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Coming dissertations at Uppsala university

  • Settling the Scales : Justice in International Environmental Negotiations and Beyond Author: Annkatrin Tritschoks Link: Publication date: 2020-01-23 12:36

    Parties to international negotiations typically invoke conflicting notions of justice. If these can be reconciled, this has positive effects on the negotiation process and outcome. If conflicts over justice persist, negotiations can stall or result in suboptimal outcomes. However, research to date paid scant attention to the means by which justice in international negotiations can be attained. This dissertation addresses this gap and studies two aspects of justice in international negotiations, as well as factors that shape them. The first two essays of the composite dissertation focus on perceptions of justice during negotiations; the latter two on shared justice formulas that parties devise to guide the negotiations. The empirical focus lies primarily on international environmental negotiations – an issue area where justice is central and often explicitly addressed. The final essay extends the analysis of justice to the Cyprus Talks – negotiations on a protracted social conflict that share some key characteristics with environmental negotiations in terms of complexity and interlinkages. Essay I develops the concept of justice and suggests a comprehensive approach to justice in international environmental negotiations. This conceptualization better explains variations in parties’ perceptions of justice than conventional approaches, which only cover some of the four components identified in the comprehensive approach. Essay II finds that the relationship between the chairperson and the negotiating parties affects perceptions of justice. Justice is attained, when the actors involved build a cooperative relationship based on their ability to form expectations and on a positive assessment of their exchange. If necessary, such relationship formation can be facilitated through the involvement of intermediary actors. Essay III distinguishes between three different types of shared justice formula that parties devise in international environmental negotiations. A cursory analysis shows that different explanatory factors shape the different types of shared justice formula, which furthermore are linked in different ways to negotiation effectiveness, both fruitful avenues for future research. Essay IV finds that ripeness theory – in a modified form that accounts for complexity and relationships among a multitude of players – helps to explain when parties devise a shared justice formula to guide negotiations. In conjunction, the essays contribute to current debates in the literature on justice and international negotiations, by taking account of complexity in the study of justice, and by stressing the importance of relationship formation with actors beyond the negotiating parties to attain justice.

  • Characterization of conjugated protease inhibitors Author: Erika Billinger Link: Publication date: 2020-01-23 09:03

    The overall theme of this thesis is a step by step approach for the design and characterization of conjugated protease inhibitors. This involves both a new assay method for protease activity and protease inhibition (paper I), a study of the stoichiometry for protease inhibitor interaction (paper II), design of inhibitory peptides (paper IV) and the construction of inhibitor conjugates (paper III & IV).

    (I) A model based primarily on erosion in gelatin for protease activity and inhibition studies was designed. The model was also extended to a separate protective layer covering the layer containing the target substrate. A good correlation between protease concentration and rate of erosion was observed. Similarly, increased concentration of inhibitors gave a systematic decrease in the erosion rate. Kinetic analyses of a two-layer model with substrate in the bottom layer displayed a strict dependence of both inhibitor concentration and thickness of the top “protective” layer.

    (II) The binding stoichiometry between pancreatic proteases and a serine protease inhibitor purified from potato tubers was determined by chromatography-coupled light scattering measurements. This revealed that the inhibitor was able to bind trypsin in a 2:1 complex, whereas the data for a-chymotrypsin clearly showed a limitation to 1:1 complex. The same experiment carried out with elastase and the potato inhibitor gave only weak indications of complex formation under the conditions used.

    (III) A serine protease inhibitor was extracted from potato tubers and conjugated to soluble, prefractionated dextran or inorganic particles. A certain degree of inhibitory activity was retained for both the dextran-conjugated and particle-conjugated inhibitor. The apparent Ki value of the dextran-conjugated inhibitor was found to be in the same range as that for free inhibitor. The dextran conjugate retained a higher activity than the free inhibitor after 1 month of storage at room temperature. Conjugation to oxide particles improved the heat stability of the inhibitor.

    (IV) New synthetic Leupeptin analogues, Ahx-Phe-Leu-Arg-COOH & Ahx-Leu-Leu-Arg-COOH, were synthesized with solid-phase peptide synthesis using Fmoc strategy. These tripeptide inhibitors were tight binding inhibitors to the target enzyme trypsin, similar to the natural occurring leupeptin. The phenylalanine containing synthetic analogue was conjugated to inorganic particles and agarose gel beads. In all cases, the inhibitory activity was well preserved.

  • Exploring evolutionary and chemical space using chemoinformatic tools and traditional methods in pharmacognosy Author: Astrid Henz Ryen Link: Publication date: 2020-01-23 08:25

    The number of new drugs coming to the market is declining while interest in lead discovery from natural resources is seeing a revival. Although methods for isolation and identification of natural products have advanced tremendously, methods for selection of potential leads have fallen behind. As part of the Marie Curie ITN “MedPlant: Phylogenetic exploration of medicinal plant diversity” this thesis contributed to the exploration of chemical diversity in angiosperms and the development of new tools to analyze and define the chemical potential of a plant.

    In Paper I, it was demonstrated that physicochemical properties of selected specialized metabolites change in different plant groups. Changes in properties were assessed using ChemGPS-NP and diversity was quantified by calculating the volume occupied by the compounds in chemical space. By discussing the results against the background of possible underlying evolutionary mechanisms, it was concluded that evolutionary processes are reflected in chemical property space. These results hold great value for further studies on the evolution of chemical diversity and biochemical traits in plants. The methods developed can be used e.g. to define and predict the chemical diversity of related taxa, providing a strategy for a guided plant selection in search for new drug leads.

    In Paper II, the scaffold and molecular diversity of over 5,200 sesquiterpene lactones (STLs) was investigated, using different chemoinformatic tools. Quantity and distribution of skeleton classes was determined and it was shown that different plant families possess specific sets of molecular frameworks, with considerable variation in their frequency. Clustering analysis enabled qualitative division of STLs into smaller groups with similar structural features, pointing out the differentiation of various plant groups. Including the study results, the dataset offers a compelling resource for chemosystematics, natural product research and drug lead discovery focused on STLs. It provides the basis for phylogenetic implementations due to the detailed taxonomic annotation. Since STLs display a source for new drugs, it is of high value for a guided search for plant derived drug leads.

    In Paper III, Lindera benzoin was subjected to phytochemical and pharmacological investigations. Phytochemical investigations led to the isolation of three new sesquiterpenes. As Native American tribes used this shrub for various medicinal purposes, e.g. cold remedy or diaphoretic, the isolated compounds were evaluated in vitro for their anti-inflammatory activity. In cellular assays, they reduced pro-inflammatory prostaglandin E2 production in A549 cells in a dose-dependent manner, which may rationalize the traditional use of this plant.