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Sent on Friday, 2010 Jan 15Search kinetoplastids OR kinetoplastid OR Kinetoplastida OR "trypanosoma brucei" OR leishmania OR brucei OR leishmaniasis OR "African trypanosomiasis"
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| PubMed Results |
| 1. | J Mol Biol. 2010 Jan 10. [Epub ahead of print]The crystal structure and activity of a putative trypanosomal nucleoside phosphorylase reveal it to be a homodimeric uridine phosphorylase.Larson ET, Mudeppa DG, Gillespie JR, Mueller N, Napuli AJ, Arif JA, Ross J, Arakaki TL, Lauricella A, Detitta G, Luft J, Zucker F, Verlinde CL, Fan E, Van Voorhis WC, Buckner FS, Rathod PK, Hol WG, Merritt EA.Medical Structural Genomics of Pathogenic Protozoa Consortium (MSGPP), www.msgpp.org; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA. Purine nucleoside phosphorylases and uridine phosphorylases are closely related enzymes involved in purine and pyrimidine salvage, respectively, which catalyze the removal of the ribosyl moiety from nucleosides so that the nucleotide base may be recycled. Parasitic protozoa generally are incapable of de novo purine biosynthesis so the purine salvage pathway is of potential therapeutic interest. Information about pyrimidine biosynthesis in these organisms is much more limited. Though all seem to carry at least a subset of enzymes from each pathway, the dependency on de novo pyrimidine synthesis versus salvage varies from organism to organism and even from one growth stage to another. We have structurally and biochemically characterized a putative nucleoside phosphorylase from the pathogenic protozoan Trypanosoma brucei and find that it is a homodimeric uridine phosphorylase. This is the first characterization of a uridine phosphorylase from a trypanosomal source despite this activity being observed decades ago. Although this gene was broadly annotated as a putative nucleoside phosphorylase, it was widely inferred to be a purine nucleoside phosphorylase. Our characterization of this trypanosomal enzyme shows that it is possible to distinguish between purine and uridine phosphorylase activity at the sequence level based on the absence or presence of a characteristic uridine phosphorylase-specificity insert. We suggest that this recognizable feature may aid in proper annotation of the substrate specificity of enzymes in the nucleoside phosphorylase family. Copyright © 2010. Published by Elsevier Ltd. |
| PMID: 20070944 [PubMed - as supplied by publisher] | |
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| 2. | Parasite Immunol. 2010 Feb;32(2):153-60.Type I IFNs promote the early IFN-gamma response and the IL-10 response in Leishmania mexicana infection.Buxbaum LU.VA Medical Center, Philadelphia, PA 19104-6073, USA. buxbaum@mail.med.upenn.edu The protozoan parasite Leishmania mexicana causes chronic cutaneous disease in humans and most mouse strains. We previously showed that STAT4-deficient mice, but not IL-12p40-deficient mice, have more parasites and progressively growing lesions unlike those of wild-type mice, the lesions and parasite burdens of which plateau by 10-12 weeks post-infection. This demonstrates a STAT4-dependent, IL-12/IL-23-independent pathway of parasite control. Type I IFNs are important in viral and other infections and can activate STAT4. We found that IFN-alpha/betaR-deficient mice have a nonpersistent, early IFN-gamma defect, and a persistent, early IL-10 defect, without changes in serum IL-12 or LN-derived nitric oxide. We found less IL-10 per cell in CD25+CD4+ T cells and possibly fewer IL-10-producing cells in the draining LN of IFN-alpha/betaR-deficient vs. wild-type mice. IFN-alpha/betaR-deficient mice have chronic, nonprogressive disease, like wild-type mice, suggesting that IL-10 and IFN-gamma defects may balance each other. Our data indicate that although type I IFNs help promote early Th1 responses, they are not the missing activators of STAT4 responsible for partial control of L. mexicana. Also, the lack of lesion resolution in IFN-alpha/betaR-deficient mice despite lower IL-10 levels indicates that other pathways independent of T cell IL-10 help prevent an IL-12-driven clearance of parasites. |
| PMID: 20070829 [PubMed - in process] | |
