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trypanosoma brucei: detection of low parasitaemias in mice by a miniature anion-exchanger/centrifugation technique.a method is described for the detection of trypanosomaemia in mice using the samples of about 55 microliter of blood which can be readily obtained from mice by puncture of the retro-orbital plexus with heparinized glass microhaematocrit tubes. the samples, mixed with an appropriate diluent, are passed through small (2 ml) anion-exchanger columns by means of peristatic pumps and the eluates collected in tubes which can be centrifuged so as to concentrate any organisms in the terminal part of the ...1977339422
curative effects of the antipiroplasms amicarbalide and imidocarb on trypanosoma brucei infection in mice.the babesicides imidocarb and amicarbalide, which have structural similarities to the antitrypanosomatid diamidines, proved active against trypanosoma brucei mouse infections: both cured infections when doses were administered daily for 3 days 24 h post-inoculation (curative dose imidocarb, 10 mg/kg; amicarbalide, 25 mg/kg). mice were considered cured after survival 30 days longer than untreated infected controls, with no trypanosomes present in blood or cerebrospinal fluid smears. both agents a ...1979544802
lymphocyte function in experimental african trypanosomiasis: mitogenic effects of trypanosome extracts in vitro.extracts of trypanosoma brucei and trypanosoma congolense were incubated in vitro with nonimmune lymphocytes of mice, rats, guinea pigs, and rabbits in order to test for mitogenic effects or for other characteristics of polyclonal b lymphocyte activators. trypanosome extracts (te) were not mitogenic for spleen cells of mice, rats, and guinea pigs in vitro, nor did the parasite extracts alter the mitogenic responses of lymphocytes from these animals to known b- and t-cell mitogens. te also failed ...1976992878
[course of trypanosoma musculi infections in nmri mice (author's transl)].the trypanosomes multiply during prepatency after minimal infection by a factor of 2.2-3.6 per day. during patency, increase of trypanosome number in the peripheral blood is basically non-logarithmic as the actual proliferating forms remain hidden in special vascular areas (kidney, placenta). the mean increase during patency is approximately linear, typically by 1-10 trypanosomes per 10(4) erythrocytes per day, and depends on the number of infective organisms introduced. - length of parasitemia ...19751236679
structural elements of ornithine decarboxylase required for intracellular degradation and polyamine-dependent regulation.mammalian ornithine decarboxylase (odc), a key enzyme in polyamine biosynthesis, is rapidly degraded in cells, an attribute important to the regulation of its activity. mutant and chimeric odcs were created to determine the structural requirements for two modes of proteolysis. constitutive degradation requires the carboxy terminus and is independent of intracellular polyamines. truncation of five or more carboxy-terminal amino acids prevents this mode of degradation, as do several internal delet ...19921569947
mouse ornithine decarboxylase is stable in trypanosoma brucei.the cdna encoding mouse ornithine decarboxylase (odc) was incorporated into a transforming vector ptsa-neo2 carrying a procyclic acidic repetitive protein promoter and a neomycin phosphotransferase gene. the plasmid thus constructed, pmod300, was introduced into the procyclic forms of trypanosoma brucei via electroporation, and the transformants, selected under g418, expressed an odc activity 100 times above the background level. contrary to the commonly observed short half-life of mouse odc in ...19921597444
cysteine is an essential growth factor for trypanosoma brucei bloodstream forms.a modified cystine-free minimum essential medium has been used to address the question whether cysteine is an essential growth factor for bloodstream form trypanosomes or if its reducing power is sufficient to support parasite growth in axenic culture. bloodstream-form trypanosomes, taken either from freshly isolated infected mouse blood or from logarithmically growing axenic cultures were transferred to a medium containing 20% dialysed foetal calf serum, 10 microm bathocuproine sulphonate and 2 ...19921741014
the optimisation of immunoglobulin secretion in vitro by mouse spleen cells and hybridoma cells.optimal culture conditions and cell densities for antibody production by spleen cells from mice infected with trypanosoma brucei, and by hybridoma cells, were assessed in vitro by a silver-immunogold (sig) blot technique and an enzyme-linked immunosorbent assay (elisa). the blot assay measured the proportion of secreting cells in the population and the elisa measured the quantity of synthesised and secreted immunoglobulin (ig) in cell lysates and in 3-h culture supernatants. marked inhibition of ...19902347604
