Publications

regulation of murine cerebral malaria pathogenesis by cd1d-restricted nkt cells and the natural killer complex.	nkt cells are specialized cells coexpressing nk and t cell receptors. upon activation they rapidly produce high levels of interferon-gamma (ifn-gamma) and interleukin-4 (il-4) and are therefore postulated to influence t(h)1/t(h)2 immune responses. the precise role of the cd1/nkt cell pathway in immune response to infection remains unclear. we show here that cd1d-restricted nkt cells from distinct genetic backgrounds differentially influence t(h)1/t(h)2 polarization, proinflammatory cytokine leve ...	2003	12648456
glutathione is involved in the antimalarial action of chloroquine and its modulation affects drug sensitivity of human and murine species of plasmodium.	ferriprotoporphyrin ix (fp) is released inside the food vacuole of the malaria parasite during the digestion of host cell hemoglobin. fp is detoxified by its biomineralization to hemozoin. this process is effectively inhibited by chloroquine (cq) and amodiaquine (aq). undegraded fp accumulates in the membrane fraction and inhibits enzymes of infected cells in parallel with parasite killing. fp is demonstrably degraded by reduced glutathione (gsh) in a radical-mediated mechanism. this degradation ...	2003	14962364
double-drug development against antioxidant enzymes from plasmodium falciparum.	new drugs against malaria are urgently and continuously needed. plasmodium parasites are exposed to higher fluxes of reactive oxygen species and need high activities of intracellular antioxidant systems. a most important antioxidative system consists of (di)thiols which are recycled by disulfide reductases (dr), namely both glutathione reductases (gr) of the malarial parasite plasmodium falciparum and man, and the thioredoxin reductase (trxr) of p. falciparum. the aim of our interdisciplinary re ...	2003	14962365
molecular biology and biochemistry of malarial parasite pyrimidine biosynthetic pathway.	metabolic pathways in the malarial parasite are markedly different from the host, eg, hemoglobin, fatty acids, folate and nucleic acids. understanding of metabolic function will illuminate new chemotherapeutic targets for drug development, including the identification of target(s) for drugs in current use. the parasite-contained pyrimidine biosynthetic pathway is essential for growth and development in the human host. plasmodium falciparum carbonic anhydrase, producing hco3- as a pyrimidine prec ...	2003	19230569
the role of nitric oxide and its up/downstream molecules in malaria: cytotoxic or preventive?	the current study investigated the involvement of nitric oxide (no) and related molecules in malaria target organs of outbred mf1 mice during lethal plasmodium berghei and non-lethal p. c. chabaudi infections, in order to evaluate whether changes in no production are beneficial or detrimental to the host. a number of methods have been applied to test this hypothesis, including griess microassay, electrochemical assay, rt-pcr and western blot. the results show that reactive nitrogen intermediate ...	2003	19230570
expression of inducible nitric oxide synthase (inos) mrna in target organs of lethal and non-lethal strains of murine malaria.	nitric oxide (no) is a putative mediator of the immunological and/or pathological responses to malaria, consequently it is a potential target for novel drug therapy. numerous cell types increase expression of inducible nitric oxide synthase (inos) under inflammatory conditions, the most relevant stimuli being cytokines and endotoxins. in this study the expression of inos mrna in several target organs (brain, liver, spleen) of malaria have been investigated in mf1 mice during lethal plasmodium (p ...	2002	12654089
leptin and leptin receptors during malaria infection in mice.	leptin, which is involved in a range of physiological processes, could be an important factor in the pathogenesis of malaria. we found that levels of leptin in serum and urine in plasmodium berghei-infected mice increased progressively after infection, reaching a maximum value on day 6 post-infection. serum values were approximately five-fold higher in infected mice than in non-infected controls. a similar relation was found for values of leptin in urine. soluble leptin receptor levels also incr ...	2002	12641196
the effect of 10 alpha-trifluoromethylhydroartemisinin on plasmodium berghei infection and its toxicity in experimental animals.	the antimalarial activity of 10 alpha-trifluoromethylhydroartemisinin (tfmha) was compared to that of dihydroartemisinin (dha) in the plamodium berghei mouse model. treatment with tfmha in mice infected with a p. berghei chloroquine-sensitive strain at 25 mg/kg for 3, 5, and 7 d, or dha at the same dose for 7 d showed the parasite was eliminated from the host within 2.6 d. the radical cure and survival rates of these mice up to 60 d after infection were 90-100%. in mice infected with the p. berg ...	2002	12625149
plasmodium berghei: analysis of the gamma-glutamylcysteine synthetase gene in drug-resistant lines.	the rapid emergence of multidrug-resistant plasmodium falciparum is a worldwide concern. despite the magnitude of the problem, the mechanisms involved in this phenomenon are not well understood. one current proposal suggests that toxic heme molecules are degraded by glutathione (gsh), and that anti-malarial drugs, such as chloroquine (cq), inhibit this degradation, thus implicating gsh in drug resistance. furthermore, in some strains of plasmodium berghei and p. falciparum, chloroquine resistanc ...	2002	12594957
azadirachtin disrupts formation of organised microtubule arrays during microgametogenesis of plasmodium berghei.	transmission of malaria parasites from vertebrate blood to the mosquito vector depends critically on the differentiation of the gametocytes into gametes. this occurs in response to environmental stimuli encountered by the parasite in the mosquito bloodmeal. male gametogenesis involves three rounds of dna replication and endomitosis, and the assembly de novo of 8 motile axonemes. azadirachtin, a plant limnoid and insecticide with an unkown mode of action, specifically inhibits the release of moti ...	2002	12503686
heptyl prodigiosin, a bacterial metabolite, is antimalarial in vivo and non-mutagenic in vitro.	heptyl prodigiosin was purified from a culture of alpha-proteobacteria isolated from a marine tunicate collected in zamboanga, philippines, as part of a program to screen natural products for antiparasitic activity. an in vitro antimalarial activity similar to that of quinine was found against the chloroquine-sensitive strain plasmodium falciparum 3d7. the in vitro antimalarial activity was about 20 times the in vitro cytotoxic activity against l5178y mouse lymphocytes. a single subcutaneous adm ...	2002	12503881
[study on inducing an artemisinin-resistant line of plasmodium berghei].	to induce a line of plasmodium berghei with resistance to artemisinin.	2002	12567543
