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Sent on Friday, 2011 Oct 07Search kinetoplastids OR kinetoplastid OR Kinetoplastida OR "trypanosoma brucei" OR leishmania OR brucei OR leishmaniasis OR "African trypanosomiasis"
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| PubMed Results |
| 1. | Nucleic Acids Res. 2011 Oct 5. [Epub ahead of print]RNA-seq analysis of small RNPs in Trypanosoma brucei reveals a rich repertoire of non-coding RNAs.Michaeli S, Doniger T, Gupta SK, Wurtzel O, Romano M, Visnovezky D, Sorek R, Unger R, Ullu E.SourceThe Mina and Everard Goodman Faculty of Life Sciences, and Advanced Materials and Nanotechnology Institute, Bar-Ilan University, Ramat-Gan 52900, Israel, Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel, Department of Internal Medicine and Cell Biology, Yale University Medical School, 295 Congress Avenue, New Haven, CT 06536-0812, USA. AbstractThe discovery of a plethora of small non-coding RNAs (ncRNAs) has fundamentally changed our understanding of how genes are regulated. In this study, we employed the power of deep sequencing of RNA (RNA-seq) to examine the repertoire of ncRNAs present in small ribonucleoprotein particles (RNPs) of Trypanosoma brucei, an important protozoan parasite. We identified new C/D and H/ACA small nucleolar RNAs (snoRNAs), as well as tens of putative novel non-coding RNAs; several of these are processed from trans-spliced and polyadenylated transcripts. The RNA-seq analysis provided information on the relative abundance of the RNAs, and their 5'- and 3'-termini. The study demonstrated that three highly abundant snoRNAs are involved in rRNA processing and highlight the unique trypanosome-specific repertoire of these RNAs. Novel RNAs were studied using in situ hybridization, association in RNP complexes, and 'RNA walk' to detect interaction with their target RNAs. Finally, we showed that the abundance of certain ncRNAs varies between the two stages of the parasite, suggesting that ncRNAs may contribute to gene regulation during the complex parasite's life cycle. This is the first study to provide a whole-genome analysis of the large repertoire of small RNPs in trypanosomes. |
| 2. | Nucleic Acids Res. 2011 Oct 5. [Epub ahead of print]Dual targeting of isoleucyl-tRNA synthetase in Trypanosoma brucei is mediated through alternative trans-splicing.Rettig J, Wang Y, Schneider A, Ochsenreiter T.SourceDepartment of Chemistry and Biochemistry, University of Bern, Freiestrasse 3 and Institute of Cell Biology, University of Bern, Baltzerstrasse 4, 3012 Bern, Switzerland. AbstractAminoacyl-tRNA synthetases catalyze the aminoacylation of tRNAs with their cognate amino acids. They are an essential part of each translation system and in eukaryotes are therefore found in both the cytosol and mitochondria. Thus, eukaryotes either have two distinct genes encoding the cytosolic and mitochondrial isoforms of each of these enzymes or a single gene encoding dually localized products. Trypanosomes require trans-splicing of a cap containing leader sequence onto the 5'-untranslated region of every mRNA. Recently we speculated that alternative trans-splicing could lead to the expression of proteins having amino-termini of different lengths that derive from the same gene. We now demonstrate that alternative trans-splicing, creating a long and a short spliced variant, is the mechanism for dual localization of trypanosomal isoleucyl-tRNA synthetase (IleRS). The protein product of the longer spliced variant possesses an amino-terminal presequence and is found exclusively in mitochondria. In contrast, the shorter spliced variant is translated to a cytosol-specific isoform lacking the presequence. Furthermore, we show that RNA stability is one mechanism determining the differential abundance of the two spliced isoforms. |
| 3. | Am J Trop Med Hyg. 2011 Oct;85(4):646-7.First Report on Natural Infection of Phlebotomus sergenti with Leishmania Promastigotes in the Cutaneous Leishmaniasis Focus in Southeastern Tunisia.Tabbabi A, Bousslimi N, Rhim A, Aoun K, Bouratbine A.SourceLaboratoire de Recherche 05SP03, et Laboratoire de Parasitologie, Institut Pasteur de Tunis, Tunis, Tunisia. AbstractAbstract. During September 2010, 133 female sand flies were caught inside houses of patients with cutaneous leishmaniasis in the focus for this disease in southeastern Tunisia and subsequently dissected. One specimen was positive for Leishmania protozoa. This sand fly species was identified as Phlebotomus sergenti, and the parasite was identified as L. tropica. This is the first report of P. sergenti involvement in transmission of L. tropica in Tunisia. |
