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isolation and analysis of the genetic diversity of repertoires of vsg expression site containing telomeres from trypanosoma brucei gambiense, t. b. brucei and t. equiperdum.african trypanosomes (including trypanosoma brucei) are unicellular parasites which multiply in the mammalian bloodstream. t. brucei has about twenty telomeric bloodstream form variant surface glycoprotein (vsg) expression sites (bess), of which one is expressed at a time in a mutually exclusive fashion. bess are polycistronic transcription units, containing a variety of families of expression site associated genes (esags) in addition to the telomeric vsg. these polymorphic esag families are tho ...200818700033
a parasite cysteine protease is key to host protein degradation and iron acquisition.cysteine proteases of the clan ca (papain) family are the predominant protease group in primitive invertebrates. cysteine protease inhibitors arrest infection by the protozoan parasite, trypanosoma brucei. rna interference studies implicated a cathepsin b-like protease, tbcatb, as a key inhibitor target. utilizing parasites in which one of the two alleles of tbcatb has been deleted, the key role of this protease in degradation of endocytosed host proteins is delineated. tbcatb deficiency results ...200818701454
base j: discovery, biosynthesis, and possible functions.in 1993, a new base, beta-d-glucopyranosyloxymethyluracil (base j), was identified in the nuclear dna of trypanosoma brucei. base j is the first hypermodified base found in eukaryotic dna. it is present in all kinetoplastid flagellates analyzed and some unicellular flagellates closely related to trypanosomatids, but it has not been found in other protozoa or in metazoa. j is invariably present in the telomeric repeats of all organisms analyzed. whereas in leishmania nearly all j is telomeric, th ...200818729733
the import and function of diatom and plant frataxins in the mitochondrion of trypanosoma brucei.frataxin is a conserved mitochondrial protein, almost universally present in prokaryotes and eukaryotes, where it is implicated in fe-s cluster assembly and several other processes. here we show that frataxins from the diatom thalassiosira pseudonana and the plant arabidopsis thaliana are efficiently targeted and processed in the mitochondrion of the evolutionary distant excavate kinetoplastid flagellate trypanosoma brucei. moreover, both heterologous frataxins are able to rescue a lethal defici ...200818765259
role of protein translocation pathways across the endoplasmic reticulum in trypanosoma brucei.the translocation of secretory and membrane proteins across the endoplasmic reticulum (er) membrane is mediated by co-translational (via the signal recognition particle (srp)) and post-translational mechanisms. in this study, we investigated the relative contributions of these two pathways in trypanosomes. a homologue of sec71, which functions in the post-translocation chaperone pathway in yeast, was identified and silenced by rna interference. this factor is essential for parasite viability. in ...200818768469
mitochondrial localization of human frataxin is necessary but processing is not for rescuing frataxin deficiency in trypanosoma brucei.trypanosoma brucei, the agent of human sleeping sickness and ruminant nagana, is the most genetically tractable representative of the domain excavata. it is evolutionarily very distant from humans, with a last common ancestor over 1 billion years ago. frataxin, a highly conserved small protein involved in iron-sulfur cluster synthesis, is present in both organisms, and its deficiency is responsible for friedreich's ataxia in humans. we have found that t. brucei growth-inhibition phenotype caused ...200818768799
centrin4 coordinates cell and nuclear division in t. brucei.centrins are ca(2+)-binding proteins that have been implicated in a number of biological processes, including organelle duplication, mrna export, dna repair and signal transduction. in the protozoan parasite trypanosoma brucei we have previously described tbcentrin2, which is present on a bi-lobed structure, and involved in the duplication and segregation of the golgi complex. recently, another centrin, tbcentrin4, was also found at the bi-lobe and has been implicated in organelle segregation an ...200818768932
trypanosoma brucei atpase subunit 6 mrna bound to ga6-14 forms a conserved three-helical structure.t. brucei survival relies on the expression of mitochondrial genes, most of which require rna editing to become translatable. in trypanosomes, rna editing involves the insertion and deletion of uridylates, a developmentally regulated process directed by guide rnas (grnas) and catalyzed by the editosome, a complex of proteins. the pathway for mrna/grna complex formation and assembly with the editosome is still unknown. work from our laboratory has suggested that distinct mrna/grna complexes annea ...200818772247
bioinformatic insights to the esag5 and gresag5 gene families in kinetoplastid parasites.trypanosoma brucei, the causative agent of african sleeping sickness, evades the immune response by expressing a coat of variant surface glycoprotein (vsg). vsg is expressed from a single telomeric expression site (es), along with a number of expression site associated genes (esags). thus far, the function of most esags is unknown. one es contains the serum resistance associated gene (sra), which confers resistance to trypanosome lytic factor in t. b. rhodesiense. only three other esags -5, 6 an ...200818773926
structural and functional association of trypanosoma brucei mix protein with cytochrome c oxidase complex.a mitochondrial inner membrane protein, designated mix, seems to be essential for cell viability. the deletion of both alleles was not possible, and the deletion of a single allele led to a loss of virulence and aberrant mitochondrial segregation and cell division in leishmania major. however, the mechanism by which mix exerts its effect has not been determined. we show here that mix is also expressed in the mitochondrion of trypanosoma brucei, and using rna interference, we found that its loss ...200818776036
a novel nervous system-induced factor inducing immune responses in the spleen.this study relates to a novel mediator signaling between the nervous system and the spleen following an immune challenge. using enzyme-linked immunospot and cell proliferation assays, we found that supernatants of cultured splenocytes prepared from subcutaneously trypanosome-inoculated rats and mice spleens obtained immediately after inoculation and added to naive cells significantly stimulate interferon-gamma production and cell proliferation compared to phosphate-buffered saline-inoculated ani ...200818779837
the rack1 signal anchor protein from trypanosoma brucei associates with eukaryotic elongation factor 1a: a role for translational control in cytokinesis.rack1 is a wd-repeat protein that forms signal complexes at appropriate locations in the cell. rack1 homologues are core components of ribosomes from yeast, plants and mammals. in contrast, a cryo-em analysis of trypanosome ribosomes failed to detect rack1, thus eliminating an important translational regulatory mechanism. here we report that tbrack1 from trypanosoma brucei associates with eukaryotic translation elongation factor-1a (eef1a) as determined by tandem ms of tap-tbrack1 affinity eluat ...200818786142
african trypanosomes contain 5-methylcytosine in nuclear dna.it is currently unclear if there are modified dna bases in trypanosoma brucei other than j-base. we identify herein a cytosine-5 dna methyltransferase gene and report the presence and location of 5-methylcytosine in genomic dna. our data demonstrate that african trypanosomes contain a functional cytosine dna methylation pathway.200818791035
