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Kinetoplastids

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https://www.readbyqxmd.com/read/28742144/genome-wide-and-protein-kinase-focused-rnai-screens-reveal-conserved-and-novel-damage-response-pathways-in-trypanosoma-brucei
#1
Jennifer A Stortz, Tiago D Serafim, Sam Alsford, Jonathan Wilkes, Fernando Fernandez-Cortes, Graham Hamilton, Emma Briggs, Leandro Lemgruber, David Horn, Jeremy C Mottram, Richard McCulloch
All cells are subject to structural damage that must be addressed for continued growth. A wide range of damage affects the genome, meaning multiple pathways have evolved to repair or bypass the resulting DNA lesions. Though many repair pathways are conserved, their presence or function can reflect the life style of individual organisms. To identify genome maintenance pathways in a divergent eukaryote and important parasite, Trypanosoma brucei, we performed RNAi screens to identify genes important for survival following exposure to the alkylating agent methyl methanesulphonate...
July 24, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28730142/taming-parasites-by-tailoring-them
#2
Bingjian Ren, Nishith Gupta
The next-generation gene editing based on CRISPR (clustered regularly interspaced short palindromic repeats) has been successfully implemented in a wide range of organisms including some protozoan parasites. However, application of such a versatile game-changing technology in molecular parasitology remains fairly underexplored. Here, we briefly introduce state-of-the-art in human and mouse research and usher new directions to drive the parasitology research in the years to come. In precise, we outline contemporary ways to embolden existing apicomplexan and kinetoplastid parasite models by commissioning front-line gene-tailoring methods, and illustrate how we can break the enduring gridlock of gene manipulation in non-model parasitic protists to tackle intriguing questions that remain long unresolved otherwise...
2017: Frontiers in Cellular and Infection Microbiology
https://www.readbyqxmd.com/read/28727985/comparative-study-and-analytical-verification-of-pcr-methods-for-the-diagnosis-of-congenital-chagas-disease
#3
Carolina Inés Cura, Juan Carlos Ramírez, Marcelo Rodríguez, Constanza Lopez-Albízu, Lucía Irazu, Karenina Scollo, Sergio Sosa-Estani
Congenital infection is currently the first cause of new cases of Chagas disease in Argentina and nonendemic areas worldwide. Its diagnosis is of utmost importance to guarantee curative treatment. To improve such diagnosis, a transfer process of PCR tests to the national laboratory network has been initiated. We performed a comparative study of four PCR assays [two end-point PCR and two duplex real-time quantitative PCR (qPCR) procedures] to detect Trypanosoma cruzi DNA in blood samples. Because satellite DNA and kinetoplastid DNA qPCR methods have the best performance and the use of two different molecular targets for confirmatory purposes has been recommended, these methods selected to perform the transfer process and, in consequence, subjected to an analytical verification protocol based on international guidelines...
July 17, 2017: Journal of Molecular Diagnostics: JMD
https://www.readbyqxmd.com/read/28724725/protein-diversity-in-discrete-structures-at-the-distal-tip-of-the-trypanosome-flagellum
#4
Vladimir Varga, Flavia Moreira-Leite, Neil Portman, Keith Gull
The distal end of the eukaryotic flagellum/cilium is important for axonemal growth and signaling and has distinct biomechanical properties. Specific flagellum tip structures exist, yet their composition, dynamics, and functions are largely unknown. We used biochemical approaches to identify seven constituents of the flagella connector at the tip of an assembling trypanosome flagellum and three constituents of the axonemal capping structure at the tips of both assembling and mature flagella. Both tip structures contain evolutionarily conserved as well as kinetoplastid-specific proteins, and component assembly into the structures occurs very early during flagellum extension...
July 19, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28719882/antileishmanial-activity-and-tubulin-polymerization-inhibition-of-podophyllotoxin-derivatives-on-leishmania-infantum
#5
José Miguel Escudero-Martínez, Yolanda Pérez-Pertejo, Rosa M Reguera, María Ángeles Castro, María Victoria Rojo, Carolina Santiago, Andrés Abad, Pablo Anselmo García, José Luis López-Pérez, Arturo San Feliciano, Rafael Balaña-Fouce
Leishmania microtubules play an important role not only in cell division, but also in keeping the shape of the parasite and motility of its free-living stages. Microtubules result from the self-assembly of alpha and beta tubulins, two phylogenetically conserved and very abundant eukaryotic proteins in kinetoplastids. The colchicine binding domain has inspired the discovery and development of several drugs currently in clinical use against parasites. However, this domain is less conserved in kinetoplastids and may be selectively targeted by new compounds...