independent regulation of b cell responses to surface and subsurface epitopes of african trypanosome variable surface glycoproteins.regulation of b cell responses to the trypanosome surface ag was examined in h-2k compatible "responder" b10.br and "nonresponder" c3h mice after infection with two variant clones of trypanosoma brucei rhodesiense. development of a selective ria for independent detection of antibody binding to surface (exposed) and subsurface (buried) epitopes of the trypanosome variable surface glycoprotein (vsg) molecule permitted sensitive quantitation and kinetic characterization of immune responses to these ...19882454998
genetics of resistance to the african trypanosomes. v. qualitative and quantitative differences in interferon production among susceptible and resistant mouse strains.the induction of interferon (ifn) was examined in different inbred mouse strains infected with trypanosoma brucei rhodesiense. relatively susceptible c3heb/fej mice that do not exhibit variant-specific immunity or control parasitemia did not exhibit detectable ifn throughout the infection. relatively resistant b10.br mice that exhibit variant-specific immunity and control the first peak of parasitemia exhibited detectable ifn at two intervals. the appearance of ifn in b10.br serum first coincide ...19852579155
growth of pleomorphic trypanosoma brucei rhodesiense in irradiated inbred mice.it was shown that irradiation (650 rad) of 7 inbred strains of mice did not block the ability of trypanosoma brucei rhodesiense to transform from the long slender (ls) to the short stumpy (ss) form or alter the plateau in parasitemia. in addition, it was observed that significant differences in parasitemia levels, in the rate of transformation from the ls to the ss form, as well as in the survival times occurred between the irradiated c3heb/fej and several of the other strains. these differences ...19883047352
trypanosoma brucei ornithine decarboxylase: enzyme purification, characterization, and expression in escherichia coli.ornithine decarboxylase from the african trypanosome is an important target for antitrypanosomal chemotherapy. despite this, the enzyme had not been previously purified or extensively characterized as it is a very low level protein. in this paper we describe the purification of trypanosoma brucei brucei ornithine decarboxylase from bloodstream form trypomastigotes by 107,000-fold to a specific activity of 2.7 x 10(6) nmol co2/h/mg of protein in the parasite. t. brucei ornithine decarboxylase had ...19883056933
heterologous synergistic interactions in concurrent experimental infection in the mouse with schistosoma mansoni, echinostoma revolutum, plasmodium yoelii, babesia microti, and trypanosoma brucei.primary infections with plasmodium yoelii and echinostoma revolutum in the mouse induced a significant increase in the heterologous schistosoma mansoni challenge worm establishment, whereas s. mansoni worm establishment remained unaffected by primary infections with trypanosoma brucei and babesia microti. concurrent infection in the mouse with p. yoelii or t. brucei, but not with b. microti, blocked the resistance to homologous e. revolutum challenge infection, and primary p. yoelii and t. bruce ...19883143108
similarity in variable antigen type composition of trypanosoma brucei rhodesiense populations in different sites within the mouse host.trypanosoma brucei rhodesiense subpopulations in different sites within the body of infected mice were isolated and enumerated on day 6 of cyclically transmitted infections. most trypanosomes were in the blood vasculature and spleen but approximately 6% occurred in lymph nodes and about 9% were extravascular. most of the extravascular trypanosomes were in the peritoneal and pleural cavities; significant numbers also occurred in the brain and kidneys. six major variable antigen types (vats) were ...19863299895
development of trypanosoma brucei in suckling mouse brain following intracerebral injection.intracerebral inoculation of trypanosoma b. brucei and t. b. rhodesiense into suckling mice produced infection of brain tissue which subsequently gave rise to an infection of the blood and other tissues, in which a normal histopathological picture was observed. treatment of other intracerebrally infected sucklings with 5 mg/kg diminazene aceturate (berenil) to clear the infection from the blood permitted a study of the course of the infection in the brain without interference from pathological p ...19873686641