the krepa3 zinc finger motifs and ob-fold domain are essential for rna editing and survival of trypanosoma brucei.three types of editosomes, each with an identical core containing six related krepa proteins, catalyze the u insertion and deletion rna editing of mitochondrial mrnas in trypanosomes. repression of expression of one of these, krepa3 (also known as tbmp42), shows that it is essential for growth and in vivo editing in both procyclic (pf) and bloodstream (bf) life cycle stages of trypanosoma brucei. rna interference knockdown results in editosome disruption and altered in vitro editing in pfs, whil ...200818794366
rapamycin inhibits trypanosome cell growth by preventing tor complex 2 formation.target of rapamycin (tor) kinases control cell growth through two functionally distinct multiprotein complexes. tor complex 1 (torc1) controls temporal cell growth and is sensitive to rapamycin, whereas tor complex 2 (torc2) is rapamycin resistant and regulates spatial cell growth. here, we identified two tor orthologues, tbtor1 and tbtor2, in the protozoan parasite trypanosoma brucei, as well as orthologues of the well-known torc1 and torc2 partners, kog1/raptor and avo3/rictor. tbtor proteins ...200818796613
selenocysteine incorporation in kinetoplastid: selenophosphate synthetase (seld) from leishmania major and trypanosoma brucei.selenophosphate synthetase (ec 2.7.9.3), the product of the seld gene, produces the biologically active selenium donor compound, monoselenophosphate, from atp and selenide, for the synthesis of selenocysteine. the kinetoplastid leishmania major and trypanosoma brucei seld genes were cloned and the seld protein overexpressed and purified to apparent homogeneity. the seld gene in l. major and t. brucei are respectively 1197 and 1179 bp long encoding proteins of 399 and 393 amino acids with molecul ...200818812192
kmp-11, a basal body and flagellar protein, is required for cell division in trypanosoma brucei.kinetoplastid membrane protein 11 (kmp-11) has been identified as a flagellar protein and is conserved among kinetoplastid parasites, but its potential function remains unknown. in a recent study, we identified kmp-11 as a microtubule-bound protein localizing to the flagellum as well as the basal body in both procyclic and bloodstream forms of trypanosoma brucei (z. li, j. h. lee, f. chu, a. l. burlingame, a. gunzl, and c. c. wang, plos one 3:e2354, 2008). silencing of kmp-11 by rna interference ...200818820079
rna interference of trypanosoma brucei cathepsin b and l affects disease progression in a mouse model.we investigated the roles played by the cysteine proteases cathepsin b and cathepsin l (brucipain) in the pathogenesis of trypansoma brucei brucei in both an in vivo mouse model and an in vitro model of the blood-brain barrier. doxycycline induction of rnai targeting cathepsin b led to parasite clearance from the bloodstream and prevent a lethal infection in the mice. in contrast, all mice infected with t. brucei containing the uninduced trypanosoma brucei cathepsin b (tbcatb) rna construct died ...200818820745
differential invasion of trypanosoma brucei brucei and lymphocytes into the brain of c57bl/6 and 129sv/ev mice.trypanosoma brucei subspecies invade the brain parenchyma at late stages of human and experimental rodent infections. in this study, we compared the outcome of infection with t. b. brucei in mhc-matched (h-2b) c57bl/6 (b6) and 129sv/ev (sv-129). sv-129 showed higher parasitaemia and lower specific igm (but not igg) antibody levels than b6 mice. the number of trypanosomes, cd4+ and cd8+ t cells in the brain parenchyma was higher in b6 mice. b6 mice lost weight and showed higher cumulative mortali ...200818822108
the blood-brain barrier significantly limits eflornithine entry into trypanosoma brucei brucei infected mouse brain.drugs to treat african trypanosomiasis are toxic, expensive and subject to parasite resistance. new drugs are urgently being sought. although the existing drug, eflornithine, is assumed to reach the brain in high concentrations, little is known about how it crosses the healthy and infected blood-brain barrier. this information is essential for the design of drug combinations and new drugs. this study used novel combinations of animal models to address these omissions. eflornithine crossed the he ...200818823367
the lamp-like protein p67 plays an essential role in the lysosome of african trypanosomes.rnai knockdown was employed to study the function of p67, a lysosome-associated membrane protein (lamp)-like type i transmembrane lysosomal glycoprotein in african trypanosomes. conditional induction of p67 dsrna resulted in specific approximately 90% reductions in de novo p67 synthesis in both mammalian bloodstream and procyclic insect-stage parasites. bloodstream cell growth was severely retarded with extensive death after > 24 h of induction. biosynthetic trafficking of residual p67, and of t ...200818430083
trypanosoma brucei brca2 acts in antigenic variation and has undergone a recent expansion in brc repeat number that is important during homologous recombination.antigenic variation in trypanosoma brucei has selected for the evolution of a massive archive of silent variant surface glycoprotein (vsg) genes, which are activated by recombination into specialized expression sites. such vsg switching can occur at rates substantially higher than background mutation and is dependent on homologous recombination, a core dna repair reaction. a key regulator of homologous recombination is brca2, a protein that binds rad51, the enzyme responsible for dna strand exch ...200818430140
glucose-induced remodeling of intermediary and energy metabolism in procyclic trypanosoma brucei.the procyclic form of trypanosoma brucei is a parasitic protozoan that normally dwells in the midgut of its insect vector. in vitro, this parasite prefers d-glucose to l -proline as a carbon source, although this amino acid is the main carbon source available in its natural habitat. here, we investigated how l -proline is metabolized in glucose-rich and glucose-depleted conditions. analysis of the excreted end products of (13)c-enriched l -proline metabolism showed that the amino acid is convert ...200818430732
identification of the heptameric lsm complex that binds u6 snrna in trypanosoma brucei.lsm proteins are ubiquitous, multifunctional proteins that are involved in nuclear processing and turnover of many rnas in eukaryotes. lsm proteins form two distinct complexes, the lsm2-8 complex, which binds u6 snrna, and the lsm1-7 complex, which governs mrna degradation. previously, seven lsm proteins were identified in trypanosoma brucei. two of these proteins were later identified as ssm proteins (specific spliceosomal sm proteins). in this study, the lsm proteins (lsm2 and lsm5) that bind ...200818433897
trypanosoma brucei rna editing protein tbmp42 (band vi) is crucial for the endonucleolytic cleavages but not the subsequent steps of u-deletion and u-insertion.trypanosome mitochondrial mrnas achieve their coding sequences through rna editing. this process, catalyzed by approximately 20s protein complexes, involves large numbers of uridylate (u) insertions and deletions within mrna precursors. here we analyze the role of the essential tbmp42 protein (band vi/krepa2) by individually examining each step of the u-deletional and u-insertional editing cycles, using reactions in the approximately linear range. we examined control extracts and rna interferenc ...200818441050