cutting edge: a new tool to evaluate human pre-erythrocytic malaria vaccines: rodent parasites bearing a hybrid plasmodium falciparum circumsporozoite protein.	malaria vaccines containing the plasmodium falciparum circumsporozoite protein repeat domain are undergoing human trials. there is no simple method to evaluate the effect of vaccine-induced responses on p. falciparum sporozoite infectivity. unlike the rodent malaria plasmodium berghei, p. falciparum sporozoites do not infect common laboratory animals and only develop in vitro in human hepatocyte cultures. we generated a recombinant p. berghei parasite bearing p. falciparum circumsporozoite prote ...	2002	12471098
regulation of endothelial cell adhesion molecule expression in an experimental model of cerebral malaria.	plasmodium falciparum malaria in humans and animal models of this disease have revealed changes in the infected host that are consistent with a systemic inflammatory response. although it has been proposed that endothelial cell adhesion molecules (cam) contribute to the adhesive interactions of plasmodium-infected erythrocytes and immune cells with vascular endothelial cells, ecam expression has not been systematically studied in plasmodium-infected animals.	2002	12483543
immune response of anopheles gambiae to the early sporogonic stages of the human malaria parasite plasmodium falciparum.	deciphering molecular interactions between the malaria parasite and its mosquito vector is an emerging area of research that will be greatly facilitated by the recent sequencing of the genomes of anopheles gambiae mosquito and of various plasmodium species. so far, most such studies have focused on plasmodium berghei, a parasite species that infects rodents and is more amenable to studies. here, we analysed the expression pattern of nine an.gambiae genes involved in immune surveillance during de ...	2002	12485988
on the pathogenic role of brain-sequestered alphabeta cd8+ t cells in experimental cerebral malaria.	cerebral malaria (cm) develops in a small proportion of persons infected with plasmodium falciparum and accounts for a substantial proportion of the mortality due to this parasite. the actual pathogenic mechanisms are still poorly understood, and in humans investigations of experimental cm are unethical. using an established plasmodium berghei-mouse cm model, we have investigated the role of host immune cells at the pathological site, the brain. we report in this study the detailed quantificatio ...	2002	12444144
mechanism-based design of parasite-targeted artemisinin derivatives: synthesis and antimalarial activity of new diamine containing analogues.	the potent antimalarial activity of chloroquine against chloroquine-sensitive strains can be attributed, in part, to its high accumulation in the acidic environment of the heme-rich parasite food vacuole. a key component of this intraparasitic chloroquine accumulation mechanism is a weak base "ion-trapping" effect whereupon the basic drug is concentrated in the acidic food vacuole in its membrane-impermeable diprotonated form. by the incorporation of amino functionality into target artemisinin a ...	2002	11855985
thrombocytopenia in an animal model of malaria is associated with an increased caspase-mediated death of thrombocytes.	infection of mice with plasmodium berghei anka (pba) leads to a thrombocytopenia, due to a reduced platelet life span, eventually associated with a syndrome of severe or cerebral malaria (cm). thrombocytopenia was associated with an increase in the number of microparticles (mcp) in plasma. more than >60% of these mcp were of platelet origin, as seen by staining with an anti-platelet antibody. the thrombocytopenia and the amount of mcp were decreased in mice treated with anti cd40l mab, suggestin ...	2002	11865192
a rodent malaria, plasmodium berghei, is experimentally transmitted to mice by merely probing of infective mosquito, anopheles stephensi.	we found that infection of a rodent malaria, plasmodium berghei, occurred when the sporozoites were injected into the skin, the muscle, the peritoneal cavity and the tail end. mice, which were injected with sporozoites in the tail end and had the site cut 5 min later, did not develop malaria. we also found that mice developed malaria when malaria infective mosquitoes, anopheles stephensi, were forced not to take blood but only to probe into the skin. moreover, the mice probed by the infective mo ...	2002	11880224
susceptibility to experimental cerebral malaria induced by plasmodium berghei anka in inbred mouse strains recently derived from wild stock.	the neurological syndrome caused by plasmodium berghei anka in rodents partially mimics the human disease. several rodent models of cerebral malaria (cm) exist for the study of the mechanisms that cause the disease. however, since common laboratory mouse strains have limited gene pools, the role of their phenotypic variations causing cm is restricted. this constitutes an obstacle for efficient genetic analysis relating to the pathogenesis of malaria. most common laboratory mouse strains are susc ...	2002	11895970
levels of circumsporozoite protein in the plasmodium oocyst determine sporozoite morphology.	the sporozoite stage of the plasmodium parasite is formed by budding from a multinucleate oocyst in the mosquito midgut. during their life, sporozoites must infect the salivary glands of the mosquito vector and the liver of the mammalian host; both events depend on the major sporozoite surface protein, the circumsporozoite protein (cs). we previously reported that plasmodium berghei oocysts in which the cs gene is inactivated do not form sporozoites. here, we analyzed the ultrastructure of p.ber ...	2002	11927543
plasmodium sporozoite invasion into insect and mammalian cells is directed by the same dual binding system.	plasmodium sporozoites, the transmission form of the malaria parasite, successively invade salivary glands in the mosquito vector and the liver in the mammalian host. sporozoite capacity to invade host cells is mechanistically related to their ability to glide on solid substrates, both activities depending on the transmembrane protein trap. here, we show that loss-of- function mutations in two adhesive modules of the trap ectodomain, an integrin-like a-domain and a thrombospondin type i repeat, ...	2002	11927544
the mechanism and significance of deletion of parasite-specific cd4(+) t cells in malaria infection.	it is thought that both helper and effector functions of cd4(+) t cells contribute to protective immunity to blood stage malaria infection. however, malaria infection does not induce long-term immunity and its mechanisms are not defined. in this study, we show that protective parasite-specific cd4(+) t cells were depleted after infection with both lethal and nonlethal species of rodent plasmodium: it is further shown that the depletion is confined to parasite-specific t cells because (a) ovalbum ...	2002	11927632
