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10. High Levels of Genetic Diversity within Nilo-Saharan Populations: Implications for Human Adaptation

Author

Mulindwa, Julius, primary, Noyes, Harry, additional, Ilboudo, Hamidou, additional, Pagani, Luca, additional, Nyangiri, Oscar, additional, Kimuda, Magambo Phillip, additional, Ahouty, Bernardin, additional, Asina, Olivier Fataki, additional, Ofon, Elvis, additional, Kamoto, Kelita, additional, Kabore, Justin Windingoudi, additional, Koffi, Mathurin, additional, Ngoyi, Dieudonne Mumba, additional, Simo, Gustave, additional, Chisi, John, additional, Sidibe, Issa, additional, Enyaru, John, additional, Simuunza, Martin, additional, Alibu, Pius, additional, Jamonneau, Vincent, additional, Camara, Mamadou, additional, Tait, Andy, additional, Hall, Neil, additional, Bucheton, Bruno, additional, MacLeod, Annette, additional, Hertz-Fowler, Christiane, additional, Matovu, Enock, additional, Mumba, Dieuodonne, additional, Alibu, Vincent P., additional, Macleod, Annette, additional, Hertzfowler, Christianne, additional, Elliot, Alison, additional, Bishop, Ozlem, additional, Mulindwa, Julius, additional, Ahouty, Bernadin, additional, and Kabore, Justin, additional

Published
2020
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11. Introducing the TrypanoGEN biobank: A valuable resource for the elimination of human African trypanosomiasis

Author

Ilboudo, Hamidou, Noyes, Harry, Mulindwa, Julius, Kimuda, Magambo Phillip, Koffi, Mathurin, Kabore, Justin Windingoudi, Ahouty, Bernadin, Ngoyi, Dieudonne Mumba, Fataki, Olivier, Simo, Gustave, Ofon, Elvis, Enyaru, John, Chisi, John, Kamoto, Kelita, Simuunza, Martin, Alibu, Vincent P, Lejon, Veerle, Jamonneau, Vincent, Macleod, Annette, Camara, Mamadou, Bucheton, Bruno, Hertz-Fowler, Christiane, Sidibe, Issa, Matovu, Enock, Grp, TrypanoGEN Res, and Consortium, H3Africa

Subjects
0301 basic medicine, Aging, Geographical Locations, Plasma, Environmental protection, Zoonoses, Medicine and Health Sciences, African trypanosomiasis, Uganda, Cameroon, Biological Specimen Banks, Aged, 80 and over, lcsh:Public aspects of medicine, Genomics, Middle Aged, Biobank, Infectious Diseases, Neglected Tropical Diseases, Adult, Resource (biology), lcsh:Arctic medicine. Tropical medicine, Adolescent, lcsh:RC955-962, Zambia, Biology, African Trypanosomiasis, 03 medical and health sciences, Young Adult, Trypanosomiasis, medicine, Parasitic Diseases, Genome-Wide Association Studies, Genetics, Humans, Genetic Predisposition to Disease, Disease Eradication, Environmental planning, Africa South of the Sahara, Aged, Symposium, Protozoan Infections, Public Health, Environmental and Occupational Health, Biology and Life Sciences, Computational Biology, Human Genetics, lcsh:RA1-1270, DNA, medicine.disease, Tropical Diseases, Genome Analysis, 030104 developmental biology, Trypanosomiasis, African, People and Places, Africa, Parasitology
Abstract

No abstract available.

Published
2017

22. Transketolase in Trypanosoma brucei

Author

Stoffel, Sabine A., primary, Alibu, Vincent P., additional, Hubert, Jane, additional, Ebikeme, Charles, additional, Portais, Jean-Charles, additional, Bringaud, Frédéric, additional, Schweingruber, M. Ernst, additional, and Barrett, Michael P., additional

Published
2011
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30. Down-Regulating Gene Expression by RNA Interference in Trypanosoma brucei.