structures of a potent phenylalkyl bisphosphonate inhibitor bound to farnesyl and geranylgeranyl diphosphate synthases.we report the x-ray crystallographic structures of the bisphosphonate n-[methyl(4-phenylbutyl)]-3-aminopropyl-1-hydroxy-1,1-bisphosphonate (bph-210), a potent analog of pamidronate (aredia), bound to farnesyl diphosphate synthase (fpps) from trypanosoma brucei as well as to geranylgeranyl diphosphate synthase from saccharomyces cerevisiae. bph-210 binds to fpps, together with 3 mg(2+), with its long, hydrophobic phenylbutyl side-chain being located in the same binding pocket that is occupied by ...200818442135
a role for caf1 in mrna deadenylation and decay in trypanosomes and human cells.the eukaryotic ccr4/caf1/not complex is involved in deadenylation of mrnas. the caf1 and ccr4 subunits both potentially have deadenylating enzyme activity. we investigate here the roles of ccr4 and caf1 in deadenylation in two organisms that separated early in eukaryotic evolution: humans and trypanosomes. in trypanosoma brucei, we found a complex containing caf1, not1, not2 and not5, dhh1 and a possible homologue of caf130; no homologue of ccr4 was found. trypanosome caf1 has deadenylation acti ...200818442996
polo-like kinase is required for golgi and bilobe biogenesis in trypanosoma brucei.a bilobed structure marked by tbcentrin2 regulates golgi duplication in the protozoan parasite trypanosoma brucei. this structure must itself duplicate during the cell cycle for golgi inheritance to proceed normally. we show here that duplication of the bilobed structure is dependent on the single polo-like kinase (plk) homologue in t. brucei (tbplk). depletion of tbplk leads to malformed bilobed structures, which is consistent with an inhibition of duplication and an increase in the number of d ...200818443217
a haptoglobin-hemoglobin receptor conveys innate immunity to trypanosoma brucei in humans.the protozoan parasite trypanosoma brucei is lysed by apolipoprotein l-i, a component of human high-density lipoprotein (hdl) particles that are also characterized by the presence of haptoglobin-related protein. we report that this process is mediated by a parasite glycoprotein receptor, which binds the haptoglobin-hemoglobin complex with high affinity for the uptake and incorporation of heme into intracellular hemoproteins. in mice, this receptor was required for optimal parasite growth and the ...200818451305
molecular analysis of archived blood slides reveals an atypical human trypanosoma infection.in 2003, a 10-month-old ghanaian boy recovered from a trypanosoma brucei infection, although the patient was not treated with antitrypanosomal drugs. only t. brucei gambiense and t. brucei rhodesiense are able to infect humans, causing human african trypanosomiasis. the disease is considered 100% fatal if left untreated. the identity of the trypanosome was determined by dna extraction from the archived stained blood slides followed by sequential application of polymerase chain reactions (pcrs) t ...200818455900
different types of tea products attenuate inflammation induced in trypanosoma brucei infected mice.an in vivo study was carried out to determine the effect of different types of kenyan tea extracts on male swiss albino mice infected with trypanosoma brucei brucei isolate ketri 2710. the isolate produced a similar clinical picture after a pre-patent period of 5 days post-infection (dpi). parasitemia levels in the untreated mice and those given different teas developed exponentially at similar rates reaching similar densities at the peak of parasitemia 8 dpi. between 9 and 13 dpi parasitemia de ...200818456544
biogenesis of the trypanosome endo-exocytotic organelle is cytoskeleton mediated.trypanosoma brucei is a protozoan parasite that is used as a model organism to study such biological phenomena as gene expression, protein trafficking, and cytoskeletal biogenesis. in t. brucei, endocytosis and exocytosis occur exclusively through a sequestered organelle called the flagellar pocket (fp), an invagination of the pellicular membrane. the pocket is the sole site for specific receptors thus maintaining them inaccessible to components of the innate immune system of the mammalian host. ...200818462016
3' adenylation determines mrna abundance and monitors completion of rna editing in t. brucei mitochondria.expression of the mitochondrial genome in protozoan parasite trypanosoma brucei is controlled post-transcriptionally and requires extensive u-insertion/deletion mrna editing. in mitochondrial extracts, 3' adenylation reportedly influences degradation kinetics of synthetic edited and pre-edited mrnas. we have identified and characterized a mitochondrial poly(a) polymerase, termed kpap1, and determined major polypeptides in the polyadenylation complex. inhibition of kpap1 expression abrogates shor ...200818464794
crusade for iron: iron uptake in unicellular eukaryotes and its significance for virulence.the effective acquisition of iron is a pre-requisite for survival of all organisms, especially parasites that have a high iron requirement. in mammals, iron homeostasis is meticulously regulated; extracellular free iron is essentially unavailable and host iron availability has a crucial role in the host-pathogen relationship. therefore, pathogens use specialized and effective mechanisms to acquire iron. in this review, we summarize the iron-uptake systems in eukaryotic unicellular organisms with ...200818467097
metabolomic profiling using orbitrap fourier transform mass spectrometry with hydrophilic interaction chromatography: a method with wide applicability to analysis of biomolecules.it was shown that coupling hydrophilic interaction chromatography (hilic) to orbitrap fourier transform mass spectrometery (ft-ms) provided an excellent tool for metabolic profiling, principally due to rapid elution of lipids in advance of most metabolites entering the mass spectrometer. we used in vitro cultivated procyclic forms of the protozoan parasite trypanosoma brucei as a source of metabolites to test the performance of the hilic column and the mass accuracy of ms. the mass accuracy achi ...200818470888
the flagellum of trypanosoma brucei: new tricks from an old dog.african trypanosomes, i.e. trypanosoma brucei and related sub-species, are devastating human and animal pathogens that cause significant human mortality and limit sustained economic development in sub-saharan africa. t. brucei is a highly motile protozoan parasite and coordinated motility is central to both disease pathogenesis in the mammalian host and parasite development in the tsetse fly vector. therefore, understanding unique aspects of the t. brucei flagellum may uncover novel targets for ...200818472102
detecting conserved secondary structures in rna molecules using constrained structural alignment.constrained sequence alignment has been studied extensively in the past. different forms of constraints have been investigated, where a constraint can be a subsequence, a regular expression, or a probability matrix of symbols and positions. however, constrained structural alignment has been investigated to a much lesser extent. in this paper, we present an efficient method for constrained structural alignment and apply the method to detecting conserved secondary structures, or structural motifs, ...200818472302
the structural mechanics of cell division in trypanosoma brucei.undoubtedly, there are fundamental processes driving the structural mechanics of cell division in eukaryotic organisms that have been conserved throughout evolution and are being revealed by studies on organisms such as yeast and mammalian cells. precision of structural mechanics of cytokinesis is however probably no better illustrated than in the protozoa. a dramatic example of this is the protozoan parasite trypanosoma brucei, a unicellular flagellated parasite that causes a devastating diseas ...200818481972
