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Sent on Tuesday, 2011 Aug 09Search kinetoplastids OR kinetoplastid OR Kinetoplastida OR "trypanosoma brucei" OR leishmania OR brucei OR leishmaniasis OR "African trypanosomiasis"
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1. | Wiley Interdiscip Rev RNA. 2011 Sep;2(5):669-85. doi: 10.1002/wrna.82. Epub 2011 Mar 23.Uridine insertion/deletion editing in trypanosomes: a playground for RNA-guided information transfer.Aphasizhev R, Aphasizheva I.SourceDepartment of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, CA, USA. ruslan@uci.edu. AbstractRNA editing is a collective term referring to enzymatic processes that change RNA sequence apart from splicing, 5' capping or 3' extension. In this article, we focus on uridine insertion/deletion mRNA editing found exclusively in mitochondria of kinetoplastid protists. This type of editing corrects frameshifts, introduces start and stops codons, and often adds much of the coding sequence to create an open reading frame. The mitochondrial genome of trypanosomatids, the most extensively studied clade within the order Kinetoplastida, is composed of ∼50 maxicircles with limited coding capacity and thousands of minicircles. To produce functional mRNAs, a multitude of nuclear-encoded factors mediate interactions of maxicircle-encoded pre-mRNAs with a vast repertoire of minicircle-encoded guide RNAs. Editing reactions of mRNA cleavage, U-insertions or U-deletions, and ligation are catalyzed by the RNA editing core complex (RECC, the 20S editosome) while each step of this enzymatic cascade is directed by guide RNAs. These 50-60 nucleotide (nt) molecules are 3' uridylated by RET1 TUTase and stabilized via association with the gRNA binding complex (GRBC). Remarkably, the information transfer between maxicircle and minicircle transcriptomes does not rely on template-dependent polymerization of nucleic acids. Instead, intrinsic substrate specificities of key enzymes are largely responsible for the fidelity of editing. Conversely, the efficiency of editing is enhanced by assembling enzymes and RNA binding proteins into stable multiprotein complexes. WIREs RNA 2011 2 669-685 DOI: 10.1002/wrna.82 For further resources related to this article, please visit the WIREs website. Copyright © 2011 John Wiley & Sons, Ltd. |
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2. | Prev Vet Med. 2011 Aug 5. [Epub ahead of print]Questionnaire-based survey on the clinical management of canine leishmaniosis in the Madrid region (central Spain).Gálvez R, Miró G, Descalzo MA, Molina R.SourceServicio de Parasitología, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Ctra. Majadahonda-Pozuelo s/n, 28220 Majadahonda, Madrid, Spain. AbstractThis paper describes a questionnaire designed to gain information on how veterinarians clinically manage canine leishmaniosis (CanL) in the Madrid region (central Spain). The present survey is one of the several similar questionnaire-based surveys conducted within the framework of the project EDEN (Emerging Diseases in a changing European eNvironment). The questionnaire sought to obtain data regarding the main clinical manifestations observed, the diagnostic methods used and the preventive measures recommended. Its Spanish version was sent by post to veterinary practitioners within the study area in two lots, one sent out in December 2006 and the other in March 2007. Only 174 of the 760 questionnaires sent were completed and returned (reply rate of 23%). Among the completed questionnaires, clinics differed widely in terms of features such as the habitats of the dogs (urban, peri-urban or rural) and patient volumes. Clinics attending dogs from peri-urban/rural habitats reported more suspected (p<0.001), confirmed (p=0.001) and newly diagnosed (p=0.001) cases/year than clinics providing service to a city clientele alone. According to the veterinary practitioners, skin lesions, lymphadenomegaly and weight loss were commonly observed, although these signs are not specific to CanL. Signs described to be of high diagnostic value were epistaxis and kidney disease. All the veterinarians polled reported that a suspicion of Leishmania infantum infection was confirmed by at least a serological method; the immunofluorescence antibody test (IFAT) being the technique most used. To prevent the disease, most vets recommended topical synthetic pyrethroids applied as impregnated collars or spot-ons. It is observed that despite considerable progress is being made in clinical management and controlling the disease, in Madrid Region its incidence continues to increase. Copyright © 2011 Elsevier B.V. All rights reserved. |