induced immunity against the mosquito anopheles stephensi (diptera: culicidae): effects of cell fraction antigens on survival, fecundity, and plasmodium berghei (eucoccidiida: plasmodiidae) transmission.	two subeellular fractions from the midgut of the malaria mosquito anopheles stephensi (liston) were used to immunize balb/c mice. mice were subsequently infected with the rodent malaria parasite plasmodium berghei (vineke & lips), and the effects of anti-mosquito immunity on mosquito survival and fecundity and on parasite transmission were investigated. mosquitoes were infected directly from mice (in vivo) or by feeding cultured ookinetes through a membrane (in vitro). infections were monitored ...	2002	11931258
changes in schizogony and drug response in two lines of rodent plasmodium, p. berghei nk 65 and p. berghei anka.	white mice were infected with two strains, anka and nk 65, of plasmodium berghei. the parasites were subjected to chloroquine pressure (60 mg/kg at each passage) during 20 passages. we then compared the behaviour of the strains as they acquired chemoresistance. the drug resistance was estimated by the 2% delay time test (d2%), and the schizogonic rhythm by the synchronicity index (si). before drug pressure, the anka strain had a d2% of 4.34, and a si of 0.2. this strain became highly drug resist ...	2002	11938696
hepatic kupffer cell phagocytotic function in rats with erythrocytic-stage malaria.	in the erythrocytic phase of malaria, kupffer cells show marked hypertrophy and hyperplasia and are filled with malarial pigment. however, phagocytic function in this state has not been well characterized. the aim of the present study was to use mouse plasmodium berghei to infect rats with malaria and study the phagocytic function and morphology of kupffer cells.	2002	12084035
influence of antimalarial treatment on acquisition of immunity in plasmodium berghei nk65 malaria.	antimalarial treatments during primary plasmodium berghei nk65 infection in balb/c mice influenced the acquisition of protective immunity against reinfection. among subcurative treatments, lower doses better enable mice to acquire protective immunity than do higher doses. eradication of parasites from the start of infection did not promote protective immunity.	2002	12093701
identification of two cerebral malaria resistance loci using an inbred wild-derived mouse strain.	malaria is a complex infectious disease in which the host/parasite interaction is strongly influenced by host genetic factors. the consequences of plasmodial infections range from asymptomatic to severe complications like the neurological syndrome cerebral malaria induced by plasmodium falciparum in humans and plasmodium berghei anka in rodents. mice infected with p. berghei anka show marked differences in disease manifestation and either die from experimental cerebral malaria (ecm) or from hemo ...	2002	12114535
apoptosis in the malaria protozoan, plasmodium berghei: a possible mechanism for limiting intensity of infection in the mosquito.	death by apoptosis regulates cell numbers in metazoan tissues and it is mediated by activation of caspases and results in characteristic morphological and biochemical changes. we report here that the malaria protozoan, plasmodium berghei, exhibits features typical of metazoan apoptotic cells including condensation of chromatin, fragmentation of the nuclear dna and movement of phosphatidylserine from the inner to the outer lamellae of the cell membrane. in addition, proteins with caspase-like act ...	2002	12117496
short-chain aliphatic polysulfonates inhibit the entry of plasmodium into red blood cells.	several steps in the pathogenesis of a plasmodium falciparum infection depend on interactions of parasite surface proteins with negatively charged sugars on the surface of host cells such as sialate residues or glycosaminoglycans. for these reasons, our previous studies examining agents that interfere with heparan sulfate-protein binding during amyloidogenesis suggested that short-chain aliphatic polysulfonates may prove useful as antimalarial agents. a series of related polysulfonates were synt ...	2002	12121942
in situ detection of rna in blood- and mosquito-stage malaria parasites.		2002	12125119
maintenance of the plasmodium berghei life cycle.		2002	12125122
construction of a gene library with mung bean nuclease-treated genomic dna.		2002	12125123
episomal transformation of plasmodium berghei.		2002	12125128
gene targeting in plasmodium berghei.		2002	12125129
cell trafficking. malaria blood-stage parasite-specific cd4+ t cells after adoptive transfer into mice.		2002	12125135
synthesis and in vitro studies of novel pyrimidinyl peptidomimetics as potential antimalarial therapeutic agents.	a class of new pyrimidinyl peptidomimetic agents (compounds 1-6) were synthesized, and their in vitro antimalarial activities against plasmodium falciparum were evaluated. the core structure of the new agents consists of a substituted 5-aminopyrimidone ring and a michael acceptor side chain methyl 2-hydroxymethyl-but-2-enoate. the synthesis of 1-6 featured a baylis-hillman reaction of various aldehydes with methyl acrylate catalyzed by 1,4-diazabicyclo[2.2.2]octane (dabco) and a s(n)2' mitsunobu ...	2002	12139460
proteoglycans mediate malaria sporozoite targeting to the liver.	malaria sporozoites are rapidly targeted to the liver where they pass through kupffer cells and infect hepatocytes, their initial site of replication in the mammalian host. we show that sporozoites, as well as their major surface proteins, the cs protein and trap, recognize distinct cell type-specific surface proteoglycans from primary kupffer cells, hepatocytes and stellate cells, but not from sinusoidal endothelia. recombinant plasmodium falciparum cs protein and trap bind to heparan sulphate ...	2002	12139612
isolation and in vitro antiplasmodial activities of alkaloids from teclea trichocarpa: in vivo antimalarial activity and x-ray crystal structure of normelicopicine.	seven alkaloids have been isolated from teclea trichocarpa including four, normelicopicine (1), arborinine (2), skimmianine (6), and dictamnine (7), that are reported for the first time in addition to the previously reported alkaloids melicopicine (3), tecleanthine (4), and 6-methoxytecleanthine (5). the structure of 1 was confirmed by single-crystal x-ray crystallography. two alkaloids, 1 and 2, displayed limited in vitro activities against plasmodium falciparum strains hb3 and k1, but there ap ...	2002	12141852
identification, expression, and functional characterization of maebl, a sporozoite and asexual blood stage chimeric erythrocyte-binding protein of plasmodium falciparum.	maebl is a chimeric erythrocyte binding protein reported in rodent malaria parasites plasmodium yoelii and plasmodium berghei, that has the gene structure similar to erythrocyte binding proteins, but n-terminal homology to subdomains i and ii of apical membrane antigen-1. we report here the sequence analysis and gene structure of the plasmodium falciparum maebl gene. we have cloned and expressed a putative red cell binding domain, m2, of this gene in escherichia coli, purified the recombinant pr ...	2002	12165387