unified qsar approach to antimicrobials. part 3: first multi-tasking qsar model for input-coded prediction, structural back-projection, and complex networks clustering of antiprotozoal compounds.several pathogen parasite species show different susceptibilities to different antiparasite drugs. unfortunately, almost all structure-based methods are one-task or one-target quantitative structure-activity relationships (ot-qsar) that predict the biological activity of drugs against only one parasite species. consequently, multi-tasking learning to predict drugs activity against different species by a single model (mt-qsar) is vitally important. in the two previous works of the present series ...200818485714
detection of trypanosoma brucei parasites in blood samples using real-time nucleic acid sequence-based amplification.currently, the conventional diagnosis of human african trypanosomiasis (hat) is by microscopic demonstration of trypomastigotes in blood, lymph, and/or cerebrospinal fluid. however, microscopic diagnosis of hat is not sensitive enough and may give false-negative results, thus, denying the patient the necessary treatment of the otherwise fatal disease. for this reason, a highly sensitive technique needs to be developed to enhance case findings. in this study, the real-time nucleic acid sequence-b ...200818486402
biochemical characterization of the initial steps of the kennedy pathway in trypanosoma brucei: the ethanolamine and choline kinases.ethanolamine and choline are major components of the trypanosome membrane phospholipids, in the form of gpetn (phosphatidylethanolamine) [corrected] and gpcho (phosphatidylcholine) [corrected] . ethanolamine is also found as an integral component of the gpi (glycosylphosphatidylinositol) anchor that is required for membrane attachment of cell-surface proteins, most notably the variant-surface glycoproteins. the de novo synthesis of gpetn and gpcho starts with the generation of phosphoethanolamin ...200818489261
phosphatidylethanolamine is the precursor of the ethanolamine phosphoglycerol moiety bound to eukaryotic elongation factor 1a.in addition to its conventional role during protein synthesis, eukaryotic elongation factor 1a is involved in other cellular processes. several regions of interaction between eukaryotic elongation factor 1a and the translational apparatus or the cytoskeleton have been identified, yet the roles of the different post-translational modifications of eukaryotic elongation factor 1a are completely unknown. one amino acid modification, which so far has only been found in eukaryotic elongation factor 1a ...200818499667
analysis of the trypanosoma brucei cell cycle by quantitative dapi imaging.trypanosoma brucei has two dna compartments: the nucleus and the kinetoplast. dna replication of these two compartments only partially coincides. woodward and gull [woodward r, gull k. timing of nuclear and kinetoplast dna replication and early morphological events in the cell cycle of trypanosoma brucei. j cell sci 1990;95:49-57] comprehensively studied the relative timing of the replication and segregation of nuclear dna (ndna) and kinetoplast dna (kdna). others have since assumed the consiste ...200818501977
novel azabicyclo[3.2.2]nonane derivatives and their activities against plasmodium falciparum k1 and trypanosoma brucei rhodesiense.new diaryl substituted 2-azabicyclo[3.2.2]nonane derivatives have been synthesized in order to investigate the influence of the aromatic substitution and of n substitution on the antiprotozoal activities of those compounds. following a manual method for the hansch approach, different 4-substituted aryl rings were systematically inserted, and moieties with varying basicity and polarity were attached to the ring nitrogen. all compounds were investigated for their activities against trypanosoma bru ...200818502136
duplicated paralogous genes subject to positive selection in the genome of trypanosoma brucei.whole genome studies have highlighted duplicated genes as important substrates for adaptive evolution. we have investigated adaptive evolution in this class of genes in the human parasite trypanosoma brucei, as indicated by the ratio of non-synonymous (amino-acid changing) to synonymous (amino acid retaining) nucleotide substitution rates.200818509460
microrna switches in trypanosoma brucei.trypanosoma brucei develops chronic infection in mammalian hosts due to a sophisticated strategy of antigenic variation of variant surface glycoprotein (vsg) coat to escape antibody-mediated lysis. micrornas are a class of non-coding rnas with presumed post-transcriptional regulatory activity. homology based informatic approach is used to identify the microrna (mirna) genes of t. brucei and their target mrnas. our observation reveals a set of micrornas targeting mrnas corresponding to vsgs. furt ...200818510949
trypanosomiasis-induced b cell apoptosis results in loss of protective anti-parasite antibody responses and abolishment of vaccine-induced memory responses.african trypanosomes of the trypanosoma brucei species are extra-cellular parasites that cause human african trypanosomiasis (hat) as well as infections in game animals and livestock. trypanosomes are known to evade the immune response of their mammalian host by continuous antigenic variation of their surface coat. here, we aim to demonstrate that in addition, trypanosomes (i) cause the loss of various b cell populations, (ii) disable the hosts' capacity to raise a long-lasting specific protecti ...200818516300
bioactivities of gossypol, 6-methoxygossypol, and 6,6'-dimethoxygossypol.6-methoxygossypol and 6,6'-dimethoxygossypol were recently isolated from the root tissue of cotton plants. together with gossypol, these natural products were investigated for a wide range of bioactivities. antioxidant effects, the potential to prevent dna damage, anticancer activity, and antitrypanosomal effects were studied. the 6-methoxygossypol generally exhibited equal bioactivities to the 6,6'-dimethoxygossypol, but gossypol showed greater activities than both methylated derivatives in sca ...200818517219
cell-penetrating peptide tp10 shows broad-spectrum activity against both plasmodium falciparum and trypanosoma brucei brucei.malaria and trypanosomiasis are diseases which afflict millions and for which novel therapies are urgently required. we have tested two well-characterized cell-penetrating peptides (cpps) for antiparasitic activity. one cpp, designated tp10, has broad-spectrum antiparasitic activity against plasmodium falciparum, both blood and mosquito stages, and against blood-stage trypanosoma brucei brucei.200818519720
structural and mechanistic insights into type ii trypanosomatid tryparedoxin-dependent peroxidases.tbtdpx (trypanosoma brucei tryparedoxin-dependent peroxidase) is a genetically validated drug target in the fight against african sleeping sickness. despite its similarity to members of the gpx (glutathione peroxidase) family, tbtdpx2 is functional as a monomer, lacks a selenocysteine residue and relies instead on peroxidatic and resolving cysteine residues for catalysis and uses tryparedoxin rather than glutathione as electron donor. kinetic studies indicate a saturable ping pong mechanism, unl ...200818522537