Author

Walker, John M., Carmichael, Gordon G., Clayton, Christine E., Estévez, Antonio M., Hartmann, Claudia, Alibu, Vincent P., Field, Mark, and Horn, David

Abstract

RNA interference (RNAi) in Trypanosoma brucei was first reported in 1998 (1). As in other eukaryotes, interference involves digestion of the interfering double-stranded RNA into short fragments (2), a polysome-associated complex (3), and Argonaute protein (4,5). T. brucei is an ideal organism for testing gene function by RNAi. A complete genome sequence is available, and liquid suspension culture is unproblematic. Various combinations of RNAi vector and host trypanosomes, with different advantages, are available; if procedures are working optimally, it should be possible to obtain a stable cell line with inducible RNAi within 2 wk. The RNAi process itself is apparently not essential for parasite survival (4), although some adverse effects have been reported (5). To analyze the process itself, it is possible to delete candidate genes completely, as the efficiency of homologous recombination is essentially 100%; in situ epitope tagging can also be effected through homologous recombination (6). For general reviews of the peculiarities of trypanosome gene expression and RNA processing, see refs. 7 and 8, and for pre-RNAi methods, such as inducible gene expression and knockouts by homologous recombination, see ref. 9. A few recent applications of RNAi in trypanosomes are found in refs. 10-16. Importantly, in trypanosomes, RNAi can also be used to deplete nuclear RNAs (8,17). In this chapter, we will describe two different options for the construction of RNAi vectors, followed by methods for trypanosome culture and selection of transfectants. At the end, we will highlight various options for testing of phenotypes, as well as various pitfalls with working with RNAi in trypanosomes. [ABSTRACT FROM AUTHOR]

Published
2005
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31. Handling Uncertainty in Dynamic Models: The Pentose Phosphate Pathway in Trypanosoma brucei.

Author

Kerkhoven, Eduard J., Achcar, Fiona, Alibu, Vincent P., Burchmore, Richard J., Gilbert, Ian H., Trybiło, Maciej, Driessen, Nicole N., Gilbert, David, Breitling, Rainer, Bakker, Barbara M., and Barrett, Michael P.

Subjects
PENTOSE phosphate pathway, TRYPANOSOMA brucei, TARGETED drug delivery, UNICELLULAR organisms, PARASITES, ADENOSINE triphosphate
Abstract

Dynamic models of metabolism can be useful in identifying potential drug targets, especially in unicellular organisms. A model of glycolysis in the causative agent of human African trypanosomiasis, Trypanosoma brucei, has already shown the utility of this approach. Here we add the pentose phosphate pathway (PPP) of T. brucei to the glycolytic model. The PPP is localized to both the cytosol and the glycosome and adding it to the glycolytic model without further adjustments leads to a draining of the essential bound-phosphate moiety within the glycosome. This phosphate “leak” must be resolved for the model to be a reasonable representation of parasite physiology. Two main types of theoretical solution to the problem could be identified: (i) including additional enzymatic reactions in the glycosome, or (ii) adding a mechanism to transfer bound phosphates between cytosol and glycosome. One example of the first type of solution would be the presence of a glycosomal ribokinase to regenerate ATP from ribose 5-phosphate and ADP. Experimental characterization of ribokinase in T. brucei showed that very low enzyme levels are sufficient for parasite survival, indicating that other mechanisms are required in controlling the phosphate leak. Examples of the second type would involve the presence of an ATP:ADP exchanger or recently described permeability pores in the glycosomal membrane, although the current absence of identified genes encoding such molecules impedes experimental testing by genetic manipulation. Confronted with this uncertainty, we present a modeling strategy that identifies robust predictions in the context of incomplete system characterization. We illustrate this strategy by exploring the mechanism underlying the essential function of one of the PPP enzymes, and validate it by confirming the model predictions experimentally. [ABSTRACT FROM AUTHOR]

Published
2013
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32. Roles for the Trypanosoma brucei P2 Transporter in DB75 Uptake and Resistance

Author

Lanteri, Charlotte A., Stewart, Mhairi L., Brock, Janice M., Alibu, Vincent P., Meshnick, Steven R., Tidwell, Richard R., and Barrett, Michael P.

