though implied that the interaction between the triple helix actors could be problematic from a multi-level governance perspective. It has been shown that since the institutional setting is horizontal and vertical fragmented, cooperation between different institutions and actors becomes difficult. In year 2005-2006 the Värmland region was one of fourteen regions in twelve countries that was included in a OECD project, that was a response to the multiplicity of initiatives across the OECD countries concerning regional development. In the report that evolved from the project actors in Värmland was recommended to improve the cooperation concerning regional development in the county. This thesis investigates the cooperation between the triple helix actors for regional growth and development in the Värmland region 1998-2008. My research questions are: Is there evidence of a lack of cooperation between the university, the public sector and the industrial actors in Värmland? And if this is the case, could these problems be related to the fragmentation of the institutional setting? The thesis is a qualitative case study, conducted through elite-interviews and document analysis. My findings implies that the cooperation between the triple helix actors in Värmland has developed dramatically the last decade. From a strive for coordination that was pervaded by institutional fragmentation to an increased closeness and mutual involvement that has come to over-bridge the institutional fragmentation on the regional level. Although, it seems like the vertical fragmentation between the regional and national level, which could impede growth and development in the region, to a great degree remains.</p>

The purpose of this Master's Thesis is to investigate the outlooks for a seed stage venture capital fund investing in biotechnology-related spinouts from public research to be established in Mecklenburg-Western Pomerania, Germany. Recommendations on how to improve any discovered deficits of the fund's prerequisites are also to be presented. Analyses showed that the spinout potential of the research in the region is weak. The entrepreneurial prerequisites of the researchers, in terms of previous experience, business knowledge and a track record that would vouch for them being suitable entrepreneurs, are generally poor. Nor is there sufficient industry in the region to facilitate the establishment of and subsequent businesses for the spinouts. The seed fund must therefore provide any future portfolio ventures with a substantial amount of Hands-on Management. To improve the prerequisites for the seed fund, PVA-MV must influence the researchers'attitude towards spinouts and make the monetary gains more visible. The researchers must be imbued with a business approach in their research and PVA-MV must market its services as being the intermediary of government, universities and industry and as being able to create opportunities for researchers as well as for industry. PVA-MV should also focus on the few institutes and individual researchers that do have some favourable entrepreneurial characteristics, in order to evoke professional entrepreneurs with a forming track record. To cope with the deficient prerequisites of the fund, PVA-MV must expand the competence of its own work force and focus on the rate of return rather than on building regional infrastructure pro bono as a governmental agency.

In the first part of the thesis, protein-ligand interactions were investigated using the chaperone LcrH, from Yersinia as target protein. The structure of a peptide encompassing the amphipathic domain (residue 278-300) of the protein YopD from Yersinia was determined by NMR in 40% TFE. The structure of YopD278-300 is a well defined α-helix with a β-turn at the C-terminus of the helix capping the structure. This turn is crucial for the structure as peptides lacking the residues involved in the turn are unstructured. NMR relaxation indicates that the peptide is not monomeric. This is supported by intermolecular NOEs found from residue Phe280 to Ile288 and Val292 indicative of a multimeric structure with the helical structures oriented in an antiparallel manner with hydrophobic residues forming the oligomer. The interaction with the chaperone LcrH was confirmed by 1H relaxation experiments and induced chemical shift changes in the peptide Protein-ligand interactions were investigated further in the second paper using a different approach. A wide range of substances were used in screening for affinity against the chaperones PapD and FimC from uropathogenic Escherichia coli using 1H relaxation NMR experiments, surface plasmon resonance and 19F NMR. Fluorine NMR proved to be advantageous as compared to proton NMR as it is straight forward to identify binding ligands due to the well resolved 19F NMR spectra. Several compounds were found to interact with PapD and FimC through induced line-broadening and chemical shift changes for the ligands. Data corroborate well with surface plasmon resonance and proton NMR experiments. However, our results indicate the substances used in this study to have poor specificity for PapD and FimC as the induced chemical shift is minor and hardly no competitive binding is observed. Paper III and IV is an investigation of the structural features of the allergenic 2S albumin Ber e 1 from Brazil nut. Ber e 1 is a 2S albumin previously identified as the major allergen of Brazil nut. Recent studies have demonstrated that endogenous Brazil nut lipids are required for an immune response to occur in vivo. The structure was obtained from 3D heteronuclear NMR experiments followed by simulated annealing using the software ARIA. Interestingly, the common fold of the 2S albumin family, described as a right-handed super helix with the core composed of a helix bundle, is not found in Ber e 1. Instead the C-terminal region is participating in the formation of the core between helix 3, 4 and 5. The dynamic properties of Ber e 1 were investigated using 15N relaxation experiments and data was analyzed using the model-free approach. The analysis showed that a few residues in the loop between helix 2 and 3 experience decreased mobility, compared to the rest of the loop. This is consistent with NOE data as long range NOEs were found from the loop to the core region of the protein. The anchoring of this loop is a unique feature of Ber e 1, as it is not found in any other structures of 2S albumins. Chemical shift mapping of Ber e 1 upon the addition of lipid extract from Brazil nut identified 4 regions in the protein where chemical shift perturbations were detected. Interestingly, all four structural clusters align along a cleft in the structure formed by helix 1-3 on one side and helix 4-5 on the other. This cleft is big enough to encompass a lipid molecule. It is therefore tempting to speculate whether this cleft is the lipid binding epitope in Ber e 1.

