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https://www.readbyqxmd.com/read/29785042/inducible-high-efficiency-crispr-cas9-targeted-gene-editing-and-precision-base-editing-in-african-trypanosomes
#1
Eva Rico, Laura Jeacock, Julie Kovářová, David Horn
The Cas9 endonuclease can be programmed by guide RNA to introduce sequence-specific breaks in genomic DNA. Thus, Cas9-based approaches present a range of novel options for genome manipulation and precision editing. African trypanosomes are parasites that cause lethal human and animal diseases. They also serve as models for studies on eukaryotic biology, including 'divergent' biology. Genome modification, exploiting the native homologous recombination machinery, has been important for studies on trypanosomes but often requires multiple rounds of transfection using selectable markers that integrate at low efficiency...
May 21, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29778893/synthesis-of-proline-derived-benzenesulfonamides-a-potent-anti-trypanosoma-brucei-gambiense-agent
#2
David I Ugwu, Uchechukwu C Okoro, Narendra K Mishra
Thousands of death in Africa and other developing nations are still attributed to trypanosomiasis. Excessive sleep has been associated with increased inflammation. We report herein, the synthesis, antitrypanosomal and anti-inflammatory activities of eight new carboxamide derivatives bearing substituted benzenesulfonamides. The base promoted reactions of l-proline and L-4-hydroxyproline with substituted benzenesulfonyl chlorides gave the benzenesulfonamides (11a-h) in excellent yields. Boric acid mediated amidation of the benzenesulfonamides (11a-h) and p-aminobenzoic acid (12) gave the new carboxamides (13a-h) in excellent yields...
May 14, 2018: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29778466/in-vitro-susceptibility-of-trypanosoma-brucei-brucei-to-selected-essential-oils-and-their-major-components
#3
Sonya Costa, Cláudia Cavadas, Carlos Cavaleiro, Lígia Salgueiro, Maria do Céu Sousa
Aiming for discovering effective and harmless antitrypanosomal agents, 17 essential oils and nine major components were screened for their effects on T. b. brucei. The essential oils were obtained by hydrodistillation from fresh plant material and analyzed by GC and GC-MS. The trypanocidal activity was assessed using blood stream trypomastigotes cultures of T. b. brucei and the colorimetric resazurin method. The MTT test was used to assess the cytotoxicity of essential oils on macrophage cells and Selectivity Indexes were calculated...
May 17, 2018: Experimental Parasitology
https://www.readbyqxmd.com/read/29778329/the-kinetoplast-dna-of-the-australian-trypanosome-trypanosoma-copemani-shares-features-with-trypanosoma-cruzi-and-trypanosoma-lewisi
#4
Adriana Botero, Irit Kapeller, Crystal Cooper, Peta L Clode, Joseph Shlomai, R C Andrew Thompson
Kinetoplast DNA (kDNA) is the mitochondrial genome of trypanosomatids. It consists of a few dozen maxicircles and several thousand minicircles, all catenated topologically to form a two-dimensional DNA network. Minicircles are heterogeneous in size and sequence among species. They present one or several conserved regions that contain three highly conserved sequence blocks (CSBs). CSB-1 (10 bp sequence) and CSB-2 (8 bp sequence) present lower interspecies homology, while CSB-3 (12 bp sequence) or the Universal Minicircle Sequence (UMS) is conserved within most trypanosomatids...
May 17, 2018: International Journal for Parasitology
https://www.readbyqxmd.com/read/29772025/shape-shifting-trypanosomes-flagellar-shortening-followed-by-asymmetric-division-in-trypanosoma-congolense-from-the-tsetse-proventriculus
#5
Lori Peacock, Christopher Kay, Mick Bailey, Wendy Gibson
Trypanosomatids such as Leishmania and Trypanosoma are digenetic, single-celled, parasitic flagellates that undergo complex life cycles involving morphological and metabolic changes to fit them for survival in different environments within their mammalian and insect hosts. According to current consensus, asymmetric division enables trypanosomatids to achieve the major morphological rearrangements associated with transition between developmental stages. Contrary to this view, here we show that the African trypanosome Trypanosoma congolense, an important livestock pathogen, undergoes extensive cell remodelling, involving shortening of the cell body and flagellum, during its transition from free-swimming proventricular forms to attached epimastigotes in vitro...