infectivity of monomorphic and pleomorphic trypanosoma brucei stocks cultivated at 28 c with various tsetse fly tissues.noninfective procyclic forms of trypanosoma brucei stocks derived from the pleomorphic eve 10 were cultivated at 28 c in cunningham's liquid medium in the presence of head-salivary gland, alimentary tract, and abdominal body wall explants of glossina morsitans morsitans. after 8 to 10 days of cultivation some of the procyclic forms transformed into metacyclic stages infective for mice. infectivity persisted for varying periods up to 66 days, when the experiments were terminated. only 10 explants ...19816115002
a comparative evaluation of the parasitological techniques currently available for the diagnosis of african trypanosomiasis in cattle.the parasitological techniques currently in use for the diagnosis of african trypanosomiasis were compared in a series of experiments for their capacity to detect trypanosoma congolense, t. vivax and t. brucei in the blood of cattle. the darkground/phase contrast buffy coat method proved to be more sensitive than the haematocrit centrifugation technique, thick, thin and wet blood films in detecting t. congolense and t. vivax. on the other hand with t. brucei, mouse inoculation was the most sensi ...19826131590
efficacy of combinations of difluoromethylornithine and bleomycin in a mouse model of central nervous system african trypanosomiasis.dl-alpha-difluoromethylornithine, a polyamine biosynthesis inhibitor, and bleomycin, a currently used antineoplastic agent, have each previously been shown to be curative for acute short-term infections of mice with trypanosoma brucei brucei, an african trypanosome closely related to those that cause the human disease african sleeping sickness. these agents were tested singly and in combination in a previously described mouse model of sleeping sickness with demonstrable brain involvement. the or ...19836193522
the course of trypanosoma brucei ssp. infection in domestic chickens.three unrelated stocks of trypanosoma (trypanozoon) brucei were tested for their ability to infect domestic chickens. one of them, lugala/55/eatro/459, regularly produced a chronic infection. this was characterized by a low parasitemia (3-100 mouse infective organisms per ml of blood) that lasted for nine months in pullets and over one year in cockerels. advances and remissions of the parasitemia were detected during the course of the infection. there was no obvious impairment of the health of t ...19827135472
domain organization and a protease-sensitive loop in eukaryotic ornithine decarboxylase.trypanosoma brucei ornithine decarboxylase was reconstituted by coexpression of two polypeptides corresponding to residues 1-305 and residues 306-425 in escherichia coli. the two peptides were coexpressed, at wild-type levels, from a single transcriptional unit that was separated by a 15-nucleotide untranslated region containing a ribosome binding site. the fragmented enzyme was purified and analyzed. the n- and c-terminal peptides are tightly associated into a fully active tetramer which has th ...19957577930
in vivo evaluation of reuterin and its combinations with suramin, melarsoprol, dl-alpha-difluoromethylornithine and bleomycin in mice infected with trypanosoma brucei brucei.1. trypanosoma brucei brucei-infected mouse models treated with a new antibiotic, reuterin, showed reduction of the levels of parasitemia and prolonged survival of the mice. 2. cures of the parasitemia were observed in groups of mice treated with combinations of reuterin and suramin or melarsoprol. 3. reuterin administered in combination with bleomycin or dl-alpha-difluoromethylornithine showed temporary remission of the parasitemia in groups of mice.19937693393
rat antizyme inhibits the activity but does not promote the degradation of mouse ornithine decarboxylase in trypanosoma brucei.ornithine decarboxylase (odc) of african trypanosomes is an important target for anti-trypanosomal chemotherapy because of its remarkable stability in vivo. the in vivo activity and stability of mammalian odc are regulated by polyamines. polyamines induce antizyme, which inactivates odc by tight association and promotes degradation of odc by the mammalian 26 s proteasome. here we found, in contrast to mammalian cells, that polyamines caused no reduction of odc activity in trypanosoma brucei. mou ...19957730330
acidic residues important for substrate binding and cofactor reactivity in eukaryotic ornithine decarboxylase identified by alanine scanning mutagenesis.ornithine decarboxylases from trypanosoma brucei, mouse, and leishmania donovani share strict specificity for three basic amino acids, ornithine, lysine, and arginine. to identify residues involved in this substrate specificity and/or in the reaction chemistry, six conserved acidic resides (asp-88, glu-94, asp-233, glu-274, asp-361, and asp-364) were mutated to alanine in the t. brucei enzyme. each mutation causes a substantial loss in enzyme efficiency. most notably, mutation of asp-361 increas ...19957744828