June 28, 2017: International Journal for Parasitology, Drugs and Drug Resistance
https://www.readbyqxmd.com/read/28674055/screening-the-mmv-pathogen-box-across-multiple-pathogens-reclassifies-starting-points-for-open-source-drug-discovery
#6
Sandra Duffy, Melissa L Sykes, Amy J Jones, Todd B Shelper, Moana Simpson, Rebecca Lang, Sally-Ann Poulsen, Brad E Sleebs, Vicky M Avery
Open access drug discovery provides a substantial resource for diseases primarily affecting the poor and disadvantaged. The open access Pathogen Box is comprised of a collection of compounds with demonstrated biological activity against specific pathogenic organisms. The supply of this resource by the Medicines for Malaria Venture has the potential to provide new chemical starting points for a number of tropical and neglected diseases, through repurposing of these compounds for use in drug discovery campaigns for these additional pathogens...
July 3, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28662026/essential-multimeric-enzymes-in-kinetoplastid-parasites-a-host-of-potentially-druggable-protein-protein-interactions
#7
Leah M Wachsmuth, Meredith G Johnson, Jason Gavenonis
Parasitic diseases caused by kinetoplastid parasites of the genera Trypanosoma and Leishmania are an urgent public health crisis in the developing world. These closely related species possess a number of multimeric enzymes in highly conserved pathways involved in vital functions, such as redox homeostasis and nucleotide synthesis. Computational alanine scanning of these protein-protein interfaces has revealed a host of potentially ligandable sites on several established and emerging anti-parasitic drug targets...
June 2017: PLoS Neglected Tropical Diseases
https://www.readbyqxmd.com/read/28659922/a-poly-lactic-co-glycolic-acid-nanovaccine-based-on-chimeric-peptides-from-different-leishmania-infantum-proteins-induces-dendritic-cells-maturation-and-promotes-peptide-specific-ifn%C3%AE-producing-cd8-t-cells-essential-for-the-protection-against-experimental-visceral
#8
Evita Athanasiou, Maria Agallou, Spyros Tastsoglou, Olga Kammona, Artemis Hatzigeorgiou, Costas Kiparissides, Evdokia Karagouni
Visceral leishmaniasis, caused by Leishmania (L.) donovani and L. infantum protozoan parasites, can provoke overwhelming and protracted epidemics, with high case-fatality rates. An effective vaccine against the disease must rely on the generation of a strong and long-lasting T cell immunity, mediated by CD4(+) TH1 and CD8(+) T cells. Multi-epitope peptide-based vaccine development is manifesting as the new era of vaccination strategies against Leishmania infection. In this study, we designed chimeric peptides containing HLA-restricted epitopes from three immunogenic L...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28645659/synthesis-in-vitro-and-in-vivo-giardicidal-activity-of-nitrothiazole-nsaid-chimeras-displaying-broad-antiprotozoal-spectrum
#9
Blanca Colín-Lozano, Ismael León-Rivera, Manuel Jesús Chan-Bacab, Benjamín Otto Ortega-Morales, Rosa Moo-Puc, Vanessa López-Guerrero, Emanuel Hernández-Núñez, Raúl Argüello-Garcia, Thomas Scior, Elizabeth Barbosa-Cabrera, Gabriel Navarrete-Vázquez
We designed and synthesized five new 5-nitrothiazole-NSAID chimeras as analogues of nitazoxanide, using a DCC-activated amidation. Compounds 1-5 were tested in vitro against a panel of five protozoa: 2 amitochondriates (Giardia intestinalis, Trichomonas vaginalis) and 3 kinetoplastids (Leishmania mexicana, Leishmania amazonensis and Trypanosoma cruzi). All chimeras showed broad spectrum and potent antiprotozoal activities, with IC50 values ranging from the low micromolar to nanomolar order. Compounds 1-5 were even more active than metronidazole and nitazoxanide, two marketed first-line drugs against giardiasis...
August 1, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28641558/bis-2-aminoimidazolines-and-bisguanidines-synthetic-approaches-antiparasitic-activity-and-dna-binding-properties
#10
Christophe Dardonville, J Jonathan Nué Martínez
BACKGROUND: Parasitic diseases caused by protozoan parasites of the genus Trypanosoma and Plasmodium cause some of the deadliest and disabling human infections in tropical and subtropical areas. Diphenyl-based bis(2-phenylimino)imidazolidines and bisguanidines are extremely potent antiparasitic agents against Trypanosoma brucei (etiological agent of African trypanosomiasis) and Plasmodium falciparum (etiological agent of severe malaria). Many of these compounds are also curative in mouse models of stage 1 African trypanosomiasis representing promising leads for the development of antitrypanosomal drugs...