bee venom phospholipase inhibits malaria parasite development in transgenic mosquitoes.	malaria kills millions of people every year, and new control measures are urgently needed. the recent demonstration that (effector) genes can be introduced into the mosquito germ line to diminish their ability to transmit the malaria parasite offers new hope toward the fight of the disease (ito, j., ghosh, a., moreira, l. a., wimmer, e. a. & jacobs-lorena, m. (2002) nature, 417, 452-455). because of the high selection pressure that an effector gene imposes on the parasite population, development ...	2002	12167627
plasmodium: assessment of the antimalarial potential of trifluralin and related compounds using a rat model of malaria, rattus norvegicus.	a rodent model of malaria, plasmodium berghei was used to assess the antimalarial potential of dinitroaniline herbicides. trifluralin, pendimethalin, oryzalin, and benfluralin were all active against p. berghei in vitro at, or close to, submicromolar concentrations, with a rank order of potency similar to that against other protozoa. the dinitroanilines did not elicit a cytotoxic effect against a mammalian cell line at concentrations 100-fold higher than those for activity against p. berghei. ne ...	2002	12173400
synthetic gpi as a candidate anti-toxic vaccine in a model of malaria.	the malaria parasite plasmodium falciparum infects 5-10% of the world's population and kills two million people annually. fatalities are thought to result in part from pathological reactions initiated by a malarial toxin. glycosylphosphatidylinositol (gpi) originating from the parasite has the properties predicted of a toxin; however, a requirement for toxins in general and gpi in particular in malarial pathogenesis and fatality remains unproven. as anti-toxic vaccines can be highly effective pu ...	2002	12181569
reverse genetics in the mosquito anopheles gambiae: targeted disruption of the defensin gene.	anopheles gambiae, the major vector of human malaria parasite, is an important insect model to study vector-parasite interactions. here, we developed a simple in vivo double-stranded rna (dsrna) knockout approach to determine the function of the mosquito antimicrobial peptide gene defensin. we injected dsrna into adults and observed efficient and reproducible silencing of defensin. analysis of the knockdown phenotype revealed that this peptide is required for the mosquito antimicrobial defense a ...	2002	12189180
orally active, water-soluble antimalarial 3-aryltrioxanes: short synthesis and preclinical efficacy testing in rodents.	short chemical syntheses of four new antimalarial trioxanes are presented, starting with inexpensive and commercially available cyclohexanone. almost exclusive formation of the trioxane 12alpha-stereoisomers simplifies product purification. carboxyphenyltrioxanes 3 and 5 are thermally stable in air even at 60 degrees c for 24 h. when administered orally, these new carboxyphenyltrioxanes are highly efficacious in curing malaria-infected mice. important for their practical in vivo administration, ...	2002	12190305
murine malaria is exacerbated by ctla-4 blockade.	cytolytic t lymphocyte-associated ag-4 (cd152) is a negatively regulating molecule, which is primarily expressed on t cells following their activation. in this study, we have examined the role of ctla-4 expression in experimental blood-stage malaria. similar to human malaria, ctla-4 is expressed on cd4(+) t cells of c57bl/6 mice after infection with plasmodium berghei. a kinetic analysis revealed that ctla-4 expression was increased on day 5 postinfection and reached a peak on day 9 postinfectio ...	2002	12193697
immuno-electron microscopic observation of plasmodium berghei ctrp localization in the midgut of the vector mosquito anopheles stephensi.	the subcellular localization of plasmodium berghei circumsporozoite protein and thrombospondin-related adhesive protein (pbctrp) in the invasive stage ookinete of p. berghei was studied in the midgut of anopheles stephensi by immuno-electron microscopic observations using polyclonal antibodies and immuno-gold labeling. pbctrp was found to be associated with the micronemes of a mature ookinete throughout the movement from the endoperitrophic space to the basal lamina of the midgut epithelium. pbc ...	2002	12197111
superoxide anion in anopheles albimanus hemolymph and midgut is toxic to plasmodium berghei ookinetes.	the mechanisms of plasmodium spp. elimination in resistant mosquitoes are not completely understood. some resistant anopheline strains are able to melanize plasmodium spp. ookinetes in their midguts. because quinoid compounds are potent catalysts for free radical generation and because these radicals can be generated in association with melanogenesis, it is probable that they play an important role in the elimination of parasites. the production of the superoxide anion (o-2) in the hemolymph and ...	2002	12197117
neurotoxicity and efficacy of arteether related to its exposure times and exposure levels in rodents.	the neurotoxicity of beta-arteether (ae) is related to drug accumulation in blood due to slow and prolonged absorption from the intramuscular injection sites. in this efficacy and toxicity study of ae, the traditional sesame oil vehicle was replaced with cremophore to decrease the accumulation and toxicity of ae. dihydroartemisinin (dqhs), a more toxic and active metabolite of ae, was also analyzed. when administered at a daily dosage of 25 mg/kg for seven days, blood accumulation of ae with ses ...	2002	12201585
stage-specific promoter activity from stably maintained episomes in plasmodium falciparum.	genomic dna is organised at its simplest level within phased arrays of nucleosomes, a structure key to the correct transcriptional regulation of the encoded genes. here we studied chromatin formation on dna transfected into plasmodium falciparum either as an episomal plasmid or following integration by homologous recombination. we show that stably maintained and replicated plasmid assembles phased arrays of nucleosomes and that a reporter gene is transcribed in an appropriate temporal manner. th ...	2002	12204219
structure-activity relationships of the antimalarial agent artemisinin. 7. direct modification of (+)-artemisinin and in vivo antimalarial screening of new, potential preclinical antimalarial candidates.	on the basis of earlier reported quantitative structure-activity relationship studies, a series of 9beta-16-(arylalkyl)-10-deoxoartemisinins were proposed for synthesis. several of the new compounds 7 and 10-14 were synthesized employing the key synthetic intermediate 23. in a second approach, the natural product (+)-artemisinic acid was utilized as an acceptor for conjugate addition, and the resultant homologated acids were subjected to singlet oxygenation and acid treatment to provide artemisi ...	2002	12213073