Gαq signaling is implicated in a number of physiological processes that include platelet activation, cardiovascular development and smooth muscle function. Historically, Gαq is known to function by activating its effector, phospholipase Cβ. Desensitization of Gαq signaling is mediated by G-protein coupled receptor kinases (GRK) such as GRK2 that phosphorylates the activated receptor and also sequesters activated Gαq and Gβγ subunits. Our crystal structure of Gαq-GRK2-Gβγ complex shows that Gαq forms effector-like interactions with the regulator of G-protein signaling (RGS) homology domain of GRK2 involving the classic effector-binding site of Gα subunits, raising the question if GRK2 can itself be a Gáq effector and initiate its own signaling cascade. In the structure, Gα and Gβγ subunits are completely dissociated from one another and the orientation of activated Gαq with respect to the predicted cell membrane is drastically different from its position in the inactive Gαβγ heterotrimer. Recent studies have identified a novel Gαq effector, p63RhoGEF that activates RhoA. Our crystal structure of the Gαq-p63RhoGEF-RhoA complex reveals that Gαq interacts with both the Dbl homology (DH) and pleckstrin homology (PH) domains of p63RhoGEF with its C-terminal helix and its effector-binding site, respectively. The structure predicts that Gαq relieves auto-inhibition of the catalytic DH domain by the PH domain. We show that Gαq activates p63RhoGEF-related family members, Trio and Kalirin, revealing several conduits by which RhoA is activated in response to Gq-coupled receptors. The Gαq effector-site interaction with p63RhoGEF/GRK2 does not overlap with the Gαq-binding site of RGS2/RGS4 that function as GTPase activating proteins (GAPs). This suggests that activated G proteins, effectors, RGS proteins, and activated receptors can form high-order complexes at the cell membrane. We confirmed the formation of RGS-Gαq-effector complexes and our results suggest that signaling pathways initiated by GRK2 and p63RhoGEF are regulated by RGS proteins via both allosteric and GAP mechanisms. Our structural studies of Gαq signaling provide insight into protein-protein interactions that induce profound physiological changes. Understanding such protein interfaces is a key step towards structure-based drug design that can be targeted to treat diseases concerned with impaired Gαq signaling. / text

We have previously shown that the arcuate organization of cell fates within the ventral midbrain critically depends upon the morphogen, Sonic Hedgehog (SHH), which is secreted from a signaling center located along the ventral midline, called the floor plate (FP). Thus, it is ultimately the specification of the FP that is responsible for the patterning and specification of ventral midbrain cell fates. Interestingly, we have found that the chick midbrain FP can be divided into medial (MFP) and lateral (LFP) regions on the basis of gene expression, mode of induction and function. Overexpression of SHH alone is sufficient to recapitulate the entire pattern of ventral cell fates, although remarkably it cannot induce MFP, consistent with the observation that the MFP is refractory to any perturbations of HH signaling. In contrast, overexpression of the winged-helix transcription factor FOXA2/HNF3[beta]robustly induced the MFP fate throughout ventral midbrain while blocking its activity resulted in the absence of the MFP. Thus, by analyzing the differences between SHH and FOXA2 blockade and overexpression, we were able to attribute functions to each the LFP and the MFP. Notably, we observed that FOXA2 overexpression caused a bending of the midbrain neurepithelium that resembled the endogenous median hinge-point observed during neurulation. Additionally, FOXA2 misexpression led to a robust induction of DA progenitors and neurons that was never observed after SHH expression alone. In contrast, we found that all other ventral cell types required HH signaling directly, at a distance and early on in the development of the midbrain when its tissue size is relatively small. Additionally, HH blockade resulted in increased cell-scatter of the arcuate territories and in the disruption of the regional boundaries between the ventral midbrain and adjacent tissue. Thus, we bring new insight into the mechanism by which midbrain FP is specified and ascribe functional roles to its subregions. We propose that while the MFP regulates the production of dopaminergic progenitors and the changes in cellshape required for bending and shaping the neural tube, the LFP appears to be largely responsible for cell survival and the formation of a spatially coherent pattern of midbrain cell fates. / text