fly transmission and mating of trypanosoma brucei brucei strain 427.like yeast, trypanosoma brucei is a model organism and has a published genome sequence. although t. b. brucei strain 427 is used for studies of trypanosome molecular biology, particularly antigenic variation, in many labs worldwide, this strain was not selected for the genome sequencing project as it is monomorphic and unable to complete development in the insect vector. instead, the fly transmissible, mating competent strain treu 927 was used for the genome project, but is not as easily grown o ...200818524395
heterologous expression, purification and characterisation of the extracellular domain of trypanosome invariant surface glycoprotein isg75.the invariant surface glycoprotein isg75 is a transmembrane glycoprotein occurring on the surface of the bloodstream-form trypanozoon. this study describes the expression and purification of the n-terminal extracellular domain of isg75, a novel target for development of diagnostic tests for trypanosomosis. to facilitate disulfide formation in the cytoplasm, a 1287-bp cdna fragment encoding isg75 from trypanosoma brucei gambiense was expressed in a thioredoxin reductase, glutathione oxidoreductas ...200818538880
structure of a trypanosoma brucei alpha/beta-hydrolase fold protein with unknown function.the structure of a structural genomics target protein, tbru020260aaa from trypanosoma brucei, has been determined to a resolution of 2.2 a using multiple-wavelength anomalous diffraction at the se k edge. this protein belongs to pfam sequence family pf08538 and is only distantly related to previously studied members of the alpha/beta-hydrolase fold family. structural superposition onto representative alpha/beta-hydrolase fold proteins of known function indicates that a possible catalytic nucleop ...200818540054
communication between the nucleotide site and the main molecular hinge of 3-phosphoglycerate kinase.3-phosphoglycerate kinase is a hinge-bending enzyme with substrate-assisted domain closure. however, the closure mechanism has not been described in terms of structural details. here we present experimental evidence of the participation of individual substrate binding side chains in the operation of the main hinge which is distant from the substrate binding sites. the combined mutational, kinetic, and structural (dsc and saxs) data for human 3-phosphoglycerate kinase have shown that catalytic re ...200818540639
identification of a novel chromosomal passenger complex and its unique localization during cytokinesis in trypanosoma brucei.aurora b kinase is a key component of the chromosomal passenger complex (cpc), which regulates chromosome segregation and cytokinesis. an ortholog of aurora b was characterized in trypanosoma brucei (tbauk1), but other conserved components of the complex have not been found. here we identified four novel tbauk1 associated proteins by tandem affinity purification and mass spectrometry. among these four proteins, tbkin-a and tbkin-b are novel kinesin homologs, whereas tbcpc1 and tbcpc2 are hypothe ...200818545648
functional characterization of cohesin subunit scc1 in trypanosoma brucei and dissection of mutant phenotypes in two life cycle stages.in yeast and metazoa, structural maintenance of chromosome (smc) complexes play key roles in chromosome segregation, architecture and dna repair. the main function of the cohesin complex is to hold replicated sister chromatids together until segregation at anaphase, which is dependent on proteolytic cleavage of the cohesin subunit scc1. analysis of trypanosomatid genomes showed that the core cohesin and condensin complexes are conserved, but smc5/6 is absent. to investigate the functional conser ...200818554326
chemical and genetic validation of dihydrofolate reductase-thymidylate synthase as a drug target in african trypanosomes.the phenotypes of single- (sko) and double-knockout (dko) lines of dihydrofolate reductase-thymidylate synthase (dhfr-ts) of bloodstream trypanosoma brucei were evaluated in vitro and in vivo. growth of sko in vitro is identical to wild-type (wt) cells, whereas dko has an absolute requirement for thymidine. removal of thymidine from the medium triggers growth arrest in s phase, associated with gross morphological changes, followed by cell death after 60 h. dko is unable to infect mice, whereas t ...200818557814
sequence homology and microhomology dominate chromosomal double-strand break repair in african trypanosomes.genetic diversity in fungi and mammals is generated through mitotic double-strand break-repair (dsbr), typically involving homologous recombination (hr) or non-homologous end joining (nhej). microhomology-mediated joining appears to serve a subsidiary function. the african trypanosome, a divergent protozoan parasite, relies upon rearrangement of subtelomeric variant surface glycoprotein (vsg) genes to achieve antigenic variation. evidence suggests an absence of nhej but chromosomal repair remain ...200818334531
the effects of bee (apis mellifera) venom phospholipase a2 on trypanosoma brucei brucei and enterobacteria.the potential role of phospholipases in trypanosomiasis was investigated using bee venom phospholipase a2 (bvpla2) as a model. the effects of bvpla2 on the survival of trypanosoma brucei brucei, 2h and 12h cultures of enterobacter cloacae, escherichia coli, citrobacter freundii were studied. about 1 mg ml(-1) bvpla2 was trypanocidal after 30 min. some growth occurred at lower concentrations up to 2h after treatment but viability decreased up to 8h. even very low concentrations of bvpla2 (10(-12) ...200818343372
assessment of the occurrence of trypanocidal drug resistance in trypanosomes of naturally infected cattle in the adamaoua region of cameroon using the standard mouse test and molecular tools.from may to november 2005, a study was carried out to assess the occurrence of trypanocidal drug resistance (dr) in trypanosomes of naturally infected cattle of the adamaoua region of cameroon. two distinct polymerase chain reaction-restriction fragment length polymorphism (pcr-rflp) procedures were used together with an allele specific-pcr (as-pcr) and the standardized single-dose mouse test. using the mouse test, 3 of the 13 trypanosoma brucei isolates and all 14 tested trypanosoma congolense ...200818355771
total syntheses of (+/-)-ovalicin, c4(s *)-isomer, and its c5-analogs and anti-trypanosomal activities.total syntheses of (+/-)-ovalicin, its c4(s( *))-isomer 44, and c5-side chain intermediate 46 were accomplished via an intramolecular heck reaction of (z)-3-(tert-butyldimethylsilyloxy)-1-iodo-1,6-heptadiene and a catalytic amount of palladium acetate. subsequent epoxidation, dihydroxylation, methylation, and oxidation led to (3s( *),5r( *),6r( *))-5-methoxy-6-(tert-butyldimethylsilyloxy)-1-oxaspiro[2.5]octan-4-one (2), a reported intermediate. the addition of a side chain with cis-1-lithio-1,5- ...200818356059
trypanosoma brucei mitochondrial ribosomes: affinity purification and component identification by mass spectrometry.although eukaryotic mitochondrial (mt) ribosomes evolved from a putative prokaryotic ancestor their compositions vary considerably among organisms. we determined the protein composition of tandem affinity-purified trypanosoma brucei mt ribosomes by mass spectrometry and identified 133 proteins of which 77 were associated with the large subunit and 56 were associated with the small subunit. comparisons with bacterial and mammalian mt ribosomal proteins identified t. brucei mt homologs of l2-4, l7 ...200818364347
turnover of glycosomes during life-cycle differentiation of trypanosoma brucei.protozoan kinetoplastida, a group that comprises the pathogenic trypanosoma brucei, compartmentalize several metabolic systems such as the major part of the glycolytic pathway, in multiple peroxisome-like organelles, designated glycosomes. trypanosomes have a complicated life cycle, involving two major, distinct stages living in the mammalian bloodstream and several stages inhabiting different body parts of the tsetse fly. previous studies on non-differentiating trypanosomes have shown that the ...200818365344