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| 3. | Parasite Immunol. 2010 Feb;32(2):101-10.Differential in vitro CD4+/CD8+ T-cell response to live vs. killed Leishmania major.Nateghi Rostami M, Keshavarz Valian H, Eskandari SE, Miramin Mohammadi A, Shahrestani ST, Sarraf-Nejad A, Khamesipour A.Medical Parasitology and Mycology Department, School of Public Health and Institute of Public Health Research, Tehran University of Medical Sciences, Tehran, Iran. Clinical trials of killed Leishmania vaccines showed a limited efficacy compared with leishmanization (LZ). The reason for this difference in protection against cutaneous leishmaniasis (CL) is not known and in vivo studies on T-cell function may provide valuable information. Nevertheless, there are limited studies on the nature of the stimulatory effects of live vs. killed parasites on human T cells in vitro. A total of nine Leishmanin Skin Test+ volunteers with a history of self-healing CL (HCL) and seven healthy volunteers were included in this study. 5,6-carboxyfluroescein diacetate succinimidyl ester-labelled CD4(+)/CD8(+) lymphocytes were cultured with killed Leishmania Lysate (Killed LL) or live Leishmania major (Live LM) and analysed for proliferation using flow cytometry. Culture supernatants were used for cytokine titration. In HCL volunteers, upon stimulation with killed LL, the number of proliferated CD4(+)/CD8(+) cells was significantly more than that of unstimulated (P < 0.001) or live LM stimulated (P < 0.05) cells, or cells from controls (CD4(+)/CD8(+): P < 0.05/P < 0.001). Stimulation of CD4(+) cells with Live LM (P < 0.001) or Killed LL (P < 0.05) induced a significantly higher IFN-gamma production compared with that of controls, but Live LM induced significantly (P < 0.05) more IFN-gamma than Killed LL. A significantly (P < 0.05) higher IFN-gamma production was observed when CD8(+) cells were stimulated with Live LM. Cells from HCL volunteers showed significantly more IL-10 production to Live LM stimulation compared with that of controls (CD4(+): P < 0.05 /CD8(+): P < 0.001) or cells stimulated with Killed LL (CD4(+)/CD8(+): P < 0.001/P < 0.0005). Whereas Killed LL induced more proliferation response in purified T cells, Live LM induced cytokine production without significant induction of proliferation. The results from healed CL volunteers in this study could be implicated in further studies on T-cell response in vaccinated individuals. |
| PMID: 20070824 [PubMed - in process] | |
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| 4. | J Cell Mol Med. 2010 Jan 11. [Epub ahead of print]Chagas' disease: an update on immune mechanisms and therapeutic strategies.Boscardin SB, Torrecilhas AC, Manarin R, Revelli S, Rey EG, Tonelli RR, Silber AM.Departamento de Parasitologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brasil. Abstract The final decade of the 20th century was marked by an alarming resurgence in infectious diseases caused by tropical parasites belonging to the kinetoplastid protozoan order. Among the pathogenic trypanosomatids, some species are of particular interest due to their medical importance. These species include the agent responsible for Chagas' disease, Trypanosoma cruzi. Aproximately 8 to 10 million people are infected in the Americas, and approximately 40 million are at risk. In the present review, we discuss in detail the immune mechanisms elicited during infection by T. cruzi and the effects of chemotherapy in controlling parasite proliferation and on the host immune system. |
| PMID: 20070438 [PubMed - as supplied by publisher] | |
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| 5. | Hist Cienc Saude Manguinhos. 2009 Jul;16 Suppl 1:75-94.Trypanosoma cruzi, cancer and the Cold War.Krementsov N.Institute for the History and Philosophy of Science and Technology, University of Toronto, Canada. n.krmentsov@utoronto.ca In the summer of 1946, the international community of cancer researchers was inspired by the announcement that two Soviet scientists, Nina Kliueva and Grigorii Roskin, had discovered anticancer properties in culture extracts made from the South American protozoan, Trypanosoma cruzi, and had produced a preparation--named after its discoverers KR--which showed clear therapeutic effects on cancer patients. Research teams from various countries enthusiastically pursued the promising new line of investigation. The story of the rise and fall of interest in the anticancer properties of T. cruzi in different countries suggests that during the second half of the twentieth century, the Cold War competition between the superpowers played an important role in shaping the research agendas of cancer studies. |
