Ribosomes are small, but complex structures, roughly 20 to 30 nm in diameter that serve as the center for protein synthesis in all cells. Here in lies the machinery that decodes information from the messenger RNA and catalyzes the ordered assembly of amino acids into proteins.. Plasmodium species face dramatic but predictable environmental changes during their life cycles, to which they must respond. These include predictable changes in temperature and the availability of nutrients. Numerous reports support the role of glucose as a central effector of change. The central questions that we have addressed relate to changes in transcription that correlate with developmental changes in the parasite. No global examination of these effects have been reported for either temperature or glucose. Features of RNAs structure appear associated with different stages of the life cycle. Our work has revealed a structural consistency that appears to correlate with changes in the stage specific ribosomes of Plasmodium. This indicates a feature of developmental control that is definable and distinctly different from that of the host. Such situations are the focal point of drug design because they offer the hope of interfering with the parasite at a biochemical level without doing damage to the host. During the course of our work on the control of developmental regulation we have shown that both ambient concentrations of glucose and thermoregulation serve to control the transcription level of both mRNA and rRNA. Changes in transcription levels in turn relate to the alteration of chromatin structure. Below we sumarize the glucose results .. The majority of the 6,000 P. falciparum genes were not significantly affected by glucose starvation. The experiment in which regulation of mRNA was confirmed by real-time PCR, a total of 213 transcripts were upregulated, with a threshold of over 2.0 fold under glucose starvation. Of these, 86 had similarity with genes of defined function and cellular location (>33% amino acid identity with a gene known function). Under the same conditions, 347 transcripts were downregulated with a threshold of less than 0.5; BLAST analysis identified 98 genes. The 86 annotated upregulated and 98 downregulated genes were categorized and assigned to groups according to their function. Such analysis revealed a number of leads as to the nature of severe malaria that we are persueing. For example, severe malaria is thought to be due to the sequestration of parasites in the microcirculation systems of important organs. P. falciparum sequestration involves the deposition of members of the PfEMP (var) protein family onto the surface of infected RBC. Logically, it can now be proposed that some of the cerebral pathology of malaria infection can be accounted for by abnormal patterns of cell-to-cell adhesion in the microcirculation relating to switches in var expression in the glucose-deprived microcirculation of the brain Further, upregulation and release of proteins such as phospholipase C and protein kinase C into capillaries, occur and would likely jeopardize the permeability of the brain""""""""s microvascular system inducing local inflammatory responses. This can be directly investigated using MRI in a fashion similar to that used to study the effect of increased levels of TNF on cerebral blood volume. Such studies reveal new options for treatment of cerebral malaria.
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