Collaboration between academic and corporate entities has increased in recent years. On many occasions Government actors (e.g. federal laboratories) will participate in these collaborations, especially when advanced technologies are involved. The following inquiry considers the degree to which the federal entities add (scientific) value to University-Industry partnerships and how this value is spatially mediated. Quantifying degrees of the value that Government actors induce across the spectrum of University-Industry collaborative arrangements is useful for identifying scales at which intervention by federal agents is more effective and/or justified. It is anticipated that the value-added by federal agents in University-Industry collaboration is not spatially uniform but will exhibit greater profitability across specific scales of interaction. Comparing these against actual scales of interaction provides room for discussion on whether Government actors engage Universities and Industry at scales that optimize the value they introduce to these partnerships.

Le marquage protéique par fluorescence est une méthode de choix permettant d’étudier l’évolution des protéines depuis leur synthèse cellulaire jusqu’à leur dégradation, en plus de rendre possible leur localisation ainsi que la visualisation des interactions entre protéines. De cet intérêt certain ont découlé différentes techniques de marquage, dont celle présentement développée dans le groupe Keillor. Le principe de celle-ci repose sur la réaction entre deux maléimides portés par un fluorogène et une séquence peptidique cible, laquelle contient deux résidus cystéines séparés par une distance appropriée. Suite à cette double addition de thiols du peptide sur les maléimides du fluorogène, la fluorescence latente de ce dernier est régénérée, menant au marquage covalent de la protéine d’intérêt. Afin d’optimiser la spécificité et la sensibilité de cette méthode de marquage, la synthèse de nouveaux fluorogènes et l’étude de l’efficacité de quench de la fluorescence par les maléimides est présentement en cours dans les laboratoires du groupe Keillor. / The fluorescent labelling of proteins is a powerful approach for following the dynamic process of their cellular synthesis and degradation, in addition to determining their localization and protein-protein interactions. We have developed a ‘small molecule’-based labelling technique that is complementary to existing methods. Our fluorogenic approach relies on the use of dimaleimide fluorogens that react with a target peptide sequence that presents appropriately spaced, solvent-exposed Cys residues. The thiol addition reaction between target sequence and dimaleimide fluorogen restores the latent fluorescence of the latter and results in the covalent fluorescent labelling of the protein of interest. Synthesis of new fluorogens and quench efficiency studies are presently taking place in the Keillor group laboratory in order to optimize the specificity and sensitivity of the labelling method.

No description available.

Cette thèse cherche à connaître le bonheur tel que Bobin conçoit et projette dans son œuvre. Pour ce but, l’approche bachelardienne nous a servi à définir dans l’œuvre de Bobin un élément symbolique pour le bonheur : la flamme. Pour traiter la question du temps et sa complexité, très liée à notre question principale, les réflexions de Bachelard, de Bergson et de la physique moderne sur le temps sont prises en référence ainsi que la « logique du contradictoire » (de Lupasco). Les images plus attachées à l’intellect sont analysées suivant les travaux d’Henry Corbin et définies comme « images-corps-réalités ». Elles témoignent d’un regard mystique chez Bobin. Une tendance vers la géopoétique pour acquérir l’Unité du monde s’ajoute aussi à ce regard. Et une langue d’« anima/animus » et un processus de la production du sens, « hélice du sens », interviennent pour traduire l’intransmissible en fragments. Cela rend l’écriture de Bobin « fragmentaire », ce que nous avons désigné comme un nouveau genre : « poésie-prose » mystique. / This thesis looks at happiness as perceived and shown in Christian Bobin's works. For this purpose, we used the approach of Bachelard to define Bobin’s symbolic element of happiness: the flame. To deal with the problem of time and its complexity, involved in our main problem, we applied theories of Bachelard, Bergson and those of modern physics, as well as the “logic of the contradictory” (of Lupasco). The images associated with intellect are analyzed based on Henry Corbin's works and are defined as “image- body-reality”. They testify of a mysticism which tends to “geopoetic” and the Unity of the universe. A language of “anima / animus” and a process of production of meaning, “the helix of sense” intervene to translate the Intransmissible in fragments. It makes the writing of Bobin fragmentary which we underlined as a new genre: mystic “poetry-prose”.