Malaria is a potentially fatal disease caused by Plasmodium parasites and poses a major medical risk in large parts of the world. The development of new, affordable antimalarial drugs is of vital ...importance as there are increasing reports of resistance to the currently available therapeutics. In addition, most of the current drugs used for chemoprophylaxis merely act on parasites already replicating in the blood. At this point, a patient might already be suffering from the symptoms associated with the disease and could additionally be infectious to an Anopheles mosquito. These insects act as a vector, subsequently spreading the disease to other humans. In order to cure not only malaria but prevent transmission as well, a drug must target both the blood- and pre-erythrocytic liver stages of the parasite. P.falciparum (Pf) enoyl acyl carrier protein (ACP) reductase (ENR) is a key enzyme of plasmodial typeII fatty acid biosynthesis (FASII). It has been shown to be essential for liver-stage development of Plasmodium berghei and is therefore qualified as a target for true causal chemoprophylaxis. Using virtual screening based on two crystal structures of PfENR, we identified a structurally novel class of FAS inhibitors. Subsequent chemical optimization yielded two compounds that are effective against multiple stages of the malaria parasite. These two most promising derivatives were found to inhibit blood-stage parasite growth with IC50 values of 1.7 and 3.0μM and lead to a more prominent developmental attenuation of liver-stage parasites than the gold-standard drug, primaquine. PUBLICATION ABSTRACT
This article provides an analysis of two mixed race memoirs from the 1990s/ 2000s. It looks at the establishment of mixed race families and mixed race history by these texts and contextualizes them ...in the larger process of the American nation coming to terms with its past.
Conceptual meadow irrigation is a historically prominent land use practice, that contributed decisively to the landscape. It enhances land-water-connectivity and might directly interact with habitats ...of Margaritifera margaritifera (L.). The aim of the presented study was to investigate, if there is a spatial correlation in the distribution of conceptual meadow irrigation and M. margerigtifera. We therefore digitalized the distribution of both in the German Federal Republic in GIS. This revealed a 68% overlap of map quarters with records of the Freshwater Pearlmussel with those, where conceptual meadow irrigation was practiced. With our findings we want to draw the readers attention to the potential of this land use practice for ecosystem functioning.
Malaria is a potentially fatal disease caused by Plasmodium parasites and poses a major medical risk in large parts of the world. The development of new, affordable antimalarial drugs is of vital ...importance as there are increasing reports of resistance to the currently available therapeutics. In addition, most of the current drugs used for chemoprophylaxis merely act on parasites already replicating in the blood. At this point, a patient might already be suffering from the symptoms associated with the disease and could additionally be infectious to an Anopheles mosquito. These insects act as a vector, subsequently spreading the disease to other humans. In order to cure not only malaria but prevent transmission as well, a drug must target both the blood‐ and pre‐erythrocytic liver stages of the parasite. P. falciparum (Pf) enoyl acyl carrier protein (ACP) reductase (ENR) is a key enzyme of plasmodial type II fatty acid biosynthesis (FAS II). It has been shown to be essential for liver‐stage development of Plasmodium berghei and is therefore qualified as a target for true causal chemoprophylaxis. Using virtual screening based on two crystal structures of PfENR, we identified a structurally novel class of FAS inhibitors. Subsequent chemical optimization yielded two compounds that are effective against multiple stages of the malaria parasite. These two most promising derivatives were found to inhibit blood‐stage parasite growth with IC50 values of 1.7 and 3.0 μM and lead to a more prominent developmental attenuation of liver‐stage parasites than the gold‐standard drug, primaquine.
Through virtual screening and molecular modeling, two structurally novel inhibitors of type II fatty acid biosynthesis (FAS II) were identified that are effective against both pre‐erythrocytic (liver stage) and blood‐stage malaria parasites. These most promising derivatives were found to inhibit multiple stages of Plasmodium more potently than the gold standard primaquine.
Using the examples of Detroit and Germany’s Ruhr Region, the photo essay addresses the challenges former industrial centers across the United States and Europe are confronted with at the end of ...production: shrinking populations, the loss of jobs and the decay of industrial sites. One popular narrative about de-industrialization in both Detroit and the Ruhr is the idea of a “rebirth through culture” following the discovery by the so-called creative class. While the media discourse is more or less similar, dealing with processes of structural change always still needs to be locally specific–there is as of yet no standard recipe for reviving these cities, and changing their image in the face of increasingly “global” demands remains difficult.
•Limp mRNA is translationally repressed in a DOZI/CITH-complex.•Limp knock-out affects ookinete infectivity of the mosquito but not gliding motility.•Limp knock-out ookinetes accumulate in the ...mosquito blood meal bolus.
Substrate-dependent gliding motility is key to malaria transmission. It mediates host cell traversal, invasion and infection by Plasmodium and related apicomplexan parasites. The 110 amino acid-long cell surface protein LIMP is essential for P. berghei sporozoites where it is required for the invasion of the mosquito’s salivary glands and the liver cells of the rodent host. Here we define an additional role for LIMP during mosquito invasion by the ookinete. limp mRNA is provided as a translationally repressed mRNP (messenger ribonucleoprotein) by the female gametocyte and the protein translated in the ookinete. Parasites depleted of limp (Δlimp) develop ookinetes with apparent normal morphology and no defect during in vitro gliding motility, and yet display a pronounced reduction in oocyst numbers; compared to wildtype 82 % more Δlimp ookinetes remain within the mosquito blood meal explaining the decrease in oocysts. As in the sporozoite, LIMP exerts a profound role on ookinete infection of the mosquito.
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