What's new for 'Trypanosomatids' in PubMed

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Search kinetoplastids OR kinetoplastid OR Kinetoplastida OR "trypanosoma brucei" OR leishmania OR brucei OR leishmaniasis OR "African trypanosomiasis"
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PubMed Results

Items 1 - 10 of 15

1.	Eukaryot Cell. 2011 Mar 4. [Epub ahead of print] Structure-function analysis of dynein light chain 1 identifies viable motility mutants in bloodstream-form Trypanosoma brucei. Ralston KS, Kisalu NK, Hill KL. Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095; Molecular Biology Institute, University of California, Los Angeles, CA 90095. Abstract The flagellum of Trypanosoma brucei is an essential and multifunctional organelle that is receiving increasing attention as a potential drug target and as a system for studying flagellum biology. RNAi knockdown is widely used to test the requirement for a protein in flagellar motility and has suggested that normal flagellar motility is essential for viability in bloodstream-form trypanosomes. However, RNAi knockdown alone provides limited functional information because the consequence is often loss of a multiprotein complex. We therefore developed an inducible system that allows for functional analysis of point mutations in flagellar proteins in T. brucei. Using this system, we identified point mutations in the outer dynein light chain 1 (LC1) that allow stable assembly of outer dynein motors, but do not support propulsive motility. In procyclic-form trypanosomes, the phenotype of LC1 point mutants differs from the motility and structural defects of LC1 knockdowns, which lack the outer arm dynein motor. Thus, our results distinguish LC1-specific functions from broader functions of outer arm dynein. In bloodstream-form trypanosomes, LC1 knockdown blocks cell division and is lethal. In contrast, LC1 point mutants cause severe motility defects without affecting viability, indicating that the lethal phenotype of LC1 RNAi knockdown is not due to defective motility. Our results demonstrate for the first time that normal motility is not essential in bloodstream-form T. brucei and that the presumed connection between motility and viability is more complex than might be interpreted from knockdown studies alone. These findings open new avenues for dissecting mechanisms of flagellar protein function and provide an important step in efforts to exploit the potential of the flagellum as a therapeutic target in African sleeping sickness.
	PMID: 21378260 [PubMed - as supplied by publisher]
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2.	J Biol Chem. 2011 Mar 4. [Epub ahead of print] Naphthalene-based RNA editing inhibitor blocks RNA editing activities and editosome assembly in Trypanosoma brucei. Moshiri H, Acoca S, Kala S, Shateri Najafabadi H, Hogues H, Purisima E, Salavati R. McGill University, Canada; Abstract RNA editing, catalyzed by the multi-protein editosome complex, is an essential step for the expression of most mitochondrial genes in trypanosomatid pathogens. It has been shown previously that Trypanosoma brucei RNA editing ligase 1 (TbREL1), a core catalytic component of editosome, is essential in mammalian life stage of these parasitic pathogens. Because of availability of its crystal structure and absence from human, the adenylylation domain of TbREL1 has recently become the focus of several studies for designing inhibitors that target its adenylylation pocket. Here, we have studied new and existing inhibitors of TbREL1 in order to better understand their mechanism of action. We found that these compounds are moderate to weak inhibitors of adenylylation of TbREL1, and in fact enhance adenylylation at higher concentrations of protein. Nevertheless, they can efficiently block deadenylylation of TbREL1 in editosome and, consequently, result in inhibition of the ligation step of RNA editing. Further experiments directly showed that the studied compounds inhibit the interaction of editosome with substrate RNA. This was supported by the observation that not only the ligation activity of TbREL1, but also the activities of other editosome proteins such as endoribonuclease, terminal RNA uridylyltransferase (TUTase), and U-specific exoribonuclease (ExoUase), all of which requiring the interaction of editosome with the substrate RNA, are efficiently inhibited by these compounds. In addition, we found that these compounds can interfere with integrity and/or assembly of editosome complex, opening the exciting possibility of using them to study the mechanism of assembly of the editosome components.