June 22, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28631386/toward-establishing-model-organisms-for-marine-protists-successful-transfection-protocols-for-parabodo-caudatus-kinetoplastida-excavata
#11
Fatma Gomaa, Paulo A Garcia, Jennifer Delaney, Peter R Girguis, Cullen R Buie, Virginia P Edgcomb
We developed protocols for, and demonstrated successful transfection of, the free-living kinetoplastid flagellate Parabodo caudatus with three plasmids carrying a fluorescence reporter gene (pEF-GFP with the EF1 alpha promoter, pUB-GFP with Ubiquitin C promoter, and pEYFP-Mitotrap with CMV promoter). We evaluated three electroporation approaches: 1) a square-wave electroporator designed for eukaryotes, 2) a novel microfluidic transfection system employing hydrodynamically-controlled electric field waveforms, and 3) a traditional exponential decay electroporator...
June 19, 2017: Environmental Microbiology
https://www.readbyqxmd.com/read/28623350/multiplexed-spliced-leader-sequencing-a-high-throughput-selective-method-for-rna-seq-in-trypanosomatids
#12
Bart Cuypers, Malgorzata A Domagalska, Pieter Meysman, Géraldine de Muylder, Manu Vanaerschot, Hideo Imamura, Franck Dumetz, Thomas Wolf Verdonckt, Peter J Myler, Gowthaman Ramasamy, Kris Laukens, Jean-Claude Dujardin
High throughput sequencing techniques are poorly adapted for in vivo studies of parasites, which require prior in vitro culturing and purification. Trypanosomatids, a group of kinetoplastid protozoans, possess a distinctive feature in their transcriptional mechanism whereby a specific Spliced Leader (SL) sequence is added to the 5'end of each mRNA by trans-splicing. This allows to discriminate Trypansomatid RNA from mammalian RNA and forms the basis of our new multiplexed protocol for high-throughput, selective RNA-sequencing called SL-seq...
June 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28573017/a-crispr-cas9-high-throughput-genome-editing-toolkit-for-kinetoplastids
#13
Tom Beneke, Ross Madden, Laura Makin, Jessica Valli, Jack Sunter, Eva Gluenz
Clustered regularly interspaced short palindromic repeats (CRISPR), CRISPR-associated gene 9 (Cas9) genome editing is set to revolutionize genetic manipulation of pathogens, including kinetoplastids. CRISPR technology provides the opportunity to develop scalable methods for high-throughput production of mutant phenotypes. Here, we report development of a CRISPR-Cas9 toolkit that allows rapid tagging and gene knockout in diverse kinetoplastid species without requiring the user to perform any DNA cloning. We developed a new protocol for single-guide RNA (sgRNA) delivery using PCR-generated DNA templates which are transcribed in vivo by T7 RNA polymerase and an online resource (LeishGEdit...
May 2017: Royal Society Open Science
https://www.readbyqxmd.com/read/28559295/polyvalent-proteins-a-pervasive-theme-in-the-intergenomic-biological-conflicts-of-bacteriophages-and-conjugative-elements
#14
Lakshminarayan M Iyer, A Maxwell Burroughs, Swadha Anand, Robson F de Souza, L Aravind
Intense biological conflicts between prokaryotic genomes and their genomic parasites have resulted in an arms race in terms of the molecular "weaponry" deployed on both sides. Using a recursive computational approach, we uncovered a remarkable class of multidomain proteins with 2 to 15 domains in the same polypeptide deployed by viruses and plasmids in such conflicts. Domain architectures and genomic contexts indicate that they are part of a widespread conflict strategy involving proteins injected into the host cell along with parasite DNA during the earliest phase of infection...
August 1, 2017: Journal of Bacteriology
https://www.readbyqxmd.com/read/28545140/the-role-of-the-zinc-finger-protein-zc3h32-in-bloodstream-form-trypanosoma-brucei
#15
Cornelia Klein, Monica Terrao, Christine Clayton
Kinetoplastids rely heavily on post-transcriptional mechanisms for control of gene expression, with regulation of mRNA processing, translation and degradation by RNA-binding proteins. ZC3H32 is a cytosolic mRNA-binding protein with three non-canonical CCCH zinc finger domains. It is much more abundant in bloodstream-form Trypanosoma brucei than in procyclic forms. Tethering of ZC3H32 to a reporter mRNA suppressed translation and resulted in mRNA degradation, and deletion analysis suggested that this activity was present in both the N- and C-terminal domains, but not the central zinc finger-containing domain...