searching the tritryp genomes for drug targets.the recent publication of the complete genome sequences of leishmania major, trypanosoma brucei and trypanosoma cruzi revealed that each genome contains 8300-12,000 protein-coding genes, of which approximately 6500 are common to all three genomes, and ushers in a new, post-genomic, era for trypanosomatid drug discovery. this vast amount of new information makes possible more comprehensive and accurate target identification using several new computational approaches, including identification of m ...200818365664
novel bisbenzimidazoles with antileishmanial effectiveness.a small library of 2,2'-[(alpha,omega-alkanediylbis(oxyphenylene)]bis-1h-benzimidazoles has been prepared and screened in vitro against pneumocystis carinii, trypanosoma brucei rhodesiense, and leishmania donovani. among the six tested compounds two derivatives emerged as promising hits characterized by ic(50) values lower than that determined for pentamidine against l. donovani.200818367395
tbrgg1, an essential protein involved in kinetoplastid rna metabolism that is associated with a novel multiprotein complex.the uridine insertion/deletion rna editing of kinetoplastid mitochondrial transcripts is performed by complex machinery involving a number of proteins and multiple protein complexes. here we describe the effect of silencing of tbrgg1 gene by rna interference on rna editing in procyclic stage of trypanosoma brucei. tbrgg1 is an essential protein for cell growth, the absence of which results in an overall decline of edited mrnas, while the levels of never-edited rnas remain unaltered. repression o ...200818369185
rna interference as a genetic tool in trypanosomes.rna interference (rnai) is a cellular mechanism that is often exploited as a technique for quelling the expression of a specific gene. rnai studies are carried out in vivo, making this a powerful means for the study of protein function in situ several trypanosomatids, including those organisms responsible for human and animal diseases, naturally possess the machinery necessary for rnai manipulations. this allows for the use of rnai in unraveling many of the pressing questions regarding the paras ...200818369780
n-acetyl d-glucosamine stimulates growth in procyclic forms of trypanosoma brucei by inducing a metabolic shift.summarythe lectin-inhibitory sugars d-glucosamine (glcn) and n-acetyl d-glucosamine (glcnac) are known to enhance susceptibility of the tsetse fly vector to infection with trypanosoma brucei. glcnac also stimulates trypanosome growth in vitro in the absence of any factor derived from the fly. here, we show that glcnac cannot be used as a direct energy source, nor is it internalized by trypanosomes. it does, however, inhibit glucose uptake by binding to the hexose transporter. deprivation of d-gl ...200818371239
cytokine and nitric oxide production by trypanosoma brucei infection in rats fed polyamine-deficient chow.feeding polyamine-deficient chow (pdc) to rats decreases blood polyamines, increases the activity of ornithine decarboxylase as an index of polyamine production, and increases resistance to trypanosoma brucei gambiense (wellcome strain) (ws) infection. in this study, we investigated the influence on cytokine and nitric oxide (no) production of feeding pdc to rats infected with ws. at 4 days postinfection with ws, serum concentration of interleukin (il)-12, tumor necrosis factor-alpha, interferon ...200818372628
the synthesis of udp-n-acetylglucosamine is essential for bloodstream form trypanosoma brucei in vitro and in vivo and udp-n-acetylglucosamine starvation reveals a hierarchy in parasite protein glycosylation.a gene encoding trypanosoma brucei udp-n-acetylglucosamine pyrophosphorylase was identified, and the recombinant protein was shown to have enzymatic activity. the parasite enzyme is unusual in having a strict substrate specificity for n-acetylglucosamine 1-phosphate and in being located inside a peroxisome-like microbody, the glycosome. a bloodstream form t. brucei conditional null mutant was constructed and shown to be unable to sustain growth in vitro or in vivo under nonpermissive conditions, ...200818381290
different trans rna splicing events in bloodstream and procyclic trypanosoma brucei.most trypanosomatid genes are transcribed into polycistronic precursor rnas that are processed into monocistronic mrnas possessing a 39-nucleotide spliced leader (sl) at their 5'-ends and polyadenylation at their 3'-ends. we show here that precursor rna derived from a luciferase gene integrated in reverse orientation at the rdna locus of trypanosoma brucei is processed into three major sl-containing rnas in bloodstream cells and a single sl-containing rna in procyclic rnas. this difference in tr ...200818384893
design, synthesis and trypanocidal activity of lead compounds based on inhibitors of parasite glycolysis.the glycolytic pathway has been considered a potential drug target against the parasitic protozoan species of trypanosoma and leishmania. we report the design and the synthesis of inhibitors targeted against trypanosoma brucei phosphofructokinase (pfk) and leishmania mexicana pyruvate kinase (pyk). stepwise library synthesis and inhibitor design from a rational starting point identified furanose sugar amino amides as a novel class of inhibitors for both enzymes with ic(50) values of 23microm and ...200818387804
assembly of heterohexameric trypanosome hexokinases reveals that hexokinase 2 is a regulable enzyme.glycolysis is essential to trypanosoma brucei, the protozoan parasite that causes african sleeping sickness in humans and nagana in cattle. hexokinase (hk), the first enzyme in glycolysis, catalyzes the phosphorylation of glucose to form glucose 6-phosphate. t. brucei harbors two hks that are 98% identical at the amino acid level, t. brucei hexokinase 1 (tbhk1) and tbhk2. recombinant tbhk1 (rtbhk1) has hk activity, whereas rtbhk2 does not. unlike other eukaryotic hks, tbhk1 is not subject to inh ...200818387941
detection of trypanosoma brucei in field-captured tsetse flies and identification of host species fed on by the infected flies.the prevalence of trypanosome infections in tsetse flies in the chiawa area of lower zambezi in zambia, with endemic trypanosomosis, was determined by a polymerase chain reaction (pcr) method that allowed the detection of trypanosome dna and determination of the type of animal host fed on by the tsetse fly glossina pallidipes, using tsetse-derived dna extracts as templates. ninety g. pallidipes (82 females and 8 males; 18.3%) of the 492 flies captured by baited biconical traps tested positive fo ...200818399780
farnesyl diphosphate synthase localizes to the cytoplasm of trypanosoma cruzi and t. brucei.the farnesyl diphosphate synthase (fpps) has previously been characterized in trypanosomes as an essential enzyme for their survival and as the target for bisphosphonates, drugs that are effective both in vitro and in vivo against these parasites. enzymes from the isoprenoid pathway have been assigned to different compartments in eukaryotes, including trypanosomatids. we here report that fpps localizes to the cytoplasm of both trypanosoma cruzi and t. brucei, and is not present in other organell ...200818406406