neuronal interferon-gamma immunoreactive molecule: bioactivities and purification.an interferon (ifn)-gamma immunoreactive molecule, localized to small neurons in peripheral sensory ganglia (n-ifn-gamma), has been detected with two mouse monoclonal antibodies (db1 and db16) directed against different epitopes of rat ifn-gamma. to define n-ifn-gamma with regard to its protein characteristics and bioactivities, db1 and db16 were used to purify n-ifn-gamma from rat trigeminal ganglia in a two-step sequential antibody-affinity procedure. sodium dodecylsulfate polyacrylamide gel e ...19948299680
cd8 is critically involved in lymphocyte activation by a t. brucei brucei-released molecule.t. brucei brucei released a lymphocyte triggering factor (tltf), which triggered purified cd8+, but not cd4+, t cells to interferon gamma (ifn-gamma) mrna expression and secretion and to [3h]thymidine incorporation. tltf also induced mrna for transforming growth factor beta, but not for interleukin-4. the action of this tltf on mononuclear cell (mnc) cultures was blocked by anti-cd8 antibodies and by soluble cd8. mncs from a mutant mouse strain lacking cd8 expression were not triggered by tltf. ...19938453666
different trypanozoan species possess cd8 dependent lymphocyte triggering factor-like activity.trypanosoma brucei brucei (t. b. brucei) release a molecule, trypanosome derived lymphocyte triggering factor (tltf), which stimulates cd8+ cells to produce cytokines and to proliferate. we now report that t. evansi, t.b. gambiense and t.b. rhodesiense also contain factor(s) with similar activity. thus, homogenates from these parasite taxa triggered mouse or rat lymphoid tissue of mononuclear cells (mnc) to produce interferon gamma (ifn-gamma) and to proliferate. these responses were dependent o ...19968793562
polyamine analysis using n-hydroxysuccinimidyl-6-aminoquinoyl carbamate for pre-column derivatization.n-hydroxysuccinimidyl-6-aminoquinoyl carbamate (accq.fluor) was used as a polyamine pre-column derivatization reagent prior to hplc analysis using a 5-micron c8 reversed-phase column. the fluorescence detector excitation wavelength was set at 250 nm and emission at 395 nm. quantitation, reproducibility, linearity, recovery and stability were demonstrated. the lower limit of detection was 660 fmol. this method is 45 and 61 times more sensitive than those using the pre-column derivatizing agents d ...19968852721
cloning and characterization of the r1 and r2 subunits of ribonucleotide reductase from trypanosoma brucei.ribonucleotide reductase (rnr) catalyzes the rate limiting step in the de novo synthesis of deoxyribonucleotides by directly reducing ribonucleotides to the corresponding deoxyribonucleotides. to keep balanced pools of deoxyribonucleotides, all nonviral rnrs studied so far are allosterically regulated. most eukaryotes contain a class i rnr, which is a heterodimer of two nonidentical subunits called proteins r1 and r2. we have isolated cdnas encoding the r1 and r2 proteins from trypanosoma brucei ...19979192674
antitrypanosomal activity of a new triazine derivative, sipi 1029, in vitro and in model infections.a recently developed diaminotriazine derivative [o,o'-bis(1, 2-dihydro-2,2-tetramethylene-4,6-diamino-s-triazin-1-yl)-1, 6-hexanediol dihydrochloride; t-46; sipi 1029] was examined for activity against african trypanosomes in in vitro and in vivo model systems. in vitro, sipi 1029 was 50% inhibitory for growth of bloodstream trypomastigotes of four strains of trypanosoma brucei brucei and trypanosoma brucei rhodesiense at 0.15 to 2.15 nm (50% inhibitory concentrations). in in vivo mouse laborato ...19989756783
trypanosoma brucei: killing of bloodstream forms in vitro and in vivo by the cysteine proteinase inhibitor z-phe-ala-chn2.cysteine proteinases were tested for their suitability as targets for chemotherapy of sleeping sickness using the peptidyl inhibitor z-phe-ala-diazomethyl ketone (z-phe-ala-chn2). in vitro, the inhibitory concentration of z-phe-ala-chn;2 required to reduce the growth rate by 50% was 400 times lower for culture-adapted bloodstream forms of trypanosoma brucei than for a mouse myeloma cell line. at an inhibitor concentration of 10;m the parasites were lysed within 48 h of incubation. parasitemia of ...199910092476
reactive oxygen species activate a ca2+-dependent cell death pathway in the unicellular organism trypanosoma brucei brucei.here we examine a cell death process induced by reactive oxygen species (ros) in the haemoflagellate trypanosoma brucei brucei. ca2+ distribution in cellular compartments was measured with stable transformants expressing aequorin targeted to the cytosol, nucleus or mitochondrion. within 1.5 h of ros production, mitochondrial ca2+ transport was impaired and the ca2+ barrier between the nuclear envelope and cytosol was disrupted. consequently the mitochondrion did not accumulate ca2+ efficiently i ...199910229656