role of the tumor necrosis factor receptor 2 (tnfr2) in cerebral malaria in mice.	infection of susceptible mice with plasmodium berghei anka leads to a syndrome of severe or cerebral malaria. tumor necrosis factor (tnf) contributes to this syndrome, apparently by acting on its receptor 2 (tnfr2) because tnfr1-/- are susceptible, whereas tnfr2-/- mice are resistant. in this work, we confirmed the essential role of the tnfr2 in cerebral malaria because 6 to 8 days after plasmodium berghei anka infection, hypothermia, coma, and death were observed in +/+ or tnfr1-/-, but never i ...	2002	12218076
a role for the alpha-chain connecting peptide motif in mediating tcr-cd8 cooperation.	to generate peripheral t cells that are both self-mhc restricted and self-mhc tolerant, thymocytes are subjected to positive and negative selection. how the tcr discriminates between positive and negative selection ligands is not well understood, although there is substantial evidence that the cd4 and cd8 coreceptors play an important role in this cell fate decision. we have previously identified an evolutionarily conserved motif in the tcr, the alpha-chain connecting peptide motif (alpha-cpm), ...	2002	12218110
implications of time bomb model of ookinete invasion of midgut cells.	in this review, we describe the experimental observations that led us to propose the time bomb model of ookinete midgut invasion and discuss potential implications of this model when considering malaria transmission-blocking strategies aimed at arresting parasite development within midgut cells. a detailed analysis of the molecular interactions between anopheles stephensi midgut epithelial cells and plasmodium berghei parasites, as they migrate through midgut cells, revealed that ookinetes induc ...	2002	12225921
requirement for tumor necrosis factor receptor 2 expression on vascular cells to induce experimental cerebral malaria.	using tumor necrosis factor receptor type 2 (tnfr2)-deficient mice and generating bone marrow chimeras which express tnfr2 on either hematopoietic or nonhematopoietic cells, we demonstrated the requirement for tnfr2 expression on tissue cells to induce lethal cerebral malaria. thus, tnfr2 on the brain vasculature mediates tumor necrosis factor-induced neurovascular lesions in experimental cerebral malaria.	2002	12228317
from noxiustoxin to scorpine and possible transgenic mosquitoes resistant to malaria.	scorpion venom contains different types of peptides toxic to a variety of organisms whose molecular targets have been described as mainly ion-channels of excitable cells where they cause impairment of function. based on mouse, cricket, and crustacean bioassays, specific toxins for each group of animals have been found. chromatographic techniques were used to isolate and chemically characterize these peptides. one of the best-studied peptides is noxiustoxin, a 39-amino acid residue-long peptide s ...	2002	12234530
plasmodium berghei: routine production of pure gametocytes, extracellular gametes, zygotes, and ookinetes.		2002	12243741
function of region i and ii adhesive motifs of plasmodium falciparum circumsporozoite protein in sporozoite motility and infectivity.	the circumsporozoite protein of plasmodium falciparum contains two conserved motifs (regions i and ii) that have been proposed to interact with mosquito and vertebrate host molecules in the process of sporozoite invasion of salivary glands and hepatocytes, respectively. to study the function of this protein we have replaced the endogenous circumsporozoite protein gene of plasmodium berghei with that of p. falciparum and with versions lacking either region i or region ii. we show here that p. fal ...	2002	12244064
solid-phase synthesis and bioevaluation of lupeol-based libraries as antimalarial agents.	the use of the triterpenoid lupeol as a scaffold for the synthesis of lupeol-based libraries is described. lupeol was anchored to a solid support (rink amide/sieber amide) through aliphatic dicarboxylic acid moieties, which also served as a site for introducing diversity. the resulting polymer linked 3beta-o (resin-alkanoyl)-lup-20(29)-ene 3 was used to generate key intermediates 3beta-o (resin-alkanoyl)-30-bromo-lup-20(29)-ene 4 and 3beta-o (resin-alkanoyl)-30-amino-lup-20(29)-ene 6 for the gen ...	2002	12270150
a malaria scavenger receptor-like protein essential for parasite development.	malaria parasites suffer severe losses in the mosquito as they cross the midgut, haemolymph and salivary gland tissues, in part caused by immune responses of the insect. the parasite compensates for these losses by multiplying during the oocyst stage to form the infectious sporozoites. upon human infection, malaria parasites are again attenuated by sustained immune attack. here, we report a single copy gene that is highly conserved amongst plasmodium species that encodes a secreted protein named ...	2002	12354219
antimalarial activity of yingzhaosu a analogues.	iodonium ion mediated cyclization of unsaturated hydroperoxides 1 afforded the expected yingzhaosu a analogues 2. in some cases, however, the corresponding cyclic ethers 5 were formed competitively with the cyclic peroxides 2, the ratios of these two products being a marked function of the structure of the starting materials. some of the cyclic peroxides 2 showed significant antimalarial activities in vitro and in vivo.	2002	12361400
the chemotherapy of rodent malaria. lx. the importance of formulation in evaluating the blood schizontocidal activity of some endoperoxide antimalarials.	the activities of artemisinin (qhs) and a number of its semi-synthetic analogues, as well as fenozan b07 (b07), a synthetic 1,2,4-trioxane, and arteflene (atf), a synthetic surrogate of yingzhaosu, were compared in mice infected with drug-sensitive plasmodium berghei or chloroquine-resistant p. yoelii ssp. ns. the studies were stimulated by the observation that b07, in certain aqueous preparations, appears to be equipotent by the subcutaneous (sc) or oral (po) routes in the rodent model but not ...	2002	12396319
chromosome number, genome size and polymorphism of european and south african isolates of large babesia parasites that infect dogs.	pulsed-field gel electrophoresis of intact chromosomes from 2 isolates of each of the 2 most pathogenic species of large babesia parasites that infect dogs, i.e. babesia canis (european species) and b. rossi (south african species), revealed 5 chromosomes in their haploid genome. the size of chromosomes 1-5 was found to be different in the 2 species, ranging from 0.8 to 6.0 mbp. the genome size was estimated to be approximately 14.5 mbp for b. canis and 16 mbp for b. rossi, respectively. within ...	2002	12403319
the role of plasmodium berghei ookinete proteins in binding to basal lamina components and transformation into oocysts.	the ookinete is a motile form of the malaria parasite that travels from the midgut lumen of the mosquito, invades the epithelial cells and settles beneath the basal lamina. the events surrounding cessation of ookinete motility and its transformation into an oocyst are poorly understood, but interaction between components of the basal lamina and the parasite surface has been implicated. here we report that interactions occur between basal lamina constituents and ookinete proteins and that these i ...	2002	11796126
