On the functional ordering of biomembranes : Implications for drug binding

Cells are packed with membrane structures, defining the inside and outside, and the different subcellular compartments. These membranes consisting mainly of phospholipids have a variety of functions in addition to providing a permeability barrier for various compounds. These functions involve cellular signaling, where lipids can act as second messengers, or direct regulation of membrane associating proteins. The first part of this study focuses on relating some of the physicochemical properties of membrane lipids to the association of drug compounds to membranes. A fluorescence based method is described allowing for determination of the membrane association of drugs. This method was subsequently applied to a novel drug, siramesine, previously shown to have anti-cancer activity. Siramesine was found to associate with anionic lipids. Especially interesting is its strong affinity for a second messenger lipid phosphatidic acid. This is the first example of a small molecule drug compound specifically interacting with a cellular lipid. Phosphatidic acid in cells is required for the activation of many signaling pathways mediating growth and proliferation. This provides an intriguing possibility for a simple molecular mechanism of the observed anti-cancer activity of siramesine. In the second part the thermal behavior and self assembly of charged and uncharged membrane assemblies was studied. Strong inter-lamellar co-operativity was observed for multilamellar DPPC vesicles using fluorescence techniques together with calorimetry. The commonly used membrane models, large unilamellar vesicles (LUV) and multilamellar vesicles (MLV) were found to possess different biophysical properties as interlamellar interactions of MLVs drive segregation of a pyrene labeled lipid analogue into clusters. The effect of a counter-ion lattice on the self assembly of a cationic gemini surfactant was studied. The presence of NaCl strongly influenced the thermal phase behavior of M-1 vesicles, causing formation of giant vesicles upon exceeding a phase transition temperature, followed by a subsequent transition into a more homogenous dispersion. Understanding the underlying biophysical aspects of cellular membranes is of fundamental importance as the complex picture of the structure and function of cells is evolving. Many of the cellular reactions take place on membranes and membranes are known to regulate the activity of many peripheral and intergral membrane associating proteins. From the point of view of drug design and gene technology, membranes can provide an interesting target for future development of drugs, but also a vehicle sensitive for environmental changes allowing for encapsulating drugs and targeting them to the desired site of action.

Struggles over resources and representations in territorial conflicts in the Northern Autonomous Atlantic Region (RAAN), Nicaragua

Territoriality is a central issue in indigenous peoples struggles. The territorial struggles involve struggles over the control of natural resources and over political participation and representation, but also over the perception of territorial rights and the symbolic representation of the territory. These struggles are carried through both in material and symbolic ways through recurring to different discourses and representations that provide legitimation for the territorial claims of the group. The study is located in the Northern Autonomous Atlantic Region of Nicaragua. The study concerns the territorial strategies, conceptions and practices of the indigenous people and other actors. Territorial conflicts exist between the autonomous region and the central government of Nicaragua, between mestizo settlers and indigenous people, between different indigenous groups, and between these and development agents such as conservation projects. The study focuses on how territorial discourses and representations are used to legitimate territorial control. Environmental, historical and cartographical discourses are the most important discourses recurred to. The influence of discourses and representations on the territorial practices and policies of the different actors, the links between the local struggles and global processes, and the broader structural factors impacting on the territorial struggles are also analysed. Among the structural factors are the problems related to land tenure and management and the use of natural resources, the advance of the agricultural frontier, the institutional weaknesses of the central and regional governments and the legislative processes. The territorial discourses are both recurred to in a strategic way and also grounded in local ideals and practices. The discourses have produced real effects for example in legislation, land tenure systems, political representation and environmental practices. Although the use of discourses and representations are an important power tool in territorial struggles, territorial control cannot be effectively accomplished merely through representing territorial claims in a legitimate way or through reforming legislation, as the conflicts are also largely a result of structural factors affecting the region. The fieldwork was carried out during a total of twelve months between 2000 and 2002. The research methods used were semi-structured interviews, participant observation and participatory research methods. A broad range of literary sources were also used to collect data. The study is located within the field of critical political geography with a discursive political ecology approach. It can be called a critical realist approach to the discursive analysis of indigenous territoriality.