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Harry P De Koning - One of the best experts on this subject based on the ideXlab platform.
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pyrimidine biosynthesis is not an Essential Function for trypanosoma brucei bloodstream forms
PLOS ONE, 2013Co-Authors: Daniel N A Tagoe, Anne M Donachie, Liam J. Morrison, Jane C Munday, Harry P De KoningAbstract:Background African trypanosomes are capable of both pyrimidine biosynthesis and salvage of preformed pyrimidines from the host, but it is unknown whether either process is Essential to the parasite.
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Pyrimidine biosynthesis is not an Essential Function for Trypanosoma brucei bloodstream forms
2013Co-Authors: Juma A. M. Ali, Daniel N A Tagoe, Anne M Donachie, Liam J. Morrison, Jane C Munday, Harry P De KoningAbstract:Background: African trypanosomes are capable of both pyrimidine biosynthesis and salvage of preformed pyrimidines from the host, but it is unknown whether either process is Essential to the parasite. Methodology/Principal Findings: Pyrimidine requirements for growth were investigated using strictly pyrimidine-free media, with or without single added pyrimidine sources. Growth rates of wild-type bloodstream form Trypanosoma brucei brucei were unchanged in pyrimidine-free medium. The Essentiality of the de novo pyrimidine biosynthesis pathway was studied by knocking out the PYR6-5 locus that produces a fusion product of orotate phosphoribosyltransferase (OPRT) and Orotidine Monophosphate Decarboxylase (OMPDCase). The pyrimidine auxotroph was dependent on a suitable extracellular pyrimidine source. Pyrimidine starvation was rapidly lethal and non-reversible, causing incomplete DNA content in new cells. The phenotype could be rescued by addition of uracil; supplementation with uridine, 29deoxyuridine, and cytidine allowed a diminished growth rate and density. PYR6-52/2 trypanosomes were more sensitive to pyrimidine antimetabolites and displayed increased uracil transport rates and uridine phosphorylase activity. Pyrimidine auxotrophs were able to infect mice although the infection developed much more slowly than infection with the parental, prototrophic trypanosome line. Conclusions/Significance: Pyrimidine salvage was not an Essential Function for bloodstream T. b. brucei. However
Jacek Kowalski - One of the best experts on this subject based on the ideXlab platform.
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Delineation of the Essential Function of Bovine Herpesvirus 1 gD: An Indication for the Modulatory Role of gD in Virus Entry
Virology, 1995Co-Authors: Xiaoping Liang, Caron Pyne, Lorne A. Babiuk, Yuanhao Li, Jacek KowalskiAbstract:Abstract The entry process of alphaherpesviruses consists of two steps, initial virus attachment and subsequent virus penetration involving membrane fusion. Glycoprotein D (gD) of the alphaherpesvirus bovine herpesvirus 1 (BHV 1) is an Essential envelope protein, and it has been previously documented that gD plays a significant part in both of the virus entry steps. In order to gain further insight into the virus entry process, we attempted to define the Essential Function of BHV 1 gD. We replaced the gD transmembrane and cytoplasmic domains with a lipid-addition signal sequence from human decay accelerating factor and produced a stably transfected Madin Darby bovine kidney (MDBK) cell line that expresses a nonfusogenic, glycosylphosphatidylinositol (GPI)-anchored gD. We found that this cell line was able to support the growth of a gD gene-deletion mutant; the resultant gD mutant progeny contained the GPI-anchored gD on its virions and was able to enter into and produce a productive infection in MDBK cells. This result suggests that fusion activity does not constitute the Essential Function of gD. In addition, we found that a gD-null virus (a virus containing no gD on its virion) could infect gD-expressing cells, but not normal MDBK cells. The ability of the gD-null virus to infect gD-expressing cells was dependent on the gD present on the cell surface, since either treating cells with phosphatidylinositol-specific phospholipase C to remove the GPI-anchored gD or incubating cells with gD monoclonal antibodies could block gD-null virus infection. This demonstrates that gD present on the cell surface can act in trans to facilitate the entry of virion lacking gD. This indicates that Essential gD Function can take place in the absence of gD-mediated virus attachment and membrane fusion. We also found that the gD monoclonal antibodies that block gD-null virus entry into gD-expressing cells are strictly restricted to the monoclonal antibodies that show postadsorption neutralization activity, indicating that the trans-acting Function exhibited by the gD present on the cell surface represents the same Function as defined by postadsorption antibody neutralization. The results from this study suggest that the Essential Function of gD in virus entry is to modulate other virus-cell interaction(s) involved in productive virus penetration.