association of a determinant on mouse chromosome 18 with experimental severe plasmodium berghei malaria.	experimental severe malaria (esm; also known as experimental cerebral malaria) is an acute lethal syndrome caused by infection with plasmodium berghei anka and associated with coma and other neurological manifestations in mice. various inbred strains of mice exhibit differences in susceptibility to the development of esm. for example, c57bl/6 mice are highly susceptible and dba/2 mice are relatively resistant. we report here the results of a genomewide scan for host genomic regions that control ...	2002	11796577
enhanced cd8 t cell immunogenicity and protective efficacy in a mouse malaria model using a recombinant adenoviral vaccine in heterologous prime-boost immunisation regimes.	recombinant replication-defective adenovirus expressing the cs gene from plasmodium berghei (ad-pbcs) was found to induce a strong cd8(+) t cell response after intra-dermal or -muscular immunisation. boosting of an adenovirus-primed immune response with the replication-impaired poxvirus, modified vaccinia virus ankara (mva) led to enhanced immunogenicity and substantial protective efficacy. the recombinant adenoviral vaccine was capable of boosting to protective levels a cd8(+) t cell response p ...	2002	11803063
new neplanocin analogues. 12. alternative synthesis and antimalarial effect of (6'r)-6'-c-methylneplanocin a, a potent adohcy hydrolase inhibitor.	an improved method for the synthesis of (6'r)-6'-c-methylneplanocin a (rmnpa, 2), a potent s-adenosyl-l-homocysteine (adohcy) hydrolase inhibitor, was developed via a chelation-controlled stereoselective addition of meticl(3) to the neplanocin a 6'-aldehyde derivative 6. compound 2 effectively inhibited the growth of malaria parasites both in vitro and in vivo. the antimalarial ec(50) value of 2 against plasmodium berghei in mice was 1.0 mg/kg/day, which was superior to that of chloroquine (ec(5 ...	2002	11806727
topology and replication of a nuclear episomal plasmid in the rodent malaria plasmodium berghei.	the rodent malaria plasmodium berghei is one of a small number of species of plasmodium that can currently be genetically transformed through experimentally controlled uptake of exogenous dna by bloodstage parasites. circular dna containing a selectable marker replicates and is maintained under selection pressure in a randomly segregating episomal form during the first weeks after transformation. in this study, using pulsed field gel electrophoresis and ionising radiation, we show that in dividi ...	2002	11809885
complete development of mosquito phases of the malaria parasite in vitro.	methods for reproducible in vitro development of the mosquito stages of malaria parasites to produce infective sporozoites have been elusive for over 40 years. we have cultured gametocytes of plasmodium berghei through to infectious sporozoites with efficiencies similar to those recorded in vivo and without the need for salivary gland invasion. oocysts developed extracellularly in a system whose essential elements include co-cultured drosophila s2 cells, basement membrane matrix, and insect tiss ...	2002	11809973
the role of il-18 in blood-stage immunity against murine malaria plasmodium yoelii 265 and plasmodium berghei anka.	a possible protective role of il-18 in host defense against blood-stage murine malarial infection was studied in balb/c mice using a nonlethal strain, plasmodium yoelii 265, and a lethal strain, plasmodium berghei anka. infection induced an increase in mrna expression of il-18, il-12p40, ifn-gamma, and tnf-alpha in the case of p. yoelii 265 and an increase of il-18, il-12p40, and ifn-gamma in the case of p. berghei anka. the timing of mrna expression of il-18 in both cases was consistent with a ...	2002	11971017
mitochondrial nadh dehydrogenase from plasmodium falciparum and plasmodium berghei.	the mitochondrial electron transport system is necessary for growth and survival of malarial parasites in mammalian host cells. nadh dehydrogenase of respiratory complex i was demonstrated in isolated mitochondrial organelles of the human parasite plasmodium falciparum and the mouse parasite plasmodium berghei by using the specific inhibitor rotenone on oxygen consumption and enzyme activity. it was partially purified by two sequential steps of fast protein liquid chromatographic techniques from ...	2002	11971654
expression of d7 and d7-related proteins in the salivary glands of the human malaria mosquito anopheles stephensi.	full-length cdna clones encoding d7 (ansd7) and d7-related (ansd7r1) secreted salivary gland proteins were isolated from anopheles stephensi. corresponding proteins were separated by sds-page and analysed by n-terminal sequencing, which also identified a second d7-related protein (ansd7r2). ansd7 encodes a protein of 37 kda, ansd7r1 of 18 kda, and ansd7r2 of 16 kda. polyclonal antibodies against recombinant ansd7 showed immunological cross-reactivity with the d7-related proteins, and alignment d ...	2002	12000641
antimalarial activity of medicinal plants used in traditional medicine in s. tomé and príncipe islands.	the present study investigates the antimalarial activity of 13 medicinal plants used in traditional medicine in s. tomé and príncipe (stp) islands in the gulf of guinea, aiming at identifying the most effective plants for further research. fieldwork was carried out with the collaboration of 37 traditional healers from both islands, during an ethnobotanical study, which was conducted from 1993 to 1999. our results indicate that the traditional healers in stp use several medicinal plants against f ...	2002	12020924
maebl is essential for malarial sporozoite infection of the mosquito salivary gland.	malarial sporozoites mature in the oocysts formed in the mosquito midgut wall and then selectively invade the salivary glands, where they wait to be transmitted to the vertebrate host via mosquito bite. invasion into the salivary gland has been thought to be mediated by specific ligand-receptor interactions, but the molecules involved in these interactions remain unknown. maebl is a single transmembrane-like protein that is structurally related to merozoite adhesive proteins. we found maebl of t ...	2002	12021311
locally up-regulated lymphotoxin alpha, not systemic tumor necrosis factor alpha, is the principle mediator of murine cerebral malaria.	cerebral malaria (cm) causes death in children and nonimmune adults. tnf-alpha has been thought to play a key role in the development of cm. in contrast, the role of the related cyto-kine lymphotoxin alpha (ltalpha) in cm has been overlooked. here we show that ltalpha, not tnfalpha, is the principal mediator of murine cm. mice deficient in tnfalpha (b6.tnfalpha-/-) were as susceptible to cm caused by plasmodium berghei (anka) as c57bl/6 mice, and died 6 to 8 d after infection after developing ne ...	2002	12021316
