Uppsala University

The European Union targets a climate-neutral economy by 2050. In the context of this initiative, hydrogen gas (H2) is regarded as a promising energy carrier; however, about 95% of the H2 industrially consumed originates from steam reformation of fossil resources and is associated with significant CO2 release. High-efficiency H2 catalysts based on rare elements like platinum are not affordable on a larger scale. To address the global need for green energy, catalysts composed of earth abundant elements are desirable. Natures’ Hydrogen Evolution Catalyst is the enzyme [FeFe]-hydrogenase. It catalyses H2 production with high rates (10 kHz), in aqueous solution (pH 7), and at low over potentials (-420 mV vs. SHE). [FeFe]-hydrogenase inspired the design of numerous synthetic catalysts, none of which could rival the efficiency of the native system. Basic research is necessary to understand hydrogenase catalysis, in particular regarding the metal hydride chemistry prior H2 release. The objective of this action is to investigate the fundamental hydride chemistry of [FeFe]-hydrogenases under turnover conditions. Catalysis will be initiated via a laser pulse and monitored by transient absorption spectroscopy. Such pump/probe experiments allow following reaction intermediates with sub-turnover time resolution. The results of this action will inspire a targeted design of synthetic catalyst based on earth abundant elements. Moreover, the developed methodology will facilitate a detailed investigation of related enzymes, catalysing global key processes in nature like N2 or CO2 fixation.

Virtually all terrestrial plants depend on symbiotic interactions with fungi. Arbuscular mycorrhizal (AM) fungi evolved over 450 million years ago, are obligate biotrophs and cannot complete their lifecycle without obtaining carbon from host roots. Mediating nutrient uptake and sequestering carbon in soil this symbiosis lie at the core of all terrestrial ecosystems. Plants on the other hand are facultative mycotrophs but under natural conditions all host roots are colonized as a result of multiple beneficial effects of AM fungi. In the symbiosis, both plants and fungi are promiscuous, forming interactions across individuals and species. In the absence of host-symbiont specificity and given their inability to discriminate among partners prior to interaction, evolutionary theory predicts that “free riders” would evolve and spread. Yet AM fungi remain evolutionary and ecologically successful. I propose that this is thanks to their unique genomic organization, a temporally dynamic heterokaryosis. Unlike other eukaryotes, AM fungi have no single nucleate stage in their life cycle, instead they reproduce asexually by forming large multinucleate spores. Genetic variation is high and nuclei can migrate and mix within extensive mycelial networks. My group has recently established a single nucleus genomics method to study genetic variation among nuclei within AM fungi. With this method I can resolve the extent of heterokaryosis in AM fungi and its temporal dynamics. I will study the emergence of “free riders” upon intra organismal segregation of genetically distinct nuclei during AM fungal adaptation to host. Further I will study how hyphal fusion and nuclear mixing counteract segregation to stabilize the symbiosis. The research program has great potential for novel discoveries of fundamental importance to evolutionary and environmental biology and will also contribute to agricultural practice and management of terrestrial ecosystems.

My research program explores molecular interplay between drug, dosage form and the complex environment of the gastrointestinal tract (GIT). Drug molecules currently being discovered to cure e.g. CNS diseases, cancer and the metabolic syndrome show poor water solubility and 70-90% of recently discovered drugs have too poor solubility to allow absorption from the GIT. For such compounds the dosage form can significantly improve the absorption. My long-term goal is to establish a computational platform that predicts, from molecular structures and computational tools, the development potential of drug molecules to well-functioning orally administered medicines. A major gap to understand drug performance in the intestine is the poor knowledge of the dynamics of solubilizing lipoidal nanostructures (micelles, vesicles, oil droplets) present in the fluid. This project explores restructuring of these lipid colloids in response to intake of food or dosage forms, enzymatic digestion, absorption and transit along the GIT. Novel experimental tools are developed to reveal the impact of these nanostructures on drug solubilization, supersaturation and likelihood of precipitation in vivo, all being important for drug absorption. The experimental results are fed into in silico models taking use of Molecular Dynamics simulations to develop a computational platform predicting drug performance in the dynamic intestinal milieu. The novel tools designed herein will allow dosage forms that improve performance and increase drug absorption after oral administration to, for the first time, be designed by computational means. The results of this project, in particular the novel in silico tools exploring rearrangement of lipoidal nanostructures, are highly important to related areas such as GIT disease models and food processing but also have wider applications in e.g. studies of intracellular vesicle rearrangements and transport processes in plants.