May 2018: PLoS Pathogens
https://www.readbyqxmd.com/read/29768499/a-fixable-probe-for-visualizing-flagella-and-plasma-membranes-of-the-african-trypanosome
#6
Justin Wiedeman, Kojo Mensa-Wilmot
The protozoan Trypanosoma brucei sp. cause diseases in humans and animals. Studies of T. brucei cell biology have revealed unique features, such as major endocytic events being limited to a single region, and mitochondrial genome segregation mediated via basal bodies. Further understanding of trypanosome cell biology can be facilitated with super-resolution fluorescence microscopy. Lack of a plasma membrane probe for fixed trypanosomes remains a persistent problem in need of a working solution. Herein, we report protocols developed using mCLING in super-resolution structured illumination fluorescence microscopy (SR-SIM)...
2018: PloS One
https://www.readbyqxmd.com/read/29764941/a-trypanosome-specific-protein-cooperates-with-the-cif1-protein-to-promote-cytokinesis-in-trypanosoma-brucei
#7
Yasuhiro Kurasawa, Huiqing Hu, Qing Zhou, Ziyin Li
Cytokinesis, the terminal step in cell division, in the protist human pathogen Trypanosoma brucei occurs along the longitudinal axis from the anterior tip of the new flagellum attachment zone (FAZ) towards the posterior cell tip. This process is regulated by a signaling cascade composed of the Polo-like kinase homolog TbPLK, the Aurora B kinase homolog TbAUK1, and the trypanosome-specific CIF1-CIF2 protein complex. However, the regulatory mechanism and the signaling pathway for this unusual mode of cytokinesis remain poorly understood...
May 15, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29758036/benzoxaborole-treatment-perturbs-s-adenosyl-l-methionine-metabolism-in-trypanosoma-brucei
#8
Pieter C Steketee, Isabel M Vincent, Fiona Achcar, Federica Giordani, Dong-Hyun Kim, Darren J Creek, Yvonne Freund, Robert Jacobs, Kevin Rattigan, David Horn, Mark C Field, Annette MacLeod, Michael P Barrett
The parasitic protozoan Trypanosoma brucei causes Human African Trypanosomiasis and Nagana in other mammals. These diseases present a major socio-economic burden to large areas of sub-Saharan Africa. Current therapies involve complex and toxic regimens, which can lead to fatal side-effects. In addition, there is emerging evidence for drug resistance. AN5568 (SCYX-7158) is a novel benzoxaborole class compound that has been selected as a lead compound for the treatment of HAT, and has demonstrated effective clearance of both early and late stage trypanosomiasis in vivo...
May 14, 2018: PLoS Neglected Tropical Diseases
https://www.readbyqxmd.com/read/29754075/corrigendum-to-optimization-of-physicochemical-properties-for-4-anilinoquinazoline-inhibitors-of-trypanosome-proliferation-eur-j-med-chem-141-2017-446-459
#9
Jennifer L Woodring, Kelly A Bachovchin, Kimberly G Brady, Mitchell F Gallerstein, Jessey Erath, Scott Tanghe, Susan E Leed, Ana Rodriguez, Kojo Mensa-Wilmot, Richard J Sciotti, Michael P Pollastri
No abstract text is available yet for this article.
May 10, 2018: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29745031/trypanosoma-cruzi-biochemical-changes-and-cell-death-induced-by-an-organometallic-platinum-based-compound
#10
M Florencia Mosquillo, Lucía Bilbao, Fabricio Hernández, Florencia Tissot, Dinorah Gambino, Beatriz Garat, Leticia Pérez-Díaz
Chagas disease is an endemic illness in Latin America caused by the parasite Trypanosoma cruzi. Current chemotherapies are old and inadequate, and the emergence of drug resistant strains underscores the need of new drugs. Platinum-based complexes have been shown to be a promising approach against parasitic diseases. In this work, the effect of 1,1'-bis(diphenylphosphino)ferrocene pyridine-2-thiolate-1-oxide Pt(II) hexafluorophosphate, Pt-dppf-mpo, was studied on T. cruzi. A promising anti-trypanosomal activity was determined for the CL Brener strain with a low cytotoxicity determined using in vitro cultured mammal cells...
May 9, 2018: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/29741138/insights-into-anti-trypanosomal-agents-based-on-synthetic-glycoconjugates
#11
Vanessa Leiria Campo, Marcelo Fiori Marchiori, Ivone Carvalho
Chagas disease is still a worldwide threat, with estimated 6 to 7 million infected people, mainly in Latin America. Current treatments still rely only on benznidazol and nifurtimox, drugs with poor efficacy in chronic infection phase and recognized toxicity. Thus, there is an urgent need for new therapeutic agents against this disease. In this review we present an updated selection over the last decade of synthetic glycoconjugates as anti-trypanosomal agents, properly addressed as monosaccharide- and disaccharide-based agents, and multivalent-based derivatives, disclosing relevant methods for their synthesis, along with their activities on T...