tbg63, a golgin involved in golgi architecture in trypanosoma brucei.golgins are coiled-coil proteins that have been implicated in the structure and function of the golgi complex. here, we identify and characterize a trypanosomal golgin, tbg63, showing that it has a c-terminal membrane anchor and an n-terminus that projects into the cytoplasm. tbg63 in procyclic parasites is localized to the golgi and interacts with the active, gtp-form of tbrab1a. overexpression of tbg63 has dramatic effects on golgi architecture -- effects that require the n-terminus -- whereas ...200818411253
analysis of small gtpase function in trypanosomes.trypanosomatids are protozoan parasites, of interest due to both their disease burden and deeply divergent position within the eukaryotic lineage. the african trypanosome, trypanosoma brucei, has emerged as a very amenable model system, with a considerable toolbox of methods available, including inducible overexpression, rna interference, and a completed genome. here we describe some of the special considerations that need to be addressed when studying trypanosome gene function, and in particula ...200818413241
global metabolic responses of mice to trypanosoma brucei brucei infection.human african trypanosomiasis (hat) is transmitted by tsetse flies and, if untreated, is fatal. treatment depends on infection stage, and early diagnosis is crucial for effective disease management. the systemic host biochemical changes induced by hat that enable biomarker discovery or relate to therapeutic outcome are largely unknown. we have characterized the multivariate temporal responses of mice to trypanosoma brucei brucei infection, using (1)h nuclear magnetic resonance (nmr) spectroscopi ...200818413599
identification of novel guide rnas from the mitochondria of trypanosoma brucei.the majority of mitochondrial mrnas in african trypanosomes are subject to an rna editing reaction, which is characterized by the insertion and/or deletion of u nucleotides only. the reaction creates functional mrnas and is catalyzed by a high molecular mass enzyme complex, the editosome. editosomes interact with a unique class of small non-coding, 3'-oligouridylated (ou) rnas, so-called guide rnas (grnas). guide rnas function as transacting templates in the u deletion/insertion reaction and thu ...200818418086
discovery of trypanocidal thiosemicarbazone inhibitors of rhodesain and tbcatb.human african trypanosomiasis (hat) is caused by the protozoan parasite trypanosoma brucei. the cysteine proteases of t. brucei have been shown to be crucial for parasite replication and represent an attractive point for therapeutic intervention. herein we describe the synthesis of a series of thiosemicarbazones and their activity against the trypanosomal cathepsins tbcatb and rhodesain, as well as human cathepsins l and b. the activity of these compounds was determined against cultured t. bruce ...200818420405
identification of a bacterial-like hslvu protease in the mitochondria of trypanosoma brucei and its role in mitochondrial dna replication.atp-dependent protease complexes are present in all living organisms, including the 26s proteasome in eukaryotes, archaea, and actinomycetales, and the hslvu protease in eubacteria. the structure of hslvu protease resembles that of the 26s proteasome, and the simultaneous presence of both proteases in one organism was deemed unlikely. however, hslvu homologs have been identified recently in some primordial eukaryotes, though their potential function remains elusive. we characterized the hslvu ho ...200818421378
solid-phase combinatorial synthesis of a lysyl-trna synthetase (lysrs) inhibitory library.the solid-phase combinatorial synthesis of a new library with potential inhibitory activity against the cytoplasmic lysyl-trna synthetase (lysrs) isoform of trypanosoma brucei is described. the library has been specifically designed to mimic the lysyl adenylate complex. the design was carried out by dividing the complex into four modular parts. proline derivatives (cis-gamma-amino-l-proline or trans-gamma-hydroxy-l-proline) were chosen as central scaffolds. after primary screening, three compoun ...200818426239
synthesis of bicyclic amines and their activities against trypanosoma brucei rhodesiense and plasmodium falciparum k1.new alkenes, aziridines, and diamines were prepared from antiprotozoal 4-dialkylaminobicyclo[2.2.2]octan-2-imines to investigate the influence of several functional groups in position 2 of the ring skeleton on the antitrypanosomal and antiplasmodial activities. they were synthesized from 4-dialkylaminobicyclo[2.2.2]octan-2-imines and tested for their activities against trypanosoma b. rhodesiense and plasmodium falciparum k1 (resistant to chloroquine and pyrimethamine) using in vitro microplate a ...200818563349
genetic analysis of the human infective trypanosome trypanosoma brucei gambiense: chromosomal segregation, crossing over, and the construction of a genetic map.trypanosoma brucei is the causative agent of human sleeping sickness and animal trypanosomiasis in sub-saharan africa, and it has been subdivided into three subspecies: trypanosoma brucei gambiense and trypanosoma brucei rhodesiense, which cause sleeping sickness in humans, and the nonhuman infective trypanosoma brucei brucei. t. b. gambiense is the most clinically relevant subspecies, being responsible for more than 90% of all trypanosomal disease in humans. the genome sequence is now available ...200818570680
determinants for association and guide rna-directed endonuclease cleavage by purified rna editing complexes from trypanosoma brucei.u-insertion/deletion rna editing in the single mitochondrion of kinetoplastids, an ancient lineage of eukaryotes, is a unique mrna maturation process needed for translation. multisubunit editing complexes recognize many pre-edited mrna sites and modify them via cycles of three catalytic steps: guide rna (grna)-directed cleavage, insertion or deletion of uridylates at the 3'-terminus of the upstream cleaved piece, and ligation of the two mrna pieces. while catalytic and many structural protein su ...200818572190
the trypanosome transcriptome is remodelled during differentiation but displays limited responsiveness within life stages.trypanosomatids utilise polycistronic transcription for production of the vast majority of protein-coding mrnas, which operates in the absence of gene-specific promoters. resolution of nascent transcripts by polyadenylation and trans-splicing, together with specific rates of mrna turnover, serve to generate steady state transcript levels that can differ in abundance across several orders of magnitude and can be developmentally regulated. we used a targeted oligonucleotide microarray, representin ...200818573209
prevalence of bovine trypanosomosis in central mozambique from 2002 to 2005.the study is the result of analyzing 16895 blood smears of cattle collected at 180 sites in the provinces of manica, sofala, zambézia and tete in mozambique. of the blood smears 73.9% were from manica, 11.8% from tete, 8.5% from sofala and 5.8% from zambézia; 75.6% of these were collected from smallholder cattle. infections with trypanosomes were highest in smallholder cattle from sofala province with 36.8% of the 872 blood smears examined positive for trypanosomes, and lowest in cattle of comme ...200818575067
tbrgg2, an essential rna editing accessory factor in two trypanosoma brucei life cycle stages.in the mitochondria of kinetoplastid protozoa, including trypanosoma brucei, rna editing inserts and/or deletes uridines from pre-mrnas to produce mature, translatable mrnas. rna editing is carried out by several related multiprotein complexes known as editosomes, which contain all of the enzymatic components required for catalysis of editing. in addition, noneditosome accessory factors necessary for editing of specific rnas have also been described. here, we report the in vitro and in vivo char ...200818583347