	PMID: 21378165 [PubMed - as supplied by publisher]
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3.	Vet Parasitol. 2011 Feb 15. [Epub ahead of print] Analysis of host genetic factors influencing African trypanosome species infection in a cohort of Tanzanian Bos indicus cattle. Karimuribo ED, Morrison LJ, Black A, Turner CM, Kambarage DM, Ballingall KT. Department of Veterinary Medicine and Public Health, Sokoine University of Agriculture, P.O. Box 3021, Morogoro, Tanzania. Abstract Trypanosomosis caused by infection with protozoan parasites of the genus Trypanosoma is a major health constraint to cattle production in many African countries. One hundred and seventy one Bos indicus cattle from traditional pastoral Maasai (87) and more intensively managed Boran (84) animals in Tanzania were screened by PCR for the presence of African animal trypanosomes (Trypanosoma congolense, Trypanosoma vivax and Trypanosoma brucei), using blood samples archived on FTA cards. All cattle screened for trypanosomes were also genotyped at the highly polymorphic major histocompatibility complex (MHC) class II DRB3 locus to investigate possible associations between host MHC and trypanosome infection. Overall, 23.4% of the 171 cattle tested positive for at least one of the three trypanosome species. The prevalence of individual trypanosome species was 8.8% (T. congolense), 4.7% (T. vivax) and 15.8% (T. brucei). The high prevalence of T. brucei compared with T. congolense and T. vivax was unexpected as this species has previously been considered to be of lesser importance in terms of African bovine trypanosomosis. Significantly higher numbers of Maasai cattle were infected with T. brucei (23.0%, p=0.009) and T. congolense (13.8%, p=0.019) compared with Boran cattle (8.3% and 3.6%, respectively). Analysis of BoLA-DRB3 diversity in this cohort identified extensive allelic diversity. Thirty-three BoLA-DRB3 PCR-RFLP defined alleles were identified. One allele (DRB3*15) was significantly associated with an increased risk (odds ratio, OR=2.71, p=0.034) of T. brucei infection and three alleles (DRB3*35, *16 and *23) were associated with increased risk of T. congolense infection. While further work is required to dissect the role of these alleles in susceptibility to T. brucei and T. congolense infections, this study demonstrates the utility of FTA archived blood samples in combined molecular analyses of both host and pathogen. Copyright © 2011 Elsevier B.V. All rights reserved.
	PMID: 21377802 [PubMed - as supplied by publisher]
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4.	Carbohydr Res. 2011 Feb 24. [Epub ahead of print] Synthesis of potential metal-binding group compounds to examine the zinc dependency of the GPI de-N-ace tylase metalloenzyme in Trypanosoma brucei. Abdelwahab NZ, Urbaniak MD, Ferguson MA, Crossman AT. Division of Biological Chemistry and Drug Discovery, College of Life Sciences, The University of Dundee, DD1 5EH Dundee, Scotland, United Kingdom. Abstract A small zinc-binding group (ZBG) library of deoxy-2-C-branched-monosaccharides, for example, 1,5-anhydroglucitols, consisting of either monodentate ligand binding carboxylic acids or bidentate ligand binding hydroxamic acids, were prepared to assess the zinc affinity of the putative metalloenzyme 2-acetamido-2-deoxy-α-d-glucopyranosyl-(1→6)-phosphatidylinositol de-N-acetylase (EC 3.5.1.89) of glycosylphosphatidylinositol biosynthesis. The N-ureido thioglucoside was also synthesised and added to the ZBG library because a previous N-ureido analogue, synthesised by us, had inhibitory activity against the aforementioned de-N-acetylase, presumably via the N-ureido motif. Copyright © 2011 Elsevier Ltd. All rights reserved.