May 9, 2018: Current Topics in Medicinal Chemistry
https://www.readbyqxmd.com/read/29720251/a-meta-analysis-of-the-prevalence-of-african-animal-trypanosomiasis-in-nigeria-from-1960-to-2017
#12
REVIEW
Paul Olalekan Odeniran, Isaiah Oluwafemi Ademola
BACKGROUND: African animal trypanosomiasis is an economically significant disease that affects the livestock industry in Nigeria. It is caused by several parasites of the genus Trypanosoma. National estimates of the disease prevalence in livestock and tsetse flies are lacking, therefore a systematic review and meta-analysis were performed to understand the trend of the disease prevalence over the years. METHODS: Publications were screened in Web of Science, Ovid MEDLINE, Global Health, EMBASE and PubMed databases...
May 2, 2018: Parasites & Vectors
https://www.readbyqxmd.com/read/29698456/trypanosomal-mitochondrial-intermediate-peptidase-does-not-behave-as-a-classical-mitochondrial-processing-peptidase
#13
Priscila Peña-Diaz, Jan Mach, Eva Kriegová, Pavel Poliak, Jan Tachezy, Julius Lukeš
Upon their translocation into the mitochondrial matrix, the N-terminal pre-sequence of nuclear-encoded proteins undergoes cleavage by mitochondrial processing peptidases. Some proteins require more than a single processing step, which involves several peptidases. Down-regulation of the putative Trypanosoma brucei mitochondrial intermediate peptidase (MIP) homolog by RNAi renders the cells unable to grow after 48 hours of induction. Ablation of MIP results in the accumulation of the precursor of the trypanosomatid-specific trCOIV protein, the largest nuclear-encoded subunit of the cytochrome c oxidase complex in this flagellate...
2018: PloS One
https://www.readbyqxmd.com/read/29693583/adenylate-cyclases-of-trypanosoma-brucei-environmental-sensors-and-controllers-of-host-innate-immune-response
#14
REVIEW
Didier Salmon
Trypanosoma brucei , etiological agent of Sleeping Sickness in Africa, is the prototype of African trypanosomes, protozoan extracellular flagellate parasites transmitted by saliva ( Salivaria ). In these parasites the molecular controls of the cell cycle and environmental sensing are elaborate and concentrated at the flagellum. Genomic analyses suggest that these parasites appear to differ considerably from the host in signaling mechanisms, with the exception of receptor-type adenylate cyclases (AC) that are topologically similar to receptor-type guanylate cyclase (GC) of higher eukaryotes but control a new class of cAMP targets of unknown function, the cAMP response proteins (CARPs), rather than the classical protein kinase A cAMP effector (PKA)...
April 25, 2018: Pathogens
https://www.readbyqxmd.com/read/29690511/anti-parasitic-activities-of-allium-sativum-and-allium-cepa-against-trypanosoma-b-brucei-and-leishmania-tarentolae
#15
Sonja Krstin, Mansour Sobeh, Markus Santhosh Braun, Michael Wink
Background: Garlics and onions have been used for the treatment of diseases caused by parasites and microbes since ancient times. Trypanosomiasis and leishmaniasis are a concern in many areas of the world, especially in poor countries. Methods: Trypanosoma brucei brucei and Leishmania tarentolae were used to investigate the anti-parasitic effects of dichloromethane extracts of Allium sativum (garlic) and Allium cepa (onion) bulbs. As a confirmation of known antimicrobial activities, they were studied against a selection of G-negative, G-positive bacteria and two fungi...
April 21, 2018: Medicines (Basel, Switzerland)
https://www.readbyqxmd.com/read/29689189/emerging-role-of-amiodarone-and-dronedarone-as-antiarrhythmic-drugs-in-treatment-of-leishmaniasis
#16
REVIEW
A Oryan, E Bemani, S Bahrami
Leishmaniasis is a group of human and animal diseases causing 20,000 to 40,000 annual deaths and its etiological agents belong to the Leishmania genus. The most current treatment against leishmaniasis is chemotherapy. Pentavalent antimonials such as glucantime and pentostam have been administrated as the first-line drugs in treatment of various forms of leishmaniasis. The second-line drugs such as amphotericin B, liposomal amphotericin B, miltefosine, pentamidine, azole drugs and paromomycin are used in resistant cases to pentavalent antimonials...
