Thesis (M.S.)--University of Wisconsin--Madison, 1981. / Typescript. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

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Plasmodium falciparum is the protozoan parasite that is the causative agent of malaria in humans. The World Health Organization estimates there were 219 million cases of malaria resulting in 435,000 deaths in 2017. Despite recent progress in control and treatment of the disease, malaria remains a major threat due to the emergence of resistance to all known antimalarial drugs. As a result, there is pressing need for the discovery of drugs with novel mechanisms of action to circumvent the current mechanisms of resistance. Protein kinases in Plasmodium serve critical functions in its life cycle and are implicated in multiple stages of cellular progression. These qualities make protein kinases attractive antimalarial drug targets. In addition, a large portion of the Plasmodium kinases have no orthologs in the mammalian kinome, which increases the potential for selective targeting. For these reasons, we hypothesized that targeting the plasmodial kinome may give rise to effective antimalarials. The goal of this study was to identify and characterize plasmodial inhibitors from a kinase-focused library of 2,480 compounds. An initial phenotypic screen was performed at a fixed one micromolar concentration to identify compounds with antiplasmodial activity. From this library, we have identified multiple scaffolds with submicromolar potency and ample selectivity. Further characterization was sought for hits including elucidating the cellular mechanism of action, physiochemical profiling, and structure-activity relationship profiling (SAR). Efforts are currently underway to identify the molecular targets of these compounds. As part of this effort, a probe-based chemoproteomics method was used. This method involved using soluble ATP probes to label kinases in lysates of inhibitor-treated cells. Samples from this experiment are currently undergoing mass spectrometric analysis. These results will help elucidate which kinases are targeted by the compounds of interest. Ultimately, this work will provide a starting point for the development of new therapeutics to treat drug-resistant malaria.

Thesis (B.A.(Hons.)) -- University of Adelaide, 1977. / Includes bibliographical references (p. 31-32).

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Bothriocephalus specimens from a single 0+ Ctenopharyngodon idella were fixed using three different techniques, and the scolex morphology was examined using scanning electron microscopy. The scolices were compared with the five species of Bothriocephalus and one species of Schyzocotyle previousley recorded from cyprinid fishes. The taxonomic history of the Bothriocephalus species parasitising cyprinid fishes was reviewed. It was concluded that the six species were synonymous, and that priority should be given to the name B. acheilognathi Yamaguti, 1934; with B. opsariichthydis Yamaguti, 1934, ~fluviatilis Yamaguti, 1952, ~ gowkongensis Yeh, 1955, .!h. phoxini Molnar, 1968 and Schyzocotyle fluviatilis as synonyms. A critical examination of the three species of Bothriocephalus reported from cyprinid fishes in Africa is presented. The characters examined did not enable the species to be differentiated, therefore it is suggested that ~ aegyptiacus Rysavy and Moravec, 1975 and B. ki vuensis Baer and Fain, 1958 are synonyms of B. acheilognathi. Laboratory experiments revealed that establishment, development and mortality of each stage of the life cycle of ~ acheilognathi was temperature dependant. In addition the infectivity of the coracidium and procercoid was age dependant. Development of the procercoid was influenced by the age of the coracidium when ingested by the copepod intermediate host, and the infecti v i ty of the procercoid was inversely related to the density of ~e. procercoids within the intermediate host. Estimation of the time taken for the completion of the life cycle at temperatures ranging from 18-30 0c showed it to be inversely related to temperature. The size of the Cyprinus carpio host influenced the ability of the plerocercoids to establish, with no establishment occuring in C. carpio greater than 63 mm fork length. The strobila of ~ acheilognathi was observed to undergo a cyclical pattern of contraction and relaxation within the host intestine. The frequency of this behaviour was associated with the feeding behav iour of the .f:. carpio host. No significant variation in scolex position was observed. Egg release by B. acheilognathi also followed a cyclical pattern,with peak egg production occurring shortly after the entry of food into the intestine. Praziquantel (Droncit, Bayer) was found to be a suitable anthelmintic for the control of ~ acheilognathi. In vitro studies indicated that praziquantel concentrations of 0.1ug per ml 0.9% saline and above, caused muscular contraction and severe tegumental damage. Exposure to drug concentrations of 100 ug praziquantel per ml saline for 24 hours was not lethal to the worms. Praziquantel had no ovicidal activity. Praziquantel was used to eliminate ~ acheilognathi from a batch of 30,000 newly imported Ctenopharyngodon idella. Dose rates of 105 and 125 mg praziquantel kg bodyweight-1 administered as a medicated feed over a three day period were used. The fish were raised to 240c in an indoor recirculating unit prior to treatment. The ponds containing infected fish were drained and limed to kill B. acheilognathi ova and copepods.

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