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3. | Adv Parasitol. 2011;75:251-83.Nuclear Structure of Trypanosoma cruzi.Schenkman S, Pascoalino Bdos S, Nardelli SC.SourceDepartamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de São Paulo, São Paulo, Brazil; Center for Tropical and Emerging Diseases, University of Georgia, Athens, Georgia, USA. AbstractThe presence of nucleus in living organisms characterizes the Eukaryote domain. The nucleus compartmentalizes the genetic material surrounded by a double membrane called nuclear envelope. The nucleus has been observed since the advent of the light microscope, and sub-compartments such as nucleoli, diverse nuclear bodies and condensed chromosomes have been later recognized, being part of highly organized and dynamic structure. The significance and function of such organization has increased with the understanding of transcription, replication, DNA repair, recombination processes. It is now recognized as consequence of adding complexity and regulation in more complex eukaryotic cells. Here we provide a description of the actual stage of knowledge of the nuclear structure of Trypanosoma cruzi. As an early divergent eukaryote, it presents unique and/or reduced events of DNA replication, transcription and repair as well as RNA processing and transport to the cytosol. Nevertheless, it shows peculiar structure changes accordingly to the cell cycle and stage of differentiation. T. cruzi proliferates only as epimastigote and amastigote stages, and when these forms differentiate in trypomastigote forms, their cell cycle is arrested. This arrested stage is capable of invading mammalian cells and of surviving harsh conditions, such as the gut of the insect vector and mammalian macrophages. Transcription and replication decrease during transformation in trypomastigotes implicating large alterations in the nuclear structure. Recent evidences also suggest that T. cruzi nucleus respond to oxidative and nutritional stresses. Due to the phylogenetic proximity with other well-known trypanosomes, such as Trypanosoma brucei and Leishmania major, they are expected to have similar nuclear organization, although differences are noticed due to distinct life cycles, cellular organizations and the specific adaptations for surviving in different host environments. Therefore, the general features of T. cruzi nuclear structure regarding unique characteristics of this protozoan parasite will be described. Copyright © 2011 Elsevier Ltd. All rights reserved. |
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4. | J Struct Biol. 2011 Jul 26. [Epub ahead of print]Solution structure and dynamics of ADF from Toxoplasma gondii.Yadav R, Pathak PP, Shukla V, Jain A, Srivastava S, Tripathi S, Krishna Pulavarti SV, Mehta S, David Sibley L, Arora A.SourceMolecular and Structural Biology Division, Central Drug Research Institute, Lucknow 226 001, India. AbstractToxoplasma gondii (TgADF) belongs to a functional subtype characterized by strong G-actin sequestering activity and low F-actin severing activity. Among the characterized ADF/cofilin proteins, TgADF has the shortest length and is missing a C-terminal helix implicated in F-actin binding. In order to understand its characteristic properties, we have determined the solution structure of TgADF and studied its backbone dynamics from (15)N-relaxation measurements. TgADF has conserved ADF/cofilin fold consisting of a central mixed β-sheet comprised of six β-strands that are partially surrounded by three α-helices and a C-terminal helical turn. The high G-actin sequestering activity of TgADF relies on highly structurally and dynamically optimized interactions between G-actin with the G-actin binding surface of TgADF. The equilibrium dissociation constant for TgADF and rabbit muscle G-actin was 23.81nM, as measured by ITC, which reflects very strong affinity of TgADF and G-actin interactions. The F-actin binding site of TgADF is partially formed, with a shortened F-loop that does not project out of the ellipsoid structure and a C-terminal helical turn in place of the C-terminal helix α4. Yet, it is more rigid than the typical F-actin binding site of Leishmania donovani cofilin. Experimental observations and structural features do not support the interaction of PIP2 with TgADF, and PIP2 does not affect the interaction of TgADF with G-actin. Overall, this study suggests that conformational flexibility of G-actin binding sites enhances the affinity of TgADF for G-actin, while conformational rigidity of F-actin binding sites of conventional ADF/cofilins is necessary for stable binding to F-actin. Copyright © 2011 Elsevier Inc. All rights reserved. |
