Recent advances in malaria genomics and epigenomics

Malaria continues to impose a significant disease burden on low- and middle-income countries in the tropics. However, revolutionary progress over the last 3 years in nucleic acid sequencing, reverse genetics, and post-genome analyses has generated step changes in our understanding of malaria parasite (Plasmodium spp.) biology and its interactions with its host and vector. Driven by the availability of vast amounts of genome sequence data from Plasmodium species strains, relevant human populations of different ethnicities, and mosquito vectors, researchers can consider any biological component of the malarial process in isolation or in the interactive setting that is infection. In particular, considerable progress has been made in the area of population genomics, with Plasmodium falciparum serving as a highly relevant model. Such studies have demonstrated that genome evolution under strong selective pressure can be detected. These data, combined with reverse genetics, have enabled the identification of the region of the P. falciparum genome that is under selective pressure and the confirmation of the functionality of the mutations in the kelch13 gene that accompany resistance to the major frontline antimalarial, artemisinin. Furthermore, the central role of epigenetic regulation of gene expression and antigenic variation and developmental fate in P. falciparum is becoming ever clearer. This review summarizes recent exciting discoveries that genome technologies have enabled in malaria research and highlights some of their applications to healthcare. The knowledge gained will help to develop surveillance approaches for the emergence or spread of drug resistance and to identify new targets for the development of antimalarial drugs and perhaps vaccines

Reconceptualising Legal Education after War

This paper considers the impact of war on legal education and assesses the contributions of legal education to post-conflict reconstruction and reconciliation

An examination of the molecular mechanisms controlling the tissue accumulation of conjugated linoleic acid (CLA) in cattle

End of project reportLong chain n-3 polyunsaturated fatty acids (n-3 PUFA) and conjugated linoleic acid (CLA) have demonstrable and potential human health benefits in terms of preventing cancer, diabetes, chronic inflammation, obesity and coronary heart disease. Supplementation of cattle diets with a blend of oils rich in n-3 PUFA and linoleic acid have a synergistic effect on the accumulation of ruminal and tissue concentrations of trans vaccenic acid (TVA), the main substrate for ?-9 desaturase which is responsible for de novo tissue synthesis of the cis 9, trans 11 isomer of CLA. This dietary strategy translates into increases in milk concentrations of CLA in dairy cows; however, concentrations in the muscle of beef animals have not always been increased. There is an apparent paradox in that n-3 PUFA supplementation enhances ruminal synthesis of trans-vaccenic acid (TVA), but then inhibits its conversion to CLA possibly through altering the activity of ?-9 desaturase. Recently, the promoter regions of the bovine ?- 9 desaturase gene has been isolated and analysed and has been shown to contain a conserved PUFA response region

Functional profiles of orphan membrane transporters in the life cycle of the malaria parasite

Assigning function to orphan membrane transport proteins and prioritizing candidates for detailed biochemical characterization remain fundamental challenges and are particularly important for medically relevant pathogens, such as malaria parasites. Here we present a comprehensive genetic analysis of 35 orphan transport proteins of Plasmodium berghei during its life cycle in mice and Anopheles mosquitoes. Six genes, including four candidate aminophospholipid transporters, are refractory to gene deletion, indicative of essential functions. We generate and phenotypically characterize 29 mutant strains with deletions of individual transporter genes. Whereas seven genes appear to be dispensable under the experimental conditions tested, deletion of any of the 22 other genes leads to specific defects in life cycle progression in vivo and/or host transition. Our study provides growing support for a potential link between heavy metal homeostasis and host switching and reveals potential targets for rational design of new intervention strategies against malaria