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Delineation of the Essential Function of Bovine Herpesvirus 1 gD: An Indication for the Modulatory Role of gD in Virus Entry
Virology, 1995Co-Authors: Xiaoping Liang, Caron Pyne, Lorne A. Babiuk, Jacek KowalskiAbstract:The entry process of alphaherpesviruses consists of two steps, initial virus attachment and subsequent virus penetration involving membrane fusion. Glycoprotein D (gD) of the alphaherpesvirus bovine herpesvirus 1 (BHV 1) is an Essential envelope protein, and it has been previously documented that gD plays a significant part in both of the virus entry steps. In order to gain further insight into the virus entry process, we attempted to define the Essential Function of BHV 1 gD. We replaced the gD transmembrane and cytoplasmic domains with a lipid-addition signal sequence from human decay accelerating factor and produced a stably transfected Madin Darby bovine kidney (MDBK) cell line that expresses a nonfusogenic, glycosylphosphatidylinositol (GPI)-anchored gD. We found that this cell line was able to support the growth of a gD gene-deletion mutant; the resultant gD mutant progeny contained the GPI-anchored gD on its virions and was able to enter into and produce a production infection in MDBK cells. This result suggests that fusion activity does not constitute the Essential Function of gD. In addition, we found that a gD-null virus (a virus containing no gD on its virion) could infect gD-expressing cells, but not normal MDBK cells. The ability of the gD-null virus to infect gD-expressing cells was dependent on the gD present on the cell surface, since either treating cells with phosphatidylinositol-specific phospholipase C to remove the GPI-anchored gD or incubating cells with gD monoclonal antibodies could block gD-null virus infection. This demonstrates that gD present on the cell surface can act in trans to facilitate the entry of virion lacking gD. This indicates that Essential gD Function can take place in the absence of gD-mediated virus attachment and membrane fusion. We also found that the gD monoclonal antibodies that block gD-null virus entry into gD-expressing cells are strictly restricted to the monoclonal antibodies that show postadsorption neutralization activity, indicating that the trans-acting Function exhibited by the gD present on the cell surface represents the same Function as defined by postadsorption antibody neurtralization. The results from this study suggest that the Essential Function of gD in virus entry is to modulate other virus-cell interaction(s) involved in productive virus penetration.
Kenneth Stuart - One of the best experts on this subject based on the ideXlab platform.
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the f1 atp synthase complex in bloodstream stage trypanosomes has an unusual and Essential Function
The EMBO Journal, 2005Co-Authors: Achim Schnaufer, Desmond G Clarkwalker, Alodie G Steinberg, Kenneth StuartAbstract:Survival of bloodstream form Trypanosoma brucei, the agent of African sleeping sickness, normally requires mitochondrial gene expression, despite the absence of oxidative phosphorylation in this stage of the parasite's life cycle. Here we report that silencing expression of the α subunit of the mitochondrial F1-ATP synthase complex is lethal for bloodstream stage T. brucei as well as for T. evansi, a closely related species that lacks mitochondrial protein coding genes (i.e. is dyskinetoplastic). Our results suggest that the lethal effect is due to collapse of the mitochondrial membrane potential, which is required for mitochondrial Function and biogenesis. We also identified a mutation in the γ subunit of F1 that is likely to be involved in circumventing the requirement for mitochondrial gene expression in another dyskinetoplastic form. Our data reveal that the mitochondrial ATP synthase complex Functions in the bloodstream stage opposite to that in the insect stage and in most other eukaryotes, namely using ATP hydrolysis to generate the mitochondrial membrane potential.
Liam J. Morrison - One of the best experts on this subject based on the ideXlab platform.
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pyrimidine biosynthesis is not an Essential Function for trypanosoma brucei bloodstream forms
PLOS ONE, 2013Co-Authors: Daniel N A Tagoe, Anne M Donachie, Liam J. Morrison, Jane C Munday, Harry P De KoningAbstract:Background African trypanosomes are capable of both pyrimidine biosynthesis and salvage of preformed pyrimidines from the host, but it is unknown whether either process is Essential to the parasite.