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5. | Biochem Biophys Res Commun. 2011 Jul 28. [Epub ahead of print]Stearoyl-CoA desaturase is an essential enzyme for the paras itic protist Trypanosoma brucei.Alloatti A, Gupta S, Gualdrón-López M, Nguewa PA, Altabe SG, Deumer G, Wallemacq P, Michels PA, Uttaro AD.SourceInstituto de Biología Molecular y Celular de Rosario (IBR), CONICET, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Santa Fe, Argentina. AbstractTrypanosoma brucei, the etiologic agent of sleeping sickness, is exposed to important changes in nutrients and temperature during its life cycle. To adapt to these changes, the fluidity of its membranes plays a crucial role. This fluidity, mediated by the fatty-acid composition, is regulated by enzymes named desaturases. We have previously shown that the oleoyl desaturase is essential for Trypanosoma cruzi and T. brucei. In this work, we present experimental support for the relevance of stearoyl-CoA desaturase (SCD) for T. brucei's survival, in both its insect or procyclic-form (PCF) and bloodstream-form (BSF) stages. We evaluated this essentiality in two different ways: by generating a SCD knocked-down parasite line using RNA interference, and by chemical inhibition of the enzyme with two compounds, Isoxyl and a thiastearate with the sulfur atom at position 10 (10-TS). The effective concentration for 50% growth inhibition (EC(50)) of PCF was 1.0±0.2μM for Isoxyl and 5±2μM for 10-TS, whereas BSF appeared more susceptible with EC(50) values 0.10±0.03μM (Isoxyl) and 1.0±0.6μM (10-TS). RNA interference showed to be deleterious for both stages of the parasite. In addition, T. brucei-infected mice were fed with Isoxyl, causing a reduction of the parasitemia and an increase of the rodents' survival. Copyright © 2011. Published by Elsevier Inc. |
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6. | Exp Parasitol. 2011 Jul 27. [Epub ahead of print]Redundancy of interleukin-6 in the differentiation of T cell and monocyte subsets during cutaneous leishmaniasis.Kling J, Gollan R, Fromm P, Körner H.SourceComparative Genomics Centre, Cellular Immunology Laboratory, James Cook University, Townsville, Australia. AbstractLeishmania (L.) major is a protozoan parasite that infects mammalian hosts and causes a spectrum of disease manifestations that is strongly associated with the genetic background of the host. Interleukin (IL)-6 is an acute phase proinflammatory cytokine, known in vitro to be involved in the inhibition of the generation of regulatory T cells. IL-6-deficient mice were infected with L. major, and T cell and monocyte subsets were analyzed with flow cytometry. Our data show that at the site of infection in the footpad and in the draining popliteal lymph node, numbers of regulatory T cells remain unchanged between WT and IL-6-deficient mice. However, the spleens of IL-6(-/-) mice contained fewer regulatory T cells after infection with L. major. The development of cutaneous lesions is similar between WT and IL-6-deficient mice, while parasite burden in IL-6(-/-) mice is reduced compared to WT. The development of IFN-γ or IL-10 producing T cells is similar in IL-6(-/-) mice. Despite a comparable adaptive T cell response, IL-6-deficient mice develop an earlier peak of some inflammatory cytokines than WT mice. This data indicate that the role of IL-6 in the differentiation of regulatory T cells is complex in vivo, and the effect of an absence of this cytokine can be counter-intuitive. Copyright © 2011 Elsevier Inc. All rights reserved. |
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7. | Parasitology. 2011 Aug 8:1-14. [Epub ahead of print]Sir2-Related Protein 1 from Leishmania amazonensis is a glycosylated NAD+-dependent deacetylase.Fessel MR, Lira CB, Giorgio S, Ramos CH, Cano MI.SourceChemistry Institute, University of Campinas UNICAMP, Campinas SP 13083-970, Brazil. AbstractSUMMARYSirtuin proteins form a family of NAD+-dependent protein deacetylases that are considered potential drug targets against parasites. Here, we present the first characterization of a sirtuin orthologue from Leishmania amazonensis, an aetiological agent of American tegumentary leishmaniasis that has been the subject of many studies focused in the development of therapeutic approaches. The protein has high sequence identity with other Kinetoplastid Silent information regulator 2 Related Protein 1 (Sir2RP1) and was named LaSir2RP1. The gene exists as a single copy, encoding a monomeric protein (LaSir2RP1) of approximately 41 kDa that has NAD+-dependent deacetylase activity. LaSir2RP1 was immunodetected in total protein extracts, in cytoplasmic granules, and in the secreted material of both promastigotes and lesion-derived amastigotes. Analysis of both lectin‑affinity purified promastigote and amastigote extracts revealed the presence of a major enriched protein of approximately 66 kDa that was recognized by an anti-LaSir2RP1 serum, suggesting that a parasite sirtuin could be glycosylated in vivo. |