Copper-transporting ATPase is important for malaria parasite fertility

Homeostasis of the trace element copper is essential to all eukaryotic life. Copper serves as a cofactor in metalloenzymes and catalyses electron transfer reactions as well as the generation of potentially toxic reactive oxygen species. Here, we describe the functional characterization of an evolutionarily highly conserved, predicted copper-transporting P-type ATPase (CuTP) in the murine malaria model parasite Plasmodium berghei. Live imaging of a parasite line expressing a fluorescently tagged CuTP demonstrated that CuTP is predominantly located in vesicular bodies of the parasite. A P. berghei loss-of-function mutant line was readily obtained and showed no apparent defect in in vivo blood stage growth. Parasite transmission through the mosquito vector was severely affected, but not entirely abolished. We show that male and female gametocytes are abundant in cutp− parasites, but activation of male microgametes and exflagellation were strongly impaired. This specific defect could be mimicked by addition of the copper chelator neocuproine to wild-type gametocytes. A cross-fertilization assay demonstrated that female fertility was also severely abrogated. In conclusion, we provide experimental genetic and pharmacological evidence that a healthy copper homeostasis is critical to malaria parasite fertility of both genders of gametocyte and, hence, to transmission to the mosquito vector

Doctor of Philosophy

dissertationThis work focuses on the study of low-magnetic field (<10mT) magnetoresistance effects of organic polymer diodes based on the n-conjugated polymer MEH-PPV in presence of oscillating magnetic fields in the radio frequency range. In these conditions, the combination of static and ac fields can magnetic resonantly influence the electronspin degree of freedom of localized charge-carrier states. As long as bipolar injection conditions influence the net current of the polymer diode, magnetic-resonance changes of the charge carrier spin state can affect spin-dependent charge carrier recombination rates and therefore the material's conductivity. Since the observed spin-dependent recombination currents are governed by the charge carrier pair's spin-permutation symmetry, magnetoresistance measurements under ac drive allow for the electrical detection of magnetic resonance under very low magnetic field conditions where inductive magnetic resonance detection schemes fail due to a lack of spin polarization. In this thesis, this effect was utilized for two effects. Firstly, for the exploration of a magnetic resonance regime where the driving field B 1 approaches the same magnitude as the static magnetic field B0. When Bi approaches B0, a regime where magnetic resonance effects become nonlinear emerges and interesting collective spin-phenomena occur. This includes spin-cooperativity, where the resonantlydriven spin ensemble assumes a macroscopically collective state. Experiments are presented that tested and confirmed previous theoretical predictions. When B}~B0, the emerging spin-cooperativity of recombining polaron pairs in organic semiconductors can be observed through magnetoresistance measurements. The experiments confirmed the theory in all aspects and demonstrated the emergence of the spin-Dicke effect. Secondly, for the exploration of whether magnetic resonantly-controlled spindependent currents can be used for magnetometry of inhomogeneous magnetic fields. This work is a continuation of the previously introduced idea to utilize spin-dependent charge carrier recombination in organic semiconductors for an absolute low-magnetic field magnetometry that is robust against fluctuating environmental conditions. The work focuses on the measurement of magnetic field distributions in gradient magnetic fields. It is shown that organic semiconductor-based magnetic resonance magnetometers can reveal magnetic field distributions. However, this measurement approach can be compromised by inductive resonance artifacts introduced by the large-bandwidth RF stripline resonators needed to operate the magnetometer

A program of X-ray astronomy from sounding rocket Final report

X-ray astronomy from sounding rocket

Analysis of sounding rocket data regarding celestial X-ray sources Final report

Celestial observation, sounding rocket data, and emission spectrum used to identify Sco X-1 of Scorpio constellatio

Results of a Sounding Rocket experiment to study celestial X-ray sources Final report

Sounding rocket experiment to study celestial X-ray source

Aerosol-assisted metallo-organic chemical vapour deposition of Bi2Se3 films using single-molecule precursors: the crystal structure of bismuth(m) dibutyldiselenocarbamate

The complexes [Bi{Se2CN(C2H5)2}3], [Bi{Se2CN(C4H9)2}3], [Bi{Se2CN(CH3)(C4H9)}3] and [Bi{Se2CN(CH3)(C6H13)}3] have been synthesized and characterized structurally using IR, 1H and 13C NMR. In addition, the crystal structure of [Bi{Se2CN(C4H9)2}3] was determined by single-crystal X-ray diffraction, showing the bismuth centre coordinated to three dialkyldiselenocarbamate ligands through the selenium donor atoms. The Bi(III) compounds were used as precursors for the deposition of Bi2Se3 films on glass substrates through aerosol-assisted metallo-organic chemical vapour deposition (AA-MOCVD)