	PMID: 21377660 [PubMed - as supplied by publisher]
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5.	Protist. 2011 Mar 4. [Epub ahead of print] Compartmentalization of a Glycolytic Enzyme in Diplonema, a Non-kinetoplastid Euglenozoan. Makiuchi T, Annoura T, Hashimoto M, Hashimoto T, Aoki T, Nara T. Department of Molecular and Cellular Parasitology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. Abstract Glycosomes are peroxisome-related organelles containing glycolytic enzymes that have been found only in kinetoplastids. We show here that a glycolytic enzyme is compartmentalized in diplonemids, the sister group of kinetoplastids. We found that, similar to kinetoplastid aldolases, the fructose 1,6-bisphosphate aldolase of Diplonema papillatum possesses a type 2-peroxisomal targeting signal. Western blotting showed that this aldolase was present predominantly in the membrane/organellar fraction. Immunofluorescence analysis showed that this aldolase had a scattered distribution in the cytosol, suggesting its compartmentalization. In contrast, orotidine-5'-monophosphate decarboxylase, a non-glycolytic glycosomal enzyme in kinetoplastids, was shown to be a cytosolic enzyme in D. papillatum. Since euglenoids, the earliest diverging branch of Euglenozoa, do not possess glycolytic compartments, these findings suggest that the routing of glycolytic enzymes into peroxisomes may have occurred in a common ancestor of diplonemids and kinetoplastids, followed by diversification of these newly established organelles in each of these euglenozoan lineages. Copyright © 2010 Elsevier GmbH. All rights reserved.
	PMID: 21377422 [PubMed - as supplied by publisher]
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6.	Nephrol Ther. 2011 Mar 2. [Epub ahead of print] [Association of post-transplant lymphoproliferative disease and visceral leishmaniasis after kidney transplantation.] [Article in French] Bacha MM, Abderrahim E, Ounissi M, Chaouech D, Cherif M, Turki S, Rajhi H, Znaidi N, Bahloul A, Trabelsi S, Khaled S, Ben Abdallah T, Ben Maïz H, Kheder A. Service de médecine interne A, hôpital Charles Nicolle, boulevard du 9-Avril, 1006 BS, Tunis, Tunisie; Laboratoire de recherche d'immunopathologie et d'immunologie de la transplantation rénale (LR03SP01), hôpital Charles Nicolle, boulevard du 9-Avril, 1006 BS, Tunis, Tunisie. Abstract Malignancies and opportunistic infections are frequently observed after solid-organ transplantation. Their occurrence strongly affects recipient survival. We report the case of a 29-year-old Tunisian kidney-recipient who was diagnosed simultaneously with post-transplant lymphoproliferative disease (PTLD) and visceral leishmaniasis (VL). Withdrawal of immunosuppressive therapy together with antiparasitic treatment using liposomal amphotericin B, and anti-CD20 antibodies medication resulted in cure of leishmaniasis and remission from PTLD. This case is of clinical interest because of the uncommon association of VL with PTLD after solid organ transplantation. It is also original by the favourable outcome of VL and PTLD, both known as life-threatening diseases. Also, it illustrates the predisposing role of immunosuppressive therapy in occurrence of opportunistic infections and malignancies after solid organ transplantation. Copyright © 2011 Association Société de néphrologie. Published by Elsevier SAS. All rights reserved.