| PMID: 20027919 [PubMed - indexed for MEDLINE] | |
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| 6. | Hist Cienc Saude Manguinhos. 2009 Jul;16 Suppl 1:35-56.The reception by French physicians of Chagas' discovery of Trypanosoma cruzi and American trypanosomiasis (1909-1925).Gachelin G, Opinel A.UMR 7219 CNRS-Université Paris 7, Histoire et Philosophie des Sciences, Site des Grands Moulins de Paris F-75013, Paris, France. ggachel@club-internet.fr As soon as they were published early in 1909, Chagas's articles on Trypanosoma cruzi and American trypanosomiasis became the topic of discussions in France. The description of T. cruzi and Chagas disease was added to parasitology textbooks as early as 1912, and elicited active research, particularly on the part of French parasitologist Emile Brumpt. He contributed towards eluciding the lifecycle of T. cruzi and the different ways it could infect humans. Laboratory research on T. cruzi was interrupted by First World War and was not resumed afterwards on the same scale, although interest in the epidemiology of Chagas disease continued. |
| PMID: 20027917 [PubMed - indexed for MEDLINE] | |
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| 7. | Hist Cienc Saude Manguinhos. 2009 Jul;16 Suppl 1:13-34.The discovery of Trypanosoma cruzi and Chagas disease (1908-1909): tropical medicine in Brazil.Kropf SP, Sá MR.Casa de Oswaldo Cruz/Fundação Oswaldo Cruz Avenida Brasil, 4036/400 21040-361, Rio de Janeiro, RJ, Brasil. simonek@coc.fiocruz.br This article analyzes the discovery of Chagas disease and the parasite that causes it (Trypanosoma cruzi) by Carlos Chagas in 1908/1909, with a special focus on the scientific and social context in which this occurred. Its inclusion in the international debate on European tropical medicine--especially with researchers from the German school of protozoology--and its connection with discussions on the modernization of the recently established Brazilian Republic are also examined. The discovery of Chagas disease became a decisive aspect in the scientific project that Oswaldo Cruz sought to establish at the institute that bears his name. It was extolled as a symbol of Brazil's scientific ability t produce knowledge in line with the international scientific agenda, while simultaneously being attuned to the specific problems of the country. |
| PMID: 20027916 [PubMed - indexed for MEDLINE] | |
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| 8. | Biochem J. 2009 Dec 10;424(3):479-90.Nucleic-acid-binding properties of the C2-L1Tc nucleic acid chaperone encoded by L1Tc retrotransposon.Heras SR, Thomas MC, Macias F, Patarroyo ME, Alonso C, López MC.Departamento de Biología Molecular, Instituto de Parasitología y Biomedicina López Neyra, CSIC, 18001 Granada, Spain. It has been reported previously that the C2-L1Tc protein located in the Trypanosoma cruzi LINE (long interspersed nuclear element) L1Tc 3' terminal end has NAC (nucleic acid chaperone) activity, an essential activity for retrotransposition of LINE-1. The C2-L1Tc protein contains two cysteine motifs of a C2H2 type, similar to those present in TFIIIA (transcription factor IIIA). The cysteine motifs are flanked by positively charged amino acid regions. The results of the present study show that the C2-L1Tc recombinant protein has at least a 16-fold higher affinity for single-stranded than for double-stranded nucleic acids, and that it exhibits a clear preference for RNA binding over DNA. The C2-L1Tc binding profile (to RNA and DNA) corresponds to a non-co-operative-binding model. The zinc fingers present in C2-L1Tc have a different binding affinity to nucleic acid molecules and also different NAC activity. The RRR and RRRKEK [NLS (nuclear localization sequence)] sequences, as well as the C2H2 zinc finger located immediately downstream of these basic stretches are the main motifs responsible for the strong affinity of C2-L1Tc to RNA. These domains also contribute to bind single- and double-stranded DNA and have a duplex-stabilizing effect. However, the peptide containing the zinc finger situated towards the C-terminal end of C2-L1Tc protein has a slight destabilization effect on a mismatched DNA duplex and shows a strong preference for single-stranded nucleic acids, such as C2-L1Tc. These results provide further insight into the essential properties of the C2-L1Tc protein as a NAC. |