Abstract

A novel trypanocide, 2,5-bis(4-amidinophenyl)furan (DB75), in its prodrug amidoxime-derivative form, 2,5-bis(4-amidinophenyl)furan-bis-O-methylamidoxime (DB289), is in trials as the first orally administered drug for human African trypanosomiasis. DB75 is a diamidine. Resistance to some diamidines correlates to loss of uptake via the P2 aminopurine transporter. We show here that uptake of DB75 into Trypanosoma brucei also occurs principally via the P2 transporter. Uptake of tritiated DB75 occurred via a high-affinity (Km app, 3.2 µM) carriermediated route that was inhibited by adenosine, adenine, and pentamidine, all known substrates of the P2 transporter. Trypanosomes lacking the TbAT1 gene that encodes the P2 transporter demonstrated an 11-fold reduction in sensitivity to DB75 when measured under controlled in vitro conditions. These knockout cells were also less sensitive to DB75 than wild-type cells in mice. Initial uptake rates of DB75 into the Δtbat1 knockout cell line were greatly reduced compared with rates in wild-type cells. A trypanosome cell line selected in vitro for DB75 resistance was shown to have lost P2-mediated DB75 uptake. The TbAT1 gene was mapped to chromosome V of the T. brucei genome and the DB75-resistant parasites were shown to have deleted both alleles of this gene. Fluorescence microscopy of DB75-treated trypanosomes revealed that DB75 fluorescence localizes rapidly within the DNA-containing organelles of wild-type trypanosomes, whereas no fluorescence was observed in Δtbat1-null parasites or in the parasites selected for resistance to DB75.

Published
2006

33. Handling Uncertainty in Dynamic Models: The Pentose Phosphate Pathway in Trypanosoma brucei.

Author

Kerkhoven, Eduard J., Achcar, Fiona, Alibu, Vincent P., Burchmore, Richard J., Gilbert, Ian H., Trybiło, Maciej, Driessen, Nicole N., Gilbert, David, Breitling, Rainer, Bakker, Barbara M., and Barrett, Michael P.

Subjects
*PENTOSE phosphate pathway, *TRYPANOSOMA brucei, *TARGETED drug delivery, *UNICELLULAR organisms, *PARASITES, *ADENOSINE triphosphate
Abstract

Dynamic models of metabolism can be useful in identifying potential drug targets, especially in unicellular organisms. A model of glycolysis in the causative agent of human African trypanosomiasis, Trypanosoma brucei, has already shown the utility of this approach. Here we add the pentose phosphate pathway (PPP) of T. brucei to the glycolytic model. The PPP is localized to both the cytosol and the glycosome and adding it to the glycolytic model without further adjustments leads to a draining of the essential bound-phosphate moiety within the glycosome. This phosphate “leak” must be resolved for the model to be a reasonable representation of parasite physiology. Two main types of theoretical solution to the problem could be identified: (i) including additional enzymatic reactions in the glycosome, or (ii) adding a mechanism to transfer bound phosphates between cytosol and glycosome. One example of the first type of solution would be the presence of a glycosomal ribokinase to regenerate ATP from ribose 5-phosphate and ADP. Experimental characterization of ribokinase in T. brucei showed that very low enzyme levels are sufficient for parasite survival, indicating that other mechanisms are required in controlling the phosphate leak. Examples of the second type would involve the presence of an ATP:ADP exchanger or recently described permeability pores in the glycosomal membrane, although the current absence of identified genes encoding such molecules impedes experimental testing by genetic manipulation. Confronted with this uncertainty, we present a modeling strategy that identifies robust predictions in the context of incomplete system characterization. We illustrate this strategy by exploring the mechanism underlying the essential function of one of the PPP enzymes, and validate it by confirming the model predictions experimentally. [ABSTRACT FROM AUTHOR]

Published
2013
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34. Down-regulating gene expression by RNA interference in Trypanosoma brucei.

Author

Clayton CE, Estévez AM, Hartmann C, Alibu VP, Field M, and Horn D

Subjects
Animals, Down-Regulation, Genetic Vectors, Protozoan Proteins genetics, RNA, Messenger genetics, RNA, Messenger metabolism, Gene Expression, Protozoan Proteins antagonists & inhibitors, RNA Interference, RNA, Messenger antagonists & inhibitors, Transcription, Genetic, Trypanosoma brucei brucei genetics
Published
2005
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