	PMID: 21376690 [PubMed - as supplied by publisher]
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7.	Infect Genet Evol. 2011 Mar 1. [Epub ahead of print] TGFB1 and IL 8 gene polymorphisms and susceptibility to Visceral Leishmaniasis. Frade AF, Oliveira LC, Costa DL, Costa CH, Aquino D, Van Weyenbergh J, Barral-Netto M, Barral A, Kalil J, Goldberg AC. Laboratory of Immunology, Heart Institute (InCor) HC-FMUSP, SP, Brazil. Abstract Visceral leishmaniasis (VL) or Kala-azar is a serious protozoan infectious disease caused by an obligate intracellular parasite. Cytokines have a major role in determining progression and severity of clinical manifestations in VL. We investigated polymorphisms in the TGFB1and IL8 genes, which are cytokines known to have a role in onset and severity of the disease. Polymorphisms at TGFB1 -509C/T and +869T/C, and IL8 -251A/T were analyzed by a PCR-RFLP technique, in 198 patients with VL, 98 individuals with asymptomatic infection positive for a delayed-type hypersensitivity test (DTH+) and in 101 individuals with no evidence of infection (DTH-). The presence of the T allele in position -509 of the TGFB1 gene conferred a two-fold risk to develop infection both when including those with clinical symptoms (DTH+ and VL, grouped) or when considering DTH+ only, respectively p = 0.007, OR=1.9 [1.19-3.02] and p = 0.012, OR=2.01 [1.17-3.79], when compared with DTH- individuals. In addition, occurrence of hemorrhage was associated with TGFB1 -509 T allele. We suggest that the -509 T allele of the TGFB1 gene, a cytokine with a biologically relevant role in the natural history of the disease, may contribute to overall susceptibility to infection by Leishmania and to severity of the clinical disease. Copyright © 2011. Published by Elsevier B.V.
	PMID: 21376140 [PubMed - as supplied by publisher]
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8.	Exp Parasitol. 2011 Mar 1. [Epub ahead of print] Trypanosoma brucei s.l.: Microsatellite markers revealed high level of multiple genotypes in the mid-guts of wild tsetse flies of the Fontem sleeping sickness focus of Cameroon. Simo G, Njitchouang GR, Njiokou F, Cuny G, Asonganyi T. Department of Biochemistry, Faculty of Science, P.O. Box 67, University of Dschang, Dschang-Cameroon. Abstract To identify Trypanosoma brucei genotypes which are potentially transmitted in a sleeping sickness focus, microsatellite markers were used to characterize Trypanosoma brucei found in the mid-guts of wild tsetse flies of the Fontem sleeping sickness focus in Cameroon. For this study, two entomological surveys were performed during which 2685 tsetse flies were collected and 1596 (59.2%) were dissected. Microscopic examination revealed 1.19% (19/1596) mid-gut infections with trypanosomes; the PCR method identified 4.7% (75/1596) infections with Trypanosoma brucei in the mid-guts. Of these 75 trypanosomes identified in the mid-guts, Trypanosoma brucei gambiense represented 0.81% (13/1596) of them, confirming the circulation of human infective parasite in the Fontem focus. Genetic characterization of the 75 Trypanosoma brucei samples using five microsatellite markers revealed not only multiple Trypanosoma brucei genotypes (47%), but also single genotypes (53%) in the mid-guts of the wild tsetse flies. These results show that there is a wide range of trypanosome genotypes circulating in the mid-guts of wild tsetse flies from the Fontem sleeping sickness focus. They open new avenues to undertake investigations on the maturation of multiple infections observed in the tsetse fly mid guts. Such investigations may allow to understand how the multiple infections evolve from the tsetse flies mid-guts to the salivary glands and also to understand the consequence of these evolutions on the dynamic (which genotype is transmitted to mammals) of trypanosomes transmission. Copyright © 2011. Published by Elsevier Inc.