2017: PloS One
https://www.readbyqxmd.com/read/28535252/trypanosome-rna-editing-mediator-complex-proteins-have-distinct-functions-in-grna-utilization
#16
Rachel M Simpson, Andrew E Bruno, Runpu Chen, Kaylen Lott, Brianna L Tylec, Jonathan E Bard, Yijun Sun, Michael J Buck, Laurie K Read
Uridine insertion/deletion RNA editing is an essential process in kinetoplastid parasites whereby mitochondrial mRNAs are modified through the specific insertion and deletion of uridines to generate functional open reading frames, many of which encode components of the mitochondrial respiratory chain. The roles of numerous non-enzymatic editing factors have remained opaque given the limitations of conventional methods to interrogate the order and mechanism by which editing progresses and thus roles of individual proteins...
May 23, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28495405/trypanosoma-cruzi-i-towards-the-need-of-genetic-subdivision-part-ii
#17
REVIEW
Juan David Ramírez, Carolina Hernández
Chagas disease is a complex zoonosis caused by the kinetoplastid parasite Trypanosoma cruzi. This protozoan exhibits remarkable genetic diversity evinced in at least six Discrete Typing Units (DTUs) with the foreseen emergence of a genotype associated to bats (TcBat). T. cruzi I is the DTU with the broadest geographical distribution and associated to severe cardiomyopathies. In 2011, we published a review questioning the need for genetic subdivision within TcI. However, after six years of intensive research herein, we attempted to determine if TcI should be subdivided or not in the light of the current genetic, biological, clinical and ecological data...
May 8, 2017: Acta Tropica
https://www.readbyqxmd.com/read/28493888/the-mitochondrial-sir2-related-protein-2-sir2rp2-impacts-leishmania-donovani-growth-and-infectivity
#18
Nimisha Mittal, Rohini Muthuswami, Rentala Madhubala
BACKGROUND: Leishmania donovani, a protozoan parasite is the major causative agent of visceral leishmaniasis. Increased toxicity and resistance to the existing repertoire of drugs has been reported. Hence, an urgent need exists for identifying newer drugs and drug targets. Previous reports have shown sirtuins (Silent Information Regulator) from kinetoplastids as promising drug targets. Leishmania species code for three SIR2 (Silent Information Regulator) related proteins. Here, we for the first time report the functional characterization of SIR2 related protein 2 (SIR2RP2) of L...
May 2017: PLoS Neglected Tropical Diseases
https://www.readbyqxmd.com/read/28483460/voacamine-alters-leishmania-ultrastructure-and-kills-parasite-by-poisoning-unusual-bi-subunit-topoisomerase-ib
#19
Somenath Roy Chowdhury, Ashish Kumar, Joseane Lima Prado Godinho, Sara Teixeira De Macedo Silva, Aline Araujo Zuma, Sourav Saha, Neha Kumari, Juliany Cola Fernandes Rodrigues, Shyam Sundar, Jean-Claude Dujardin, Syamal Roy, Wanderley De Souza, Sibabrata Mukhopadhyay, Hemanta K Majumder
Indole alkaloids possess a large spectrum of biological activities including anti-protozoal action. Here we report for the first time that voacamine, isolated from the plant Tabernaemontana coronaria, is an antiprotozoal agent effective against a large array of trypanosomatid parasites including Indian strain of Leishmania donovani and Brazilian strains of Leishmania amazonensis and Trypanosoma cruzi. It inhibits the relaxation activity of topoisomerase IB of L. donovani (LdTop1B) and stabilizes the cleavable complex...
August 15, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28462832/6-nitro-2-3-dihydroimidazo-2-1-b-1-3-thiazoles-facile-synthesis-and-comparative-appraisal-against-tuberculosis-and-neglected-tropical-diseases
#20
Andrew M Thompson, Adrian Blaser, Brian D Palmer, Robert F Anderson, Sujata S Shinde, Delphine Launay, Eric Chatelain, Louis Maes, Scott G Franzblau, Baojie Wan, Yuehong Wang, Zhenkun Ma, William A Denny
As part of a quest for backups to the antitubercular drug pretomanid (PA-824), we investigated the unexplored 6-nitro-2,3-dihydroimidazo[2,1-b][1,3]-thiazoles and related -oxazoles. The nitroimidazothiazoles were prepared in high yield from 2-bromo-4-nitroimidazole via heating with substituted thiiranes and diisopropylethylamine. Equivalent examples of these two structural classes provided broadly comparable MICs, with 2-methyl substitution and extended aryloxymethyl side chains preferred; albeit, S-oxidised thiazoles were ineffective for tuberculosis...
March 27, 2017: Bioorganic & Medicinal Chemistry Letters
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