l-arginine availability modulates local nitric oxide production and parasite killing in experimental trypanosomiasis.nitric oxide (no) is an important effector molecule of the immune system in eliminating numerous pathogens. peritoneal macrophages from trypanosoma brucei brucei-infected mice express type ii no synthase (nos-ii), produce no, and kill parasites in the presence of l-arginine in vitro. nevertheless, parasites proliferate in the vicinity of these macrophages in vivo. the present study shows that l-arginine availability modulates no production. trypanosomes use l-arginine for polyamine synthesis, re ...200010899869
chalcone, acyl hydrazide, and related amides kill cultured trypanosoma brucei brucei.protozoan parasites of the genus trypanosoma cause disease in a wide range of mammalian hosts. trypanosoma brucei brucei, transmitted by tsetse fly to cattle, causes a disease (nagana) of great economic importance in parts of africa. t. b. brucei also serves as a model for related trypanosoma species, which cause human sleeping sickness.200011055585
in vitro and in vivo activities of aminoadamantane and aminoalkylcyclohexane derivatives against trypanosoma brucei.we reported recently that the bloodstream form of the african trypanosome, trypanosoma brucei, is sensitive to the anti-influenza virus drug rimantadine. in the present report we describe the trypanocidal properties of a further 62 aminoadamantane and aminoalkylcyclohexane derivatives. seventeen of the compounds were found to be more active than rimantadine, with four inhibiting growth in vitro of t. brucei by >90% at concentrations of 1 microm. the most active derivative (1-adamantyl-4-amino-cy ...200111302796
trypanosoma brucei ctp synthetase: a target for the treatment of african sleeping sickness.the drugs in clinical use against african sleeping sickness are toxic, costly, or inefficient. we show that trypanosoma brucei, which causes this disease, has very low levels of ctp, which are due to a limited capacity for de novo synthesis and the lack of salvage pathways. the ctp synthetase inhibitors 6-diazo-5-oxo-l-norleucine (don) and alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid (acivicin) reduced the parasite ctp levels even further and inhibited trypanosome proliferation in vit ...200111353848
sero-epizootiologic survey of trypanosoma brucei in kenyan nonhuman primates.blood samples were collected from 121 individuals of three species of wild-caught nonhuman primates from kenya, including african green monkeys (cercopithecus aethiops), syke's monkeys (c. mitis), and olive baboons (papio cynocephalus anubis), and were examined for circulating trypanosoma brucei and for t. brucei antigen and anti-trypanosome antibody. indirect antibody enzyme-linked immunosorbent assay detected titers of anti-t. brucei antibodies in 13 of the primates sampled, and field-oriented ...200212564531
concurrent infections with trypanosoma brucei and nippostrongylus brasiliensis in mice deficient in inducible nitric oxide.concurrent infection with trypanosoma brucei (tb) delays the normal protective responses of mice to the gastrointestinal parasite nippostrongylus brasiliensis (nb). the course of such infections was followed in mice genetically deficient in inducible nitric oxide synthase (inos) to assess the role of nitric oxide (no) in this effect. the time course of trypanosome infection in inos deficient (inos-/-) mice was similar to that in wild type (wt) and heterozygote (inos+/-) mice but did not result i ...200312798922
enhanced endothelial nitric oxide-synthase activity in mice infected with trypanosoma brucei.infection of humans with trypanosoma brucei causes sleeping sickness, which is invariably fatal if left untreated. the course of infection is characterised, among others, by multiple organ damage including cardiovascular dysfunctions such as hypotension and breakdown of the blood-brain barrier. the latter eventually leads to the parasite invasion into central nervous system and ultimately to the death of the patient. nitric oxide (no) synthesised from l-arginine via endothelial no-synthase (enos ...200313129532
p75 tumor necrosis factor-receptor shedding occurs as a protective host response during african trypanosomiasis.in experimental murine trypanosomiasis, resistance is often scored as the capacity to control peak parasitemia levels, which results in prolonged survival. infection-induced pathology has not systematically been used as a resistance criterion. because this parameter could be the most relevant for comparative analysis of natural and experimental infections, as well as for understanding of pathology-associated immune alterations, we analyzed trypanosoma brucei infections in 4 different established ...200414745712