	PMID: 21376044 [PubMed - as supplied by publisher]
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9.	Exp Parasitol. 2011 Mar 1. [Epub ahead of print] Trypanosoma brucei brucei: A comparison of gene expression in the liver and spleen of infected mice utilizing cDNA microarray technology. Li SQ, Luckins A, Lun ZR. Center for Parasitic Organisms, State Key Laboratory of Biocontrol, School of Life Sciences, and Key Laboratory of Tropical Diseases Control, the Ministry of Education, Sun Yat-Sen (Zhongshan) University, Guangzhou 510275, P.R. China; Department of Biochemistry and Molecular Biology, Medical College, Henan University of Science and Technology, Luoyang 471003, P.R. China. Abstract Trypanosoma brucei brucei, the infectious agent of the disease known as Nagana, is a pathogenic trypanosome occurring in Africa, where it causes significant economic loss to domesticated livestock. Although many studies on the histopathology of organs of mice infected with T. b. brucei have been reported, little work has been done regarding gene expression in these organs in infected mice. In this paper we describe the use of cDNA microarray to determine gene expression profiles in the liver and spleen of mice infected with T. b. brucei (STIB 920) at peak parasitaemia (12 days after infection). Our results showed that a total of 123 genes in the liver and 389 genes in the spleen were expressed differentially in T. b. brucei infected mice. In contrast, however, in an acute infection in mice caused by T. brucei evansi, a species genetically related to T. b. brucei, 336 genes in the liver and 190 genes in the spleen were expressed, differentially, indicating that the liver of mice was more affected by the acute T. b. evansi infection whilst the spleen was more affected by the subacute T. b. brucei infection. Our results provide a number of possible reasons why mice infected with T. b. evansi die sooner than those infected with T. b. brucei: (1) mice infected with T. b. evansi may need more stress response proteins to help them pass through the infection and these are probably excessively consumed; (2) Proliferating cell nuclear antigen was more down-regulated in the liver of mice infected with T. b. evansi, which indicated that the inhibition of proliferation of hepatocytes in mice infected with T. b. evansi might be more severe than that in T. b. brucei infection; and (3) more hepatocyte apoptosis occurred in the mice infected with T. b. evansi and this might be probably the most important reason why mice died sooner than those infected with T. b. brucei. Studies of the changes in the gene expression profile in the liver and spleen of mice infected with T. b. brucei may be helpful in understanding the mechanisms of pathogenesis in Nagana disease at the molecular level. By comparing the gene profiles of the liver and spleen of mice infected with T. b. brucei with T. b. evansi, we have identified a number of factors that could explain the differences in pathogenesis in mice infected with these two African trypanosomes. Copyright © 2011. Published by Elsevier Inc.
	PMID: 21376043 [PubMed - as supplied by publisher]
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10.	Trials. 2011 Mar 6;12(1):66. [Epub ahead of print] Single-dose Liposomal Amphotericin B (AmBisome(R)) for the treatment of Visceral Leishma niasis in East Africa: study protocol for a randomized controlled trial. Edwards T, Omollo R, Khalil EA, Yifru S, Musa B, Musa A, Wasunna M, Smith PG, Royce C, Ellis S, Balasegaram M, Hailu A. Abstract ABSTRACT: BACKGROUND: AmBisome(R) is an efficacious, safe anti-leishmanial treatment. There is growing interest in its use, either as a single dose or in combination treatments. In East Africa, the minimum optimal single-dosage has not been identified. METHODS: An open-label, 2-arm, non-inferiority, multi-centre randomised controlled trial is being conducted to determine the optimal single-dose treatment with AmBisome(R). Patients in the single-dose arm will receive one infusion on day 1, at a dose depending on body weight. For the first group of patients entered to the trial, the dose will be 7.5mg/kg, but if this dose is found to be ineffective then in subsequent patient series the dose will be escalated progressively to 10, 12.5 and 15mg/kg. Patients in the reference arm will receive a multi-dose regimen of AmBisome(R) (3mg/kg/day on days 1-5, 14 and 21: total dose 21mg/kg). Patients will be hospitalised for approximately one month after the start of treatment and then followed up at three and six months. The primary endpoint is the status of patients six months after treatment. A secondary endpoint is assessment at day 30. Treatment success is determined as the absence of parasites on microscopy samples taken from bone marrow, lymph node or splenic aspirates. Interim analyses to assess the comparative efficacy of the single dose are planned after recruitment of 20 and 40 patients per arm. The final non-inferiority analysis will include 120 patients per arm, to determine if the single-dose efficacy 6 months after treatment is not more than 10% inferior to the multi-dose. DISCUSSION: An effective, safe single-dose treatment would reduce hospitalization and treatment costs. Results will inform the design of combination treatment studies. Trial Registration: ClinicalTrials.gov NCT00832208.
	PMID: 21375777 [PubMed - as supplied by publisher]
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