| 4. | Am J Trop Med Hyg. 2011 Oct;85(4):644-645.First Report on Ambisome-Associated Allergic Reaction in Two Sudanese Leishmaniasis Patients.Mukhtar M, Aboud M, Kheir M, Bakhiet S, Abdullah N, Ali A, Hassan N, Elamin E, Elagib A.SourceInstitute of Endemic Diseases, University of Khartoum, Khartoum, Sudan; Umdurman Tropical Disease Hospital, Khartoum, Sudan; Faculty of Medicine, University of Khartoum, Khartoum, Sudan; Faculty of Medicine, University of Khartoum, Khartoum, Sudan; Faculty of Medicine, Al Nilian University, Khartoum, Sudan; Faculty of Medicine, Al Nilian University, Khartoum, Sudan; Faculty of Medical Laboratory Sciences, AL Zaim Al Azhary University, Khartoum, Sudan; Tropical Diseases Research Institute, National Center for Research, Ministry of Science and Technology, Khartoum, Sudan. AbstractAbstract. Post kala-azar dermal leishmaniasis (PKDL) and mucosal leishmaniasis (ML) are serious clinical forms of leishmaniasis caused by Leishmania donovani parasites in Sudan. Although pentavalent antimonys are used as the first line of treatment of all clinical forms of leishmaniasis, persistent PKDL and ML patients are treated with liposomal amphotericin B (Ambisome) as a second-line drug. In this work, we report the development of allergic reactions by a PKDL and a ML Sudanese patient to Ambisome. The findings warrant future close supervision of patients to be treated with the drug. |
| 5. | Am J Trop Med Hyg. 2011 Oct;85(4):639-43.Effect of human urine on cell cycle and infectivity of leismania species promastigotes in vitro.Allahverdiyev AM, Bagirova M, Elcicek S, Koc RC, Oztel ON.SourceDepartment of Bioengineering, Yildiz Technical University, Istanbul, Turkey; Department of Bioengineering, Firat University, Elazig, Turkey. AbstractAbstract. In vitro cultivation of Leishmania parasites plays an important role in diagnosis and treatment of leishmaniasis and in vaccine and drug development studies. Conversely, long-term cultivation of Leishmania parasites usually results in decreased infectivity potential. Some studies reported a stimulatory effect of human urine in Leishmania promastigotes. However, there is no information about the effects of urine within culture on the infectivity of Leishmania parasites. Analysis of the effect of urine have showed that proliferation indexes were significantly increased in culture medium supplemented with human urine (L. tropica = 38.17 ± 5.12, L. donovani = 34.74 ± 5.6, L. major = 34.22 ± 4.66, and L. infantum 35.88 ± 6.40) than in controls. Infection indexes were 13 ± 1.7 for L. tropica, 55 ± 2.2 for L. infantum, 41 ± 3.14 for L. donovani, and 49 ± 3.26 for L. major. Our results showed that human urine increased the infectivity and proliferation of Leishmania parasites. |
| 6. | Clin Nucl Med. 2011 Nov;36(11):1041-3.Diffuse Splenic F-18 FDG Uptake in Visceral Leishmaniasis.Yapar AF, Reyhan M, Kocer NE, Aydin M, Nursal GN.SourceFrom the Departments of *Nuclear Medicine and †Pathology, Baskent University School of Medicine, Adana, Turkey. AbstractA 51-year-old woman had splenomegaly and enlarged multiple splenic hilar lymph nodes. The patient was referred to our department for F-18 fluorodeoxyglucose positron emission tomography/computed tomography (F-18 FDG PET/CT) evaluation to determine the metabolic activity of lymph nodes and define a biopsy site. PET/CT images showed diffuse increased FDG uptake in an enlarged spleen and hypermetabolic splenic hilar lymph nodes. The metabolic activity in bone marrow also seemed diffusely increased. After splenectomy, histopathologic analysis showed the growth of Leishmania amastigotes in splenic tissue, and bone marrow biopsy did not reveal any significant pathology but only mild hypercellularity. |
| 7. | Biol Chem. 2011 Oct 5. [Epub ahead of print]Cloning, expression, characterization, and inhibition studies on Trypanothione Synthetase, a drug target enzyme, from Leishmania donovani.Saudagar P, Dubey VK.SourceDepartment of Biotechnology, Indian Institute of Technology, Guwahati 781039, Assam, India. AbstractAbstract Trypanothione synthetase, a validated drug target, synthesizes trypanothione form glutathione (GSH) and spermidine. We report cloning, expressing, characterization and inhibition studies of Trypanothione synthetase from Leishmania donovani (LdTryS). The purified recombinant LdTryS enzyme obeyed Michaelis-Menten kinetics. High substrate inhibition was observed with glutathione (K(m)= 33.24 µM, K(cat)= 1.3s(-1), K(i)= 866 µM). Enzyme obeyed simple hyperbolic kinetics with fixed glutathione concentration and with other substrates limiting K(m) values for Mg∙ATP and spermidine (Spd) of 14.2 µM and 139.6 µM, respectively. LdTryS was also screened for inhibitors. Tomatine, conessine, uvaol as well as butelin are identified as inhibitors of the enzyme. The inhibitors are tested for leishmanicidal activity. Finally, effect of LdTryS inhibitors on redox homeostasis of parasite gave a broader picture of their action against leishmaniasis. |