April 21, 2018: Acta Tropica
https://www.readbyqxmd.com/read/29684709/the-role-of-natural-selection-in-shaping-genetic-variation-in-a-promising-chagas-disease-drug-target-trypanosoma-cruzi-trans-sialidase
#17
Joseph P Gallant, Raquel Asunción Lima-Cordón, Silvia Justi, Maria Carlota Monroy, Toni Viola, Lori Stevens
Rational drug design creates innovative therapeutics based on knowledge of the biological target to provide more effective and responsible therapeutics. Chagas disease, endemic throughout Latin America, is caused by Trypanosoma cruzi, a protozoan parasite. Current therapeutics are problematic with widespread calls for new approaches. Researchers are using rational drug design for Chagas disease and one target receiving considerable attention is the T. cruzi trans-sialidase protein (TcTS). In T. cruzi, trans-sialidase catalyzes the transfer of sialic acid from a mammalian host to coat the parasite surface membrane and avoid immuno-detection...
April 20, 2018: Infection, Genetics and Evolution
https://www.readbyqxmd.com/read/29679486/tblpn-a-key-enzyme-in-lipid-droplet-formation-and-phospholipid-metabolism-is-essential-for-mitochondrial-integrity-and-growth-of-trypanosoma-brucei
#18
Ladan Dawoody Nejad, Mauro Serricchio, Jennifer Jelk, Andrew Hemphill, Peter Bütikofer
Mammalian phosphatidic acid phosphatases, also called lipins, show high amino acid sequence identity to Saccharomyces cerevisiae Pah1p and catalyze the dephosphorylation of phosphatidic acid (PA) to diacylglycerol. Both the substrate and product of the reaction are key precursors for the synthesis of phospholipids and triacylglycerol (TAG). We now show that expression of the Trypanosoma brucei lipin homolog TbLpn is essential for parasite survival in culture. Inducible down-regulation of TbLpn in T. brucei procyclic forms increased cellular PA content, decreased the numbers of lipid droplets, reduced TAG steady-state levels and inhibited in vivo [3 H]TAG formation after labeling trypanosomes with [3 H]glycerol...
April 21, 2018: Molecular Microbiology
https://www.readbyqxmd.com/read/29679043/identification-and-heterologous-expression-of-the-actinoallolide-biosynthetic-gene-cluster
#19
Yuki Inahashi, Taro Shiraishi, Akira Také, Atsuko Matsumoto, Yōko Takahashi, Satoshi Ōmura, Tomohisa Kuzuyama, Takuji Nakashima
Actinoallolides are anti-trypanosomal macrolides isolated from the secondary metabolites of two endophytic actinomycete strains, Actinoallomurus fulvus MK10-036 and K09-0307. A putative actinoallolide biosynthetic gene cluster was predicted from the genome sequence of the strain K09-0307. The gene cluster spans a contiguous 53 kb DNA region that comprises seven genes encoding three PKSs (aalA1, aalA2, and aalA3), cytochrome P450 (aalB), acyl-CoA dehydrogenase (aalC), crotonyl-CoA reductase (aalD), and TetR family regulator (aalR)...
April 20, 2018: Journal of Antibiotics
https://www.readbyqxmd.com/read/29672041/targeting-a-subpocket-in-trypanosoma-brucei-phosphodiesterase-b1-tbrpdeb1-enables-the-structure-based-discovery-of-selective-inhibitors-with-trypanocidal-activity
#20
Antoni R Blaazer, Abhimanyu Kumar Singh, Erik de Heuvel, Ewald Edink, Kristina M Orrling, Johan J N Veerman, Toine van den Bergh, Chimed Jansen, Erin Balasubramaniam, Wouter J Mooij, Hans Custers, Maarten Sijm, Daniel N A Tagoe, Titilola D Kalejaiye, Jane C Munday, Hermann Tenor, An Matheeussen, Maikel Wijtmans, Marco Siderius, Chris de Graaf, Louis Maes, Harry P de Koning, David S Bailey, Geert Jan Sterk, Iwan J P De Esch, David G Brown, Rob Leurs
Several trypanosomatid cyclic nucleotide phosphodiesterases (PDEs) possess a unique, parasite-specific cavity near the ligand-binding region that is referred to as the P-pocket. One of these enzymes, Trypanosoma brucei PDE B1 (TbrPDEB1), is considered a drug target for the treatment of African sleeping sickness. Here, we elucidate the molecular determinants of inhibitor binding and reveal that the P-pocket is amenable to directed design. By iterative cycles of design, synthesis, pharmacological evaluation, and by elucidating the structures of inhibitor-bound TbrPDEB1, hPDE4B and hPDE4D complexes, we have developed 4a,5,8,8a-tetrahydrophthalazinones as the first selective TbrPDEB1 inhibitor series...
April 19, 2018: Journal of Medicinal Chemistry
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