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Pyrimidine biosynthesis is not an Essential Function for Trypanosoma brucei bloodstream forms
2013Co-Authors: Juma A. M. Ali, Daniel N A Tagoe, Anne M Donachie, Liam J. Morrison, Jane C Munday, Harry P De KoningAbstract:Background: African trypanosomes are capable of both pyrimidine biosynthesis and salvage of preformed pyrimidines from the host, but it is unknown whether either process is Essential to the parasite. Methodology/Principal Findings: Pyrimidine requirements for growth were investigated using strictly pyrimidine-free media, with or without single added pyrimidine sources. Growth rates of wild-type bloodstream form Trypanosoma brucei brucei were unchanged in pyrimidine-free medium. The Essentiality of the de novo pyrimidine biosynthesis pathway was studied by knocking out the PYR6-5 locus that produces a fusion product of orotate phosphoribosyltransferase (OPRT) and Orotidine Monophosphate Decarboxylase (OMPDCase). The pyrimidine auxotroph was dependent on a suitable extracellular pyrimidine source. Pyrimidine starvation was rapidly lethal and non-reversible, causing incomplete DNA content in new cells. The phenotype could be rescued by addition of uracil; supplementation with uridine, 29deoxyuridine, and cytidine allowed a diminished growth rate and density. PYR6-52/2 trypanosomes were more sensitive to pyrimidine antimetabolites and displayed increased uracil transport rates and uridine phosphorylase activity. Pyrimidine auxotrophs were able to infect mice although the infection developed much more slowly than infection with the parental, prototrophic trypanosome line. Conclusions/Significance: Pyrimidine salvage was not an Essential Function for bloodstream T. b. brucei. However
Shizuo Akira - One of the best experts on this subject based on the ideXlab platform.
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Essential Function for the kinase TAK1 in innate and adaptive immune responses
Nature Immunology, 2005Co-Authors: Shintaro Sato, Hideki Sanjo, Kiyoshi Takeda, Jun Ninomiya-tsuji, Masahiro Yamamoto, Taro Kawai, Kunihiro Matsumoto, Osamu Takeuchi, Shizuo AkiraAbstract:Transforming growth factor-β–activated kinase 1 (TAK1) has been linked to interleukin 1 receptor and tumor necrosis factor receptor signaling. Here we generated mouse strains with conditional expression of a Map3k7 allele encoding part of TAK1. TAK1-deficient embryonic fibroblasts demonstrated loss of responses to interleukin 1β and tumor necrosis factor. Studies of mice with B cell–specific TAK1 deficiency showed that TAK1 was indispensable for cellular responses to Toll-like receptor ligands, CD40 and B cell receptor crosslinking. In addition, antigen-induced immune responses were considerably impaired in mice with B cell–specific TAK1 deficiency. TAK1-deficient cells failed to activate transcription factor NF-κB and mitogen-activated protein kinases in response to interleukin 1β, tumor necrosis factor and Toll-like receptor ligands. However, TAK1-deficient B cells were able to activate NF-κB but not the kinase Jnk in response to B cell receptor stimulation. These results collectively indicate that TAK1 is key in the cellular response to a variety of stimuli.
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Essential Function for the kinase tak1 in innate and adaptive immune responses
Nature Immunology, 2005Co-Authors: Shintaro Sato, Hideki Sanjo, Kiyoshi Takeda, Masahiro Yamamoto, Taro Kawai, Kunihiro Matsumoto, Osamu Takeuchi, Jun Ninomiyatsuji, Shizuo AkiraAbstract:Transforming growth factor-beta-activated kinase 1 (TAK1) has been linked to interleukin 1 receptor and tumor necrosis factor receptor signaling. Here we generated mouse strains with conditional expression of a Map3k7 allele encoding part of TAK1. TAK1-deficient embryonic fibroblasts demonstrated loss of responses to interleukin 1beta and tumor necrosis factor. Studies of mice with B cell-specific TAK1 deficiency showed that TAK1 was indispensable for cellular responses to Toll-like receptor ligands, CD40 and B cell receptor crosslinking. In addition, antigen-induced immune responses were considerably impaired in mice with B cell-specific TAK1 deficiency. TAK1-deficient cells failed to activate transcription factor NF-kappaB and mitogen-activated protein kinases in response to interleukin 1beta, tumor necrosis factor and Toll-like receptor ligands. However, TAK1-deficient B cells were able to activate NF-kappaB but not the kinase Jnk in response to B cell receptor stimulation. These results collectively indicate that TAK1 is key in the cellular response to a variety of stimuli.