transgenic anopheline mosquitoes impaired in transmission of a malaria parasite.	malaria is estimated to cause 0.7 to 2.7 million deaths per year, but the actual figures could be substantially higher owing to under-reporting and difficulties in diagnosis. if no new control measures are developed, the malaria death toll is projected to double in the next 20 years. efforts to control the disease are hampered by drug resistance in the plasmodium parasites, insecticide resistance in mosquitoes, and the lack of an effective vaccine. because mosquitoes are obligatory vectors for m ...	2002	12024215
potent antimalarial febrifugine analogues against the plasmodium malaria parasite.	although febrifugine (1) and isofebrifugine (2), alkaloids isolated from roots of the dichroa febrifuga plant, show powerful antimalarial activity against plasmodium falciparum, strong side effects such as the emetic effect have precluded their clinical use against malaria. however, their antimalarial potency makes them attractive substances as leads for developing new types of chemotherapeutic antimalarial drugs. thus, we have evaluated the in vitro antimalarial activity of the analogues of feb ...	2002	12036365
stromal cell derived factor 1 synthesis by spleen cells in rodent malaria, and the effects of in vivo supplementation of sdf-1alpha and cxcr4 receptor blocker.	the mechanisms of malaria parasite clearance in the host are not well understood, but are ascribed to the intact spleen, the site for parasite clearance. the infection induces a huge increase in spleen volume and cellularity. there is, however, a lack of studies on the splenic production of chemokines, which are small proteins that control homing and activation of immune cells and must be crucial for organized tissue growth. we studied the spleen cell production of sdf-1, a primordial chemokine ...	2002	12057854
mouse models of blood-stage malaria infections: immune responses and cytokines involved in protection and pathology.		2002	12058640
immune responses to liver-stage parasites: implications for vaccine development.		2002	12058653
deletion of t cells bearing the v beta8.1 t-cell receptor following mouse mammary tumor virus 7 integration confers resistance to murine cerebral malaria.	plasmodium berghei anka induces a fatal neurological syndrome known as cerebral malaria (cm) in susceptible mice. host genetic elements are among the key factors determining susceptibility or resistance to cm. analysis of mice of the same h-2 haplotype revealed that mouse mammary tumor virus 7 (mtv-7) integration into chromosome 1 is one of the key factors associated with resistance to neurological disease during p. berghei anka infection. we investigated this phenomenon by infecting a series of ...	2002	12065512
antimalarial activities of ring-substituted bioimidazoles.	we report in vitro antimalarial activities against chloroquine sensitive and resistant plasmodium falciparum strains, and in vivo activities against plasmodium berghei in mice for four series of ring-substituted-l-histidines and histamines.	2002	12067541
design and activity of antimicrobial peptides against sporogonic-stage parasites causing murine malarias.	insects produce several types of peptides to combat a broad spectrum of invasive pathogenic microbes, including protozoans. however, despite this defense response, infections are often established. our aim was to design novel peptides that produce high rates of mortality among protozoa of the genus plasmodium, the malaria parasites. using existing antimicrobial peptide sequences as templates, we designed and synthesized three short novel hybrids, designated vida1 to vida3. each has a slightly di ...	2002	12069961
demonstrating the validity of natural products as anti-infective drugs.	this presentation reviews the synthetic or classical development pathway of drug development and contrasts it with developing natural products as drugs. also presented is an example of a traditional medicine that has been developed from a natural product and has become a "new/old" antiparasitic drug used in the treatment of malaria. the classic paradigm of synthetic drug development breaks down into drug discovery, drug design, preclinical studies, and clinical studies. this paradigm, constructe ...	2001	11822638
human antibodies against plasmodium falciparum liver-stage antigen 3 cross-react with plasmodium yoelii preerythrocytic-stage epitopes and inhibit sporozoite invasion in vitro and in vivo.	the plasmodium falciparum liver-stage antigen 3 (lsa3), a recently identified preerythrocytic antigen, induces protection against malaria in chimpanzees. using antibodies from individuals with hyperimmunity to malaria affinity purified on recombinant or synthetic polypeptides of lsa3, we identified four non-cross-reactive b-cell epitopes in plasmodium yoelii preerythrocytic stages. on sporozoites the p. yoelii protein detected has a molecular mass similar to that of lsa3. t-cell epitopes cross-r ...	2001	11349050
knockout of the rodent malaria parasite chitinase pbcht1 reduces infectivity to mosquitoes.	during mosquito transmission, malaria ookinetes must cross a chitin-containing structure known as the peritrophic matrix (pm), which surrounds the infected blood meal in the mosquito midgut. in turn, ookinetes produce multiple chitinase activities presumably aimed at disrupting this physical barrier to allow ookinete invasion of the midgut epithelium. plasmodium chitinase activities are demonstrated targets for human and avian malaria transmission blockade with the chitinase inhibitor allosamidi ...	2001	11349074
interspecies conservation of gene order and intron-exon structure in a genomic locus of high gene density and complexity in plasmodium.	a 13.6 kb contig of chromosome 5 of plasmodium berghei, a rodent malaria parasite, has been sequenced and analysed for its coding potential. assembly and comparison of this genomic locus with the orthologous locus on chromosome 10 of the human malaria plasmodium falciparum revealed an unexpectedly high level of conservation of the gene organisation and complexity, only partially predicted by current gene-finder algorithms. adjacent putative genes, transcribed from complementary strands, overlap ...	2001	11353075
assay of gamma-glutamylcysteine synthetase activity in plasmodium berghei by liquid chromatography with electrochemical detection.	this work describes a high-performance liquid chromatography (hplc) method to determine gamma-glutamylcysteine (gamma-gc), the intermediate product of glutathione biosynthesis. separation relies on isocratic reversed-phase chromatography using a symmetry c18 hplc column, particle size 5 microm, 4.6 x 250 mm i.d. the mobile phase is methanol-dibasic sodium phosphate (ph 6.6; 2.8 mm) (10:90, v/v) at the flow-rate of 0.5 ml/min and detection is operated electrochemically (+200 and +550 mv) with a p ...	2001	11377058
