I will investigate what mediates an effective human immune response to infection with Plasmodium falciparum malaria. I will approach this through studying the Fulani ethnic group of West Africa, who are relatively resistant to malaria infection. The basis of the Fulani protection from malaria has never been established. However, we have performed a pilot study which suggests that reduced levels of adenosine-to-inosine (A-to-I) editing of RNA by ADAR1 following P. falciparum infection can drive a more effective innate immune response in the Fulani. We have an established collaboration with the Malaria Research and Training Centre at University of Sciences Technique and Technology in Mali, who have strong ties to the Fulani community. At Stockholm University, I have had the opportunity to develop a strong background in immunology research techniques, specifically utilizing in vitro models of malaria infection in human monocytes, in the research group of Eva Sverremark-Ekström. As the role of RNA modifications is an emerging field, I plan to move to CEITEC, Czech Republic, to work with Mary O’Connell, who has pioneered the role of A-to-I RNA modification in the innate immune response to RNA. Specifically, we will test the hypothesis that reduced rates of A-to-I editing of RNA in the Fulani following infection enables them to mount a more effective innate immune response to P. falciparum malaria, and contributes to their relative protection from the disease. Further, targeting of ADAR1 and/or reduction in levels of A-to-I RNA levels may present a novel strategy to boost effective immune response to malaria.
Characteristic by indisputable quality and profound cultural syncretism, the art of medieval Georgia arose from a cultural crossroads between Europe and Asia and has unjustly been put off the side-lines of the art historical canon. The marginalization is due in large part to historiographic factors. Russian and Western scholars presented it from a colonial perspective as the art of the Byzantine periphery, analogous to the marginal political position of the South Caucasus within the USSR. In contrast, Georgian scholars throughout the 20th century were determined to demonstrate that Georgian “national” medieval art was fully autonomous and original. That reflected the Georgian impulse to achieve political autonomy within the Soviet Union. Deploying methods proper to the epistemology of art history, DeMGeo aims to investigate the historiographic construction of the three dominant narratives – Russian, Western, and Georgian – developed in art history textbooks about Georgian medieval art, within the context of the 20th century political and social history. By revealing and deconstructing political and ideological strategies in past scholarship, the ambition is to de-marginalize Georgian medieval art and to prepare the terrain for new research in the field within the framework of a transcultural approach. The results will be applicable for other marginalized art histories marked by contested historiography, specifically in the context of the countries behind the Iron Curtain, and/or of the young nation-states born from multi-ethnic empires. The project is in line with EU cultural diplomacy, contributing to debates about World cultural heritage as a peace-building and soft power tool in societies marked by conflict. DeMGeo will be targeted at diverse audiences, thanks to the support of the CEMS (HI), developing and applying innovative methods in the communication of academic research.
Antibiotic-resistant bacteria cause more than 700 000 deaths per year, and the forecast is 10 million per year in 2050. Moreover, emerging strains of bacteria resistant to all available antibiotics may lead to a global post-antibiotic era. Because of this threat, the WHO and the UN are encouraging the research and development of new treatments. The aim of this proposal is to design new peptides that selectively target and disrupt the membranes of pathogens but not those of human cells. To obtain such peptides, we will develop an innovative coarse-grained model of membranes and an original growth method, which will enable us to establish the relationship between peptide sequence motifs and their affinity to membranes with specific lipid compositions. Moreover, we will determine the critical peptide properties required for membrane disruption via the formation of transmembrane pores and spontaneous peptide translocation across membranes by devising new collective variables capturing these processes. Our computational advances will be complemented by experimental verification from peptide-membrane affinity measurements plus leakage and flip-flop fluorescence assays assessing membrane disruption. The most effective peptides will be evaluated for antimicrobial activity and human cell toxicity using growth inhibition and hemolytic assays, respectively. We will investigate mixtures of peptides for their synergistic increase in antimicrobial activity, and we will uncover the molecular mechanism of their synergism. The peptide behaviour will be quantified under equilibrium and more biologically relevant non-equilibrium conditions. The methods and knowledge obtained within this project will not only enable us to determine new peptides selectively killing bacteria, but will also enable the development of peptides targeted against membranes of enveloped viruses, cancer cells, or even cellular organelles with potential application as sensors, biomarkers, or therapeutics.