phosphatidylethanolamine in trypanosoma brucei is organized in two separate pools and is synthesized exclusively by the kennedy pathway.phosphatidylethanolamine is a major phospholipid class of all eukaryotic cells. it can be synthesized via the cdp-ethanolamine branch of the kennedy pathway, by decarboxylation of phosphatidylserine, or by base exchange with phosphatidylserine. the contributions of these pathways to total phosphatidylethanolamine synthesis have remained unclear. although trypanosoma brucei, the causative agent of human and animal trypanosomiasis, has served as a model organism to elucidate the entire reaction se ...200818587155
single-locus targeting constructs for reliable regulated rnai and transgene expression in trypanosoma brucei.a major obstacle to reproducible expression of recombinant transcripts lies in the epigenetic effects of the flanking chromatin following integration. we previously presented a strategy to overcome this problem in bloodstream form trypanosoma brucei, using a reporter to identify a ribosomal-spacer locus that supports optimal expression and then marking that locus for subsequent targeting. advantages include elimination of variable-expression position-effects and the easy confirmation of correct ...200818588918
a histone methyltransferase modulates antigenic variation in african trypanosomes.to evade the host immune system, several pathogens periodically change their cell-surface epitopes. in the african trypanosomes, antigenic variation is achieved by tightly regulating the expression of a multigene family encoding a large repertoire of variant surface glycoproteins (vsgs). immune evasion relies on two important features: exposing a single type of vsg at the cell surface and periodically and very rapidly switching the expressed vsg. transcriptional switching between resident telome ...200818597556
structural insights into the recognition of peroxisomal targeting signal 1 by trypanosoma brucei peroxin 5.glycosomes are peroxisome-like organelles essential for trypanosomatid parasites. glycosome biogenesis is mediated by proteins called "peroxins," which are considered to be promising drug targets in pathogenic trypanosomatidae. the first step during protein translocation across the glycosomal membrane of peroxisomal targeting signal 1 (pts1)-harboring proteins is signal recognition by the cytosolic receptor peroxin 5 (pex5). the c-terminal pts1 motifs interact with the pts1 binding domain (p1bd) ...200818598704
biochemical characterization of stage-specific isoforms of aspartate aminotransferases from trypanosoma cruzi and trypanosoma brucei.three genes encoding putative aspartate aminotransferases (asats) were identified in the trypanosoma cruzi genome. two of these asat genes, presumably corresponding to a cytosolic and mitochondrial isoform, were cloned and expressed as soluble his-tagged proteins in escherichia coli. the specific activities determined for both t. cruzi isozymes were notably higher than the values previously reported for trypanosoma brucei orthologues. to confirm these differences, t. brucei masat and casat were ...200818602174
alternative rna editing produces a novel protein involved in mitochondrial dna maintenance in trypanosomes.the mitochondrial genome of trypanosomes is composed of thousands of topologically interlocked circular dna molecules that form the kinetoplast dna (kdna). most genes encoded by the kdna require a posttranscriptional modification process called rna editing to form functional mrnas. here, we show that alternative editing of the mitochondrial cytochrome c oxidase iii (coxiii) mrna in trypanosoma brucei produces a novel dna binding protein, alternatively edited protein 1 (aep-1). aep-1 localizes to ...200818606780
distinct roles of apolipoprotein components within the trypanosome lytic factor complex revealed in a novel transgenic mouse model.humans express a unique subset of high-density lipoproteins (hdls) called trypanosome lytic factors (tlfs) that kill many trypanosoma parasite species. the proteins apolipoprotein (apo) a-i, apol-i, and haptoglobin-related protein, which are involved in tlf structure and function, were expressed through the introduction of transgenes in mice to explore their physiological roles in vivo. transgenic expression of human apolipoprotein l-i alone conferred trypanolytic activity in vivo. coexpression ...200818606856
the rna-binding protein tbdrbd3 regulates the stability of a specific subset of mrnas in trypanosomes.in trypanosomes, the apparent lack of regulation of rna polymerase ii-dependent transcription initiation poses a challenge to understand how these eukaryotes adjust gene expression to adapt to the contrasting environments they find during their life cycles. evidence so far indicates that mrna turnover and translation are the major control points in which regulation is exerted in trypanosomes. however, very little is known about which proteins are involved, and how do they regulate the abundance ...200818611951
polo-like kinase is expressed in s/g2/m phase and associated with the flagellum attachment zone in both procyclic and bloodstream forms of trypanosoma brucei.trypanosoma brucei, the etiologic agent of african sleeping sickness, divides into insect (procyclic) and bloodstream forms. these two forms are subject to distinct cell cycle regulations, with cytokinesis controlled primarily by basal body/kinetoplast segregation in the procyclic form but by mitosis in the bloodstream form. polo-like kinases (plks), known to play essential roles in regulating both mitosis and cytokinesis among eukaryotes, have a homologue in t. brucei, tbplk, which regulates on ...200818621923
experimental expansion of the regulatory t cell population increases resistance to african trypanosomiasis.inflammatory responses mounted to eliminate parasites can be lethal if not counterbalanced by regulatory responses protecting the host from collateral tissue damage. here, we show that the maintained inflammation associated with tissue damage, anemia, and reduced survival of trypanosoma brucei-infected mice correlates with the absence of the expansion of the regulatory t (t(reg)) cell population. induction of t(reg) cell expansion via cd28 superagonist antibody treatment in these mice down-regul ...200818627271
identification and characterization of two trypanosome tfiis proteins exhibiting particular domain architectures and differential nuclear localizations.nuclear transcription of trypanosoma brucei displays unusual features. most protein-coding genes are organized in large directional gene clusters, which are transcribed polycistronically by rna polymerase ii (pol ii) with subsequent processing to generate mature mrna. here, we describe the identification and characterization of two trypanosome homologues of transcription elongation factor tfiis (tbtfiis1 and tbtfiis2-1). tfiis has been shown to aid transcription elongation by relieving arrested ...200818627464
two essential myst-family proteins display distinct roles in histone h4k10 acetylation and telomeric silencing in trypanosomes.chromatin modification is important for virtually all aspects of dna metabolism but little is known about the consequences of such modification in trypanosomatids, early branching protozoa of significant medical and veterinary importance. myst-family histone acetyltransferases in other species function in transcription regulation, dna replication, recombination and repair. trypanosoma brucei hat3 was recently shown to acetylate histone h4k4 and we now report characterization of all three t. bruc ...200818631159
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