| PMID: 19751212 [PubMed - indexed for MEDLINE] | |
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| 9. | Cell Microbiol. 2009 Nov;11(11):1600-11. Epub 2009 Jun 22.Sialylated ligands on pathogenic Trypanosoma cruzi interact with Siglec-E (sialic acid-binding Ig-like lectin-E).Erdmann H, Steeg C, Koch-Nolte F, Fleischer B, Jacobs T.Department of Immunology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany. Trypanosoma cruzi causes a suppression of the immune system leading to persistence in host cells. The trans-sialidase expressed by T. cruzi is a major virulence factor and transfers sialic acid from host glycoconjugates to mucin-like molecules on the parasite. Here we demonstrate that these sialylated structures play a role in the immunosuppression. We used two T. cruzi strains, whose TS activity correlated with their pathogenicity. The Tulahuen strain, characterized by a high TS activity efficiently infected mice, whereas the Tehuantepec strain showing a reduced TS activity could not establish a patent parasitemia. In vitro analysis revealed that these two strains invaded phagocytic and non-phagocytic host cells at a comparable rate, but they exhibited different potentials to modulate dendritic cell function. In contrast to Tehuantepec, the Tulahuen strain suppressed the production of the proinflammatory cytokine IL-12 and subsequent T-cell activation. This inhibitory effect was absent upon desialylation of the parasite. Therefore, we analysed whether sialylated structures of T. cruzi interact with the inhibitory sialic acid-binding protein Siglec-E on DC. Indeed, Siglec-E interacted with the pathogenic Tulahuen strain, but showed a diminished binding to the Tehuantepec strain. Ligation of Siglec-E on DC using antibodies confirmed this inhibitory effect on DC function. |
| PMID: 19552697 [PubMed - indexed for MEDLINE] | |
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| 10. | Br J Pharmacol. 2009 Aug;157(7):1111-27. Epub 2009 Jun 5.The 'sweet' and 'bitter' involvement of glycosaminoglycans in lung diseases: pharmacotherapeutic relevance.Papakonstantinou E, Karakiulakis G.2nd Department of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece. epap@med.auth.gr The extracellular matrix (ECM) plays a significant role in the structure and function of the lung. The ECM is a three-dimensional fibre mesh, comprised of various interconnected and intercalated macromolecules, among which are the glycosaminoglycans (GAG). GAG are long, linear and highly charged, heterogeneous polysaccharides that are composed of a variable number of repeating disaccharide units (macromolecular sugars) and most of them, as their name implies, have a sweet taste. In the lung, GAG support the structure of the interstitium, the subepithelial tissue and the bronchial walls, and are secreted in the airway secretions. Besides maintaining lung tissue structure, GAG also play an important role in lung function as they regulate hydration and water homeostasis, modulate the inflammatory response and influence lung tissue repair and remodelling. However, depending on their size and/or degree of sulphation, and their immobilization or solubilization in the ECM, specific GAG in the lung either live up to their sweet taste/name, supporting normal lung physiology, or they are associated to 'bitter' effects, related to lung pathology. The present review discusses the biological role of GAG in the lung as well as the involvement of these molecules in various respiratory diseases. Given the great structural diversity of GAG, understanding the changes in GAG expression that occur in lung diseases may lead to novel targets for pharmacological intervention in order to prevent and/or to treat a range of lung diseases. PMCID: PMC2743830 [Available on 2010/8/1] |
| PMID: 19508395 [PubMed - indexed for MEDLINE] | |
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