antiplasmodial activities of some ghanaian plants traditionally used for fever/malaria treatment and of some alkaloids isolated from pleiocarpa mutica; in vivo antimalarial activity of pleiocarpine.	fourteen ghanaian plants used in folk medicine to treat fever/malaria were screened for activity against plasmodium falciparum (strain k1) and were tested for general toxicity to the brine shrimp. extracts from three of the plants, pleiocarpa mutica, cleistopholis patens and uvaria chamae were found to have significant antiplasmodial activity. the extract of u. chamae was toxic to brine shrimps. these findings lend support to the use of these plants in traditional medicine. possible toxicity due ...	2001	11378289
immunomodulatory potential of hydrophobic analogs of rigin and their role in providing protection against plasmodium berghei infection in mice.	here, we report the immunomodulating potential of n-palmitoyl-amino-ethyl-rigin amide (pr) and n-cholestanyl-amino-ethyl-rigin amide (cr), the two new structural analogs of rigin (an igg-derived tetrapeptide). their activity profiles are compared with native tuftsin (nt) and/or n-palmitoyl-amino-ethyl-tuftsin amide (pt) taken as positive control. to explore the possibility of their use as targeting molecules, they are incorporated into the liposome bilayer and, subsequently, interacted with macr ...	2001	11379040
[experimental infection in mice by plasmodium berghei: an evidence of antiparasitic action of azithromycin].	infections of plasmodium berghei in mice was stopped by azithromycin which was administered orally in dosages of 100mg/kg, for 28 days. this antibiotic was given since the same day that the animals were infected. the outcome suggests the necessity of more investigations on this antiparasitic activity.	2001	11391444
(31)p nmr of apicomplexans and the effects of risedronate on cryptosporidium parvum growth.	high-resolution 303.6 mhz (31)p nmr spectra have been obtained of perchloric acid extracts of plasmodium berghei trophozoites, toxoplasma gondii tachyzoites, and cryptosporidium parvum oocysts. essentially complete resonance assignments have been made based on chemical shifts and by coaddition of authentic reference compounds. signals corresponding to inorganic pyrophosphate were detected in all three species. in t. gondii and c. parvum, additional resonances were observed corresponding to linea ...	2001	11396947
down-regulation of il-12 p40 gene in plasmodium berghei-infected mice.	we analyzed the mechanism that causes suppression of il-12 p40 gene induction during plasmodium berghei infection. although il-12 together with ifn-gamma plays an important role in protection against pathogenic infection, the il-12 p70 protein production of infected macrophages is lower than that by the uninfected macrophages. we showed in the present study that the induction of il-12 p40 gene but not il-12 p35 gene in macrophages of p. berghei-infected mice was profoundly inhibited. the inhibit ...	2001	11418654
fluorescent plasmodium berghei sporozoites and pre-erythrocytic stages: a new tool to study mosquito and mammalian host interactions with malaria parasites.	to track malaria parasites for biological studies within the mosquito and mammalian hosts, we constructed a stably transformed clonal line of plasmodium berghei, pbfluspo, in which sporogonic and pre-erythrocytic liver-stage parasites are autonomously fluorescent. a cassette containing the structural gene for the facs-adapted green fluorescent protein mutant 2 (gfpmut2), expressed from the 5' and 3' flanking sequences of the circumsporozoite (cs) protein gene, was integrated and expressed at the ...	2001	11422080
penetration of erythrocytes by merozoites of mammalian and avian malarial parasites. 1969.		2001	11426708
synthesis and antimalarial activity of novel medium-sized 1,2,4,5-tetraoxacycloalkanes.	csoh- or ag(2)o-mediated cycloalkylation of (alkylidene)bisperoxides 3 and 1,n-dihaloalkanes (n = 3-8) provided the corresponding medium-sized 1,2,4,5-tetraoxacycloalkanes 4-8 in moderate yields. subsequent evaluation of the antimalarial activity of the cyclic peroxides 4-8 in vitro and in vivo revealed that 1,2,6,7-tetraoxaspiro[7.11]nonadecane 4a has considerable potential as a new, inexpensive, and potent antimalarial drug.	2001	11428929
changes in rodent-erythrocyte methemoglobin reductase system produced by two malaria parasites, viz. plasmodium yoelii nigeriensis and plasmodium berghei.	the methemoglobin reductase system plays a vital role in maintaining the equilibrium between hemoglobin and methemoglobin in blood. exposure of red blood cells to oxidative stress (pathological/physiological) may cause impairment to this equilibrium. we studied the status of erythrocytic methemoglobin and the related reductase system during plasmodium yoelii nigeriensis infection in mice and p. berghei infection in mastomys. malaria infection was induced by intraperitoneal inoculation with 10(6) ...	2001	11435127
cytokine and chemokine mrna expression in neutrophils from cba/nslc mice infected with plasmodium berghei anka that induces experimental cerebral malaria.	to investigate the role of neutrophils in experimental cerebral malaria (ecm), in a previous study we found that early neutrophil depletion prevented the development of ecm and down regulated the expression of th1 cytokines in the brain. to further clarify the mechanisms responsible for these findings, in the present study, using rt-pcr, we examined the expression of cytokine and chemokine mrnas in neutrophils and macrophages after pba infection. we found that, after infection, neutrophils not o ...	2001	11438437
interaction between host complement and mosquito-midgut-stage plasmodium berghei.	after ingestion by mosquitoes, gametocytes of malaria parasites become activated and form extracellular gametes that are no longer protected by the red blood cell membrane against immune effectors of host blood. we have studied the action of complement on plasmodium developmental stages in the mosquito blood meal using the rodent malaria parasite plasmodium berghei and rat complement as a model. we have shown that in the mosquito midgut, rat complement components necessary to initiate the altern ...	2001	11447187
potentiation by a novel alkaloid glycoside adjuvant of a protective cytotoxic t cell immune response specific for a preerythrocytic malaria vaccine candidate antigen.	we have recently demonstrated that the novel glycoalkaloid tomatine, derived from leaves of the wild tomato lycopersicon pimpinellifolium, can act as a powerful adjuvant for the elicitation of antigen-specific cd8+ t cell responses. here, we have extended our previous investigation with the model antigen ovalbumin to an established malaria infection system in mice and evaluated the cellular immune response to a major preerythrocytic stage malaria vaccine candidate antigen when administered with ...	2001	11457540