kola acuminata proanthocyanidins: a class of anti-trypanosomal compounds effective against trypanosoma brucei.human african trypanosomiasis is undergoing an alarming rate of recrudescence in many parts of sub-saharan africa. yet, there is no successful chemotherapy for the disease due to a limited number of useful drugs, side effects and drawbacks of the existing medication, as well as the development of drug resistance by the parasite. here we describe a new lead anti-trypanosomal compound isolated from kola acuminata (makasu). we purified a proanthocyanidin by chromatographic procedures and confirmed ...200415619520
treatment of african trypanosomiasis with cordycepin and adenosine deaminase inhibitors in a mouse model.there is an urgent need to discontinue the use of highly toxic compounds still in use for treatment of the encephalitic stage of human african trypanosomiasis (hat). we show here that intraperitoneal injection of the adenosine analogue cordycepin (3'-deoxyadenosine), together with an adenosine deaminase (ada) inhibitor (coformycin or deoxycoformycin), cures trypanosoma brucei brucei infection in mice. treatment was also effective at a stage when the trypanosomes had penetrated into the brain par ...200516206083
dna binding affinity of bisguanidine and bis(2-aminoimidazoline) derivatives with in vivo antitrypanosomal activity.a new antitrypanosomal hit compound that cures an acute (stib 900) mouse model of trypanosoma brucei rhodesiense trypanosomiasis is described. this bis(2-aminoimidazolinium) dicationic compound proved to be an excellent dna minor groove binder, suggesting a possible mechanism for its trypanocidal activity. from these studies, the 4,4'-diaminodiphenylamine skeleton emerged as a good scaffold for antitrypanosomal drugs.200616759117
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
activity of indenoisoquinolines against african trypanosomes.african trypanosomiasis (sleeping sickness), caused by protozoan trypanosoma brucei species, is a debilitating disease that is lethal if untreated. available drugs are antiquated, toxic, and compromised by emerging resistance. the indenoisoquinolines are a class of noncamptothecin topoisomerase ib poisons that are under development as anticancer agents. we tested a variety of indenoisoquinolines for their ability to kill t. brucei. indenoisoquinolines proved trypanocidal at submicromolar concent ...200918824603
immunization with recombinant actin from trypanosoma evansi induces protective immunity against t. evansi, t. equiperdum and t. b. brucei infection.actin gene of trypanosoma evansi (stib 806) was cloned and expressed in escherichia coli. the predicted amino acid sequence of t. evansi actin shows 100%, 98.7%, and 93.1%, homology with trypanosoma equiperdum, trypanosoma brucei brucei, and trypanosoma cruzi. recombinant actin was expressed as inclusion bodies in e. coli. it was purified and renatured for immunological studies. mice immunized with the renatured recombinant actin were protected from lethal challenge with t. evansi stib 806, t. e ...200918923843
protective effect of humus extract against trypanosoma brucei infection in mice.humic substances are formed during the decomposition of organic matter in humus, and are found in many natural environments in which organic materials and microorganisms are present. oral administration of humus extract to mice successfully induced effective protection against experimental challenge by the two subspecies, trypanosoma brucei brucei and t. brucei gambiense. mortality was most reduced among mice who received a 3% humus extract for 21 days in drinking water ad libitum. spleen cells ...200819057136
new treatment option for second-stage african sleeping sickness: in vitro and in vivo efficacy of aza analogs of db289.african sleeping sickness is a fatal parasitic disease, and all drugs currently in use for treatment have strong liabilities. it is essential to find new, effective, and less toxic drugs, ideally with oral application, to control the disease. in this study, the aromatic diamidine db75 (furamidine) and two aza analogs, db820 and db829 (cpd-0801), as well as their methoxyamidine prodrugs and amidoxime metabolites, were evaluated against african trypanosomes. the active parent diamidines showed sim ...200919620327
quantitative differences in immune responses in mouse strains that differ in their susceptibility to trypanosoma brucei brucei infection.we compared the relative resistance and soluble variant surface glycoprotein (vsg)-specific responses in (c57bl/6 x balb/c)-f1 (b6b-f1) and c3h mice during infection with trypanosoma brucei brucei, the hemoprotozoan parasite causing a debilitating disease in man and livestock. we demonstrated that c3h mice are relatively more trypanosusceptible, as evidenced by their reduced ability to control parasitemia and shorter survival time, than b6b-f1 mice. quantitative differences in the pattern of cyt ...200919652484