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8. | Parasitology. 2011 Aug 8:1-8. [Epub ahead of print]Increased metacyclogenesis of antimony-resistant Leishmania donovani clinical lines.Ouakad M, Vanaerschot M, Rijal S, Sundar S, Speybroeck N, Kestens L, Boel L, DE Doncker S, Maes I, Decuypere S, Dujardin JC.SourceUnit of Molecular Parasitology, Department of Parasitology, Institute of Tropical Medicine, Antwerp, Belgium. AbstractSUMMARYMathematical models predict that the future of epidemics of drug-resistant pathogens depends in part on the competitive fitness of drug-resistant strains. Considering metacyclogenesis (differentiation process essential for infectivity) as a major contributor to the fitness of Leishmania donovani, we tested its relationship with pentavalent antimony (SbV) resistance in clinical lines. Different methods for the assessment of metacyclogenesis were cross-validated: gene expression profiling (META1 and SHERP), morphometry (microscopy and FACS), in vitro infectivity to macrophages and resistance to complement lysis. This was done on a model constituted by 2 pairs of reference strains cloned from a SbV-resistant and -sensitive isolate. We selected the most adequate parameter and extended the analysis of metacyclogenesis diversity to a sample of 20 clinical lines with different in vitro susceptibility to the drug. The capacity of metacyclogenesis, as measured by the complement lysis test, was shown to be significantly higher in SbV-resistant clinical lines of L. donovani than in SbV-sensitive lines. Together with other lines of evidence, it is concluded that L. donovani constitutes a unique example and model of drug-resistant pathogens with traits of increased fitness. These findings raise a fundamental question about the potential risks of selecting more virulent pathogens through massive chemotherapeutic interventions. |
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9. | Cell Microbiol. 2011 Aug 5. doi: 10.1111/j.1462-5822.2011.01658.x. [Epub ahead of print]Leishmania-Host Interactions: What has imaging taught us?Beattie L, Kaye PM.SourceCentre for Immunology and Infection, Hull York Medical School and Department of Biology, University of York, York, UK, YO10 5DD. |
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10. | Mol Microbiol. 2011 Aug 8. doi: 10.1111/j.1365-2958.2011.07799.x. [Epub ahead of print]The Leishmania nicotinamidase is essential for NAD+ production and parasite proliferation.Gazanion E, Garcia D, Silvestre R, Gérard C, Guichou J, Labesse G, Seveno M, Cordeiro-Da-Silva A, Ouaissi A, Sereno D, Vergnes B.SourceMIVEGEC (UM1-CNRS 5290-IRD 224), Institut de Recherche pour le Développement (IRD), BP 64501, 34394 Montpellier Cedex 5, France. Parasite Disease Group, Instituto de Biologia Molecular e Celular - IBMC Universidade do Porto, Rua Campo Alegre 823, 4150-180 Porto, Portugal. UMR5048 CNRS, Universités Montpellier I & II and INSERM U554, 29 Rue de Navacelles, 34090 Montpellier Cedex, France. INSERM, CNRS UMR5235, Université Montpellier II, Place E. Bataillon - Bât. 24, 34095 Montpellier Cedex 5, Montpellier, France. AbstractNAD(+) is a central co-factor that plays important roles in cellular metabolism and energy production in all living cells. Genomics-based reconstruction of NAD(+) metabolism revealed that Leishmania protozoan parasites are NAD(+) auxotrophs. Consequently, these parasites require assimilating NAD(+) precursors (nicotinamide, nicotinic acid, nicotinamide riboside) from their host environment to synthesize NAD(+) by a salvage pathway. Nicotinamidase is a key enzyme of this salvage pathway that catalyzes conversion of nicotinamide (NAm) to nicotinic acid (Na), and that is absent in higher eukaryotes. We present here the biochemical and functional characterizations of the Leishmania infantum nicotinamidase (LiPNC1). Generation of Lipnc1 null mutants leads to a decrease in NAD(+) content, associated with a metabolic shutdown-like phenotype with an extensive lag phase of growth. Both phenotypes could be rescued by an add-back construct or by addition of exogenous Na. In addition, Lipnc1 null mutants were unable to establish a sustained infection in a murine experimental model. Altogether, these results illustrate that NAD(+) homeostasis is a fundamental component of Leishmania biology and virulence, and that NAm constitutes its main NAD(+) source in the mammalian host. The crystal structure of LiPNC1 we solved allows now the design of rational inhibitors against this new promising therapeutic target. © 2011 Blackwell Publishing Ltd. |
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