Investigating Toxoplasma gondii peroxisome and the discovery of two Bisabolane Sesquiterpenes as anti-leshmanials.

The use of natural products for treating protozoan infections can be traced back to Rome in 1631, where cinchona tree bark was used to cure malaria. The discovery of novel naturally derived compounds for the treatment of cutaneous leishmaniasis and toxoplasmosis is vital for many vaccine deficient protozoan infections today. Here, the assessment of natural products against Leishmania mexicana (L. mexicana) was explored using a library of compounds screened against the mammalian stage of L. mexicana in in vitro assays. Two hit compounds from the screen were then used in metabolomic studies to determine mode of action. In addition, another natural compound, Aureobasidin A and its derivatives, and peroxisome inhibitors were screened against Toxoplasma gondii (T. gondii). Peroxisomes are organelles involved in the metabolism of fatty acids and choles- terol. Other than lipid metabolism, peroxisomes contain many enzymes involved in several different metabolic processes. Catalase is involved in the neutralization of hydrogen peroxide thereby, preventing toxic build up within cells. This enzyme over time has become a key identifier of peroxisomes in many organisms. However, this is controversial when it comes to T. gondii. The use of catalase as a marker for peroxisomes in this parasite has been disputed, and in some cases led to the belief that the T. gondii does not possess these organelles. In this thesis, we take a dif- ferent approach in to establishing the existence of peroxisomes. Through evolution T. gondii has maintained, within its genome, genes encoding peroxisomal proteins, named peroxins (Pex). Here we investigated the presence of peroxisomes within T. gondii using Pex proteins. Our experimental approach involved characterization of putative TgPex5 and protein ligand TgSCP2. Using molecular biology, reverse genetics and protein characterization, we show that through pull-down assays, lo- calisation and complementation of TgPex5 in yeast expression systems, we are able to provide evidence to prove the presence of peroxisomes within T. gondii

Making regional integration supportive of economic development

Abstract: A development-focused approach should be underpinned by expanded development assistance to help address supply capacity constraints in poor countries. This requires identifying needs, prioritising them and providing funds to address them

Viewpoint : WTO; the knowledge deficit in trade negotiations

French version available in IDRC Digital Library: Point de vue : OMC; le déficit des connaissances dans les négociations commercialesVietnamese research highlights the needs of developing countries for special transitional provisions in any new WTO trade-liberalizing arrangement — provisions giving poor countries extra time, and aid, to adjust to global competition and to distribute the gains of globalization within their own societies. Moreover, domestic policy reform makes sense even without any reciprocation by trading partners. Successful trade policy and trade agreements must fit coherently alongside sound domestic development policy based on rigorous local research. Poor-country negotiators are too often expected to protect the interests of their people with no confident or complete knowledge of what those interests are

Point de vue : OMC; le déficit des connaissances dans les négociations commerciales

Version anglaise disponible dans la Bibliothèque numérique du CRDI: Viewpoint : WTO; the knowledge deficit in trade negotiation

Functional analyses of a putative, membrane-bound, peroxisomal import mechanism from the apicomplexan protozoan Toxoplasma gondii

Peroxisomes are central to eukaryotic metabolism, including the oxidation of fatty acids—which subsequently provide an important source of metabolic energy—and in the biosynthesis of cholesterol and plasmalogens. However, the presence and nature of peroxisomes in the parasitic apicomplexan protozoa remains controversial. A survey of the available genomes revealed that genes encoding peroxisome biogenesis factors, so-called peroxins (Pex), are only present in a subset of these parasites, the coccidia. The basic principle of peroxisomal protein import is evolutionarily conserved, proteins harbouring a peroxisomal-targeting signal 1 (PTS1) interact in the cytosol with the shuttling receptor Pex5 and are then imported into the peroxisome via the membrane-bound protein complex formed by Pex13 and Pex14. Surprisingly, whilst Pex5 is clearly identifiable, Pex13 and, perhaps, Pex14 are apparently absent from the coccidian genomes. To investigate the functionality of the PTS1 import mechanism in these parasites, expression of Pex5 from the model coccidian Toxoplasma gondii was shown to rescue the import defect of Pex5-deleted Saccharomyces cerevisiae. In support of these data, green fluorescent protein (GFP) bearing the enhanced (e)PTS1 known to efficiently localise to peroxisomes in yeast, localised to peroxisome-like bodies when expressed in Toxoplasma. Furthermore, the PTS1-binding domain of Pex5 and a PTS1 ligand from the putatively peroxisome-localised Toxoplasma sterol carrier protein (SCP2) were shown to interact in vitro. Taken together, these data demonstrate that the Pex5–PTS1 interaction is functional in the coccidia and indicate that a nonconventional peroxisomal import mechanism may operate in the absence of Pex13 and Pex14

Unilateral anterior uveitis complicating zoledronic acid therapy in breast cancer

BACKGROUND: Zoledronic acid is very widely used in patients with metastatic bone disease and osteoporosis. Only one case of bilateral uveitis was recently reported related to its use. CASE PRESENTATION: We report the first case of severe unilateral anterior uveitis in a patient with breast cancer and an intraocular lens. Following zoledronic acid infusion, the patient developed severe and dramatic right eye pain with decreased visual acuity within 24 hours and was found to have a fibrinous anterior uveitis of moderate severity The patient was treated with topical prednisone and atropine eyedrops and recovered slowly over several months. CONCLUSION: Internists, oncologists, endocrinologists, and ophtalmologists should be aware of uveitis as a possible complication of zoledronic acid therapy. Patients should be instructed to report immediately to their physicians and treatment with topical prednisone and atropine eyedrops should be instituted immediately at the onset of symptoms. This report documents anterior uveitis as a complication of zoledronic acid therapy. This reaction could be an idiosyncratic one but further research may shed more light on the etiology