probing for primary functions of prohibitin in trypanosoma brucei.prohibitins (phbs) 1 and 2 are small conserved proteins implicated in a number of functions in the mitochondrion, as well as in the nucleus of eukaryotic cells. the current understanding of phb functions comes from studies of model organisms such as yeast, worm and mouse, but considerable debate remains with regard to the primary functions of these ubiquitous proteins. we exploit the tractable reverse genetics of trypanosoma brucei, the causative agent of african sleeping sickness, in order to s ...201019683530
calflagin inhibition prolongs host survival and suppresses parasitemia in trypanosoma brucei infection.african trypanosomes express a family of dually acylated, ef-hand calcium-binding proteins called the calflagins. these proteins associate with lipid raft microdomains in the flagellar membrane, where they putatively function as calcium signaling proteins. here we show that these proteins bind calcium with high affinity and that their expression is regulated during the life cycle stage of the parasite, with protein levels approximately 10-fold higher in the mammalian bloodstream form than in the ...201020418379
bottlenecks and the maintenance of minor genotypes during the life cycle of trypanosoma brucei.african trypanosomes are digenetic parasites that undergo part of their developmental cycle in mammals and part in tsetse flies. we established a novel technique to monitor the population dynamics of trypanosoma brucei throughout its life cycle while minimising the confounding factors of strain differences or variation in fitness. clones derived from a single trypanosome were tagged with short synthetic dna sequences in a non-transcribed region of the genome. infections were initiated with mixtu ...201020686656
tip-dc development during parasitic infection is regulated by il-10 and requires ccl2/ccr2, ifn-gamma and myd88 signaling.the development of classically activated monocytic cells (m1) is a prerequisite for effective elimination of parasites, including african trypanosomes. however, persistent activation of m1 that produce pathogenic molecules such as tnf and no contributes to the development of trypanosome infection-associated tissue injury including liver cell necrosis in experimental mouse models. aiming to identify mechanisms involved in regulation of m1 activity, we have recently documented that during trypanos ...201020714353
tbunc119 and its binding protein complex are essential for propagation, motility, and morphogenesis of trypanosoma brucei procyclic form cells.flagellum-mediated motility of trypanosoma brucei is considered to be essential for the parasite to complete stage development in the tsetse fly vector, while the mechanism by which flagellum-mediated motility is controlled are not fully understood. we thus compared t. brucei whole gene products (amino acid sequence) with caenorhabditis elegans unc (uncoordinated) proteins, in order to find uncharacterized motility-related t. brucei genes. through in silico analysis, we found 88 gene products wh ...201021203515
requirement for acetyl-coa carboxylase in trypanosoma brucei is dependent upon the growth environment.trypanosoma brucei, the causative agent of human african trypanosomiasis, possesses two fatty acid synthesis pathways: a major de novo synthesis pathway in the er and a mitochondrial pathway. the 2-carbon donor for both pathways is malonyl-coa, which is synthesized from acetyl-coa by acetyl-coa carboxylase (acc). here, we show that t. brucei acc shares the same enzyme architecture and moderate ~ 30% identity with yeast and human accs. acc is cytoplasmic and appears to be distributed throughout t ...201121306439
sar of 2-amino and 2,4-diamino pyrimidines with in vivo efficacy against trypanosoma brucei.a series of 2,4-diaminopyrimidines was investigated and compounds were found to have in vivo efficacy against trypanosoma brucei in an acute mouse model. however, in vitro permeability data suggested the 2,4-diaminopyrimidenes would have poor permeability through the blood brain barrier. consequently a series of 4-desamino analogs were synthesized and found to have improved in vitro permeability.201121507639
Trypanosoma brucei brucei oligopeptidase B null mutants display increased prolyl oligopeptidase-like activity.African trypanosomosis is a parasitic disease in man and animals caused by protozoan parasites of the genus Trypanosoma. Nagana, the cattle form of the disease, is caused by Trypanosoma congolense, Trypanosoma vivax and Trypanosoma brucei brucei. An option for developing vaccines and chemotherapeutic agents against trypanosomosis is to target pathogenic factors released by the parasite during infection, namely an "anti-disease" approach. One such pathogenic factor is oligopeptidase B (TbOPB), a ...201122123425
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