| 8. | Vector Borne Zoonotic Dis. 2011 Oct;11(10):1359-64. Epub 2011 Sep 16.A Novel 12.6-kDa Protein of Leishmania donovani for the Diagnosis of Indian Visceral Leishmaniasis.Kumar D, Kumar S, Chakravarty J, Sundar S.SourceDepartment of Medicine, Institute of Medical Sciences, Banaras Hindu University , Varanasi, India . AbstractAbstract Background: For the diagnosis of visceral leishmaniasis (VL), rK39 antigen-based rapid test is widely used. Unfortunately, up to 32% healthy individuals from endemic region test positive with this antigen. There is an urgent need to search for a more specific antigen with sensitivity similar to rK39. Methods: We identified a Leishmania donovani-specific 12.6-kDa (BHUP3) soluble promastigote antigen through sensitive western blot technique. The identified protein was partially purified from sodium dodecyl sulfate-polyacrylamide gel electrophoresis and the antigenic response of eluted protein was determined by western blot with different groups of individual sera. The diagnostic potential was further validated by enzyme-linked immunosorbent assay using serum of 100 VL patients, 93 nonendemic healthy control individuals, 110 endemic healthy control individuals, and 110 disease control individuals. Further, it was characterized by two-dimensional gel electrophoresis followed by matrix-assisted laser desorption/ionization-time-of-flight analysis. Results: On blotting, antibody against this protein was recognized by all (9/9) VL patient's sera, but it was absent in every control group (nonendemic healthy control and endemic healthy control). Sensitivity of the enzyme-linked immunosorbent assay was 88% (89/101), whereas the specificity for endemic healthy, nonendemic healthy, and different disease groups were 96% (106/110), 100% (93/93), and 97% (107/110), respectively. The two-dimensional gel electrophoresis showed a single spot, and matrix-assisted laser desorption/ionization-time-of-flight analysis revealed that it is a 113-amino-acid-long putative uncharacterized protein of 12.6-kDa anamorsin homolog matched completely with Leishmania major (GenBank accession number: Q4QIS1). Conclusion: Despite marginally lower sensitivity of BHUP3, excellent specificity warrants its further development as a tool for diagnosis of VL. |
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| 9. | J Chem Inf Model. 2011 Oct 5. [Epub ahead of print]CrystalDock: A Novel Approach to Fragment-Based Drug Design.Durrant JD, Friedman AJ, McCammon JA.SourceChemistry & Biochemistry, University of California-San Diego , La Jolla, California 92093-0365, United States. AbstractWe present a novel algorithm called CrystalDock that analyzes a molecular pocket of interest and identifies potential binding fragments. The program first identifies groups of pocket-lining receptor residues (i.e., microenvironments) and then searches for geometrically similar microenvironments present in publically available databases of ligand-bound experimental structures. Germane fragments from the crystallographic or NMR ligands are subsequently placed within the novel binding pocket. These positioned fragments can be linked together to produce ligands that are likely to be potent; alternatively, they can be joined to an inhibitor with a known or suspected binding pose to potentially improve binding affinity. To demonstrate the utility of the algorithm, CrystalDock is used to analyze the principal binding pockets of influenza neuraminidase and Trypanosoma brucei RNA editing ligase 1, validated drug targets in the fight against pandemic influenza and African sleeping sickness, respectively. In both cases, CrystalDock suggests modifications to known inhibitors that may improve binding affinity. |
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| 10. | J Med Chem. 2011 Oct 13;54(19):6514-30. Epub 2011 Sep 1.Dihydroquinazolines as a Novel Class of Trypanosoma brucei Trypanothione Reductase Inhibitors: Discovery, Synthesis, and Characterization of their Binding Mode by Protein Crystallography.Patterson S, Alphey MS, Jones DC, Shanks EJ, Street IP, Frearson JA, Wyatt PG, Gilbert IH, Fairlamb AH.SourceDivision of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee , Dow Street, Dundee DD1 5EH, U.K. AbstractTrypanothione reductase (TryR) is a genetically validated drug target in the parasite Trypanosoma brucei , the causative agent of human African trypanosomiasis. Here we report the discovery, synthesis, and development of a novel series of TryR inhibitors based on a 3,4-dihydroquinazoline scaffold. In addition, a high resolution crystal structure of TryR, alone and in complex with substrates and inhibitors from this series, is presented. This represents the first report of a high resolution complex between a noncovalent ligand and this enzyme. Structural studies revealed that upon ligand binding the enzyme undergoes a conformational change to create a new subpocket which is occupied by an aryl group on the ligand. Therefore, the inhibitor, in effect, creates its own small binding pocket within the otherwise large, solvent exposed active site. The TryR-ligand structure was subsequently used to guide the synthesis of inhibitors, including analogues that challenged the induced subpocket. This resulted in the development of inhibitors with improved potency against both TryR and T. brucei parasites in a whole cell assay. |
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