Publications

a common cross-species function for the double epidermal growth factor-like modules of the highly divergent plasmodium surface proteins msp-1 and msp-8.	an understanding of structural and functional constraints on the c-terminal double epidermal growth factor (egf)-like modules of merozoite surface protein (msp)-1 and related proteins is of importance to the development of these molecules as malaria vaccines and drug targets. using allelic replacement, we show that plasmodium falciparum parasites can invade erythrocytes and grow efficiently in the absence of an msp-1 protein with authentic msp-1 egf domains. in this mutant parasite line, the msp ...	2004	14976193
enhanced cd8+ t cell immune responses and protection elicited against plasmodium berghei malaria by prime boost immunization regimens using a novel attenuated fowlpox virus.	sterile immunity can be provided against the pre-erythrocytic stages of malaria by ifn-gamma-secreting cd8(+) t cells that recognize parasite-infected hepatocytes. in this study, we have investigated the use of attenuated fowlpox virus (fpv) strains as recombinant vaccine vectors for eliciting cd8(+) t cells against plasmodium berghei. the gene encoding the p. berghei circumsporozoite (pbcs) protein was inserted into an fpv vaccine strain licensed for use in chickens, webster's fpv, and the nove ...	2004	14978115
synthesis and blood-schizontocidal antimalarial activities of 2-substituted/2,5-disubstituted-8-quinolinamines and some of their amino acid conjugates.	thirteen new analogues (32-40, 45-48) of recently discovered potent blood-schizontocidal antimalarial agent, 2-tert-butylprimaquine (2) are synthesized and evaluated for in vivo antimalarial activities against drug-sensitive p. berghei strain and multi-drug resistant p. yoelii nigeriensis strain. two of the amino acid conjugates (47-48) have exhibited potent antimalarial activities similar to that of 2 against both drug-sensitive and multi-drug resistant strains.	2004	14980613
antimalarial activity of phenazines from lapachol, beta-lapachone and its derivatives against plasmodium falciparum in vitro and plasmodium berghei in vivo.	the antimalarial activity of benzo[a]phenazines synthesized from 1,2-naphthoquinone, lapachol, beta-lapachone and several derivatives have been tested against plasmodium falciparum in vitro using isolates of parasites with various susceptibilities to chloroquine and/or mefloquine. parasite growth in the presence of the test drugs was measured by incorporation of [(3)h]-hipoxanthine in comparison to controls with no drugs, always testing in parallel chloroquine, a standard antimalarial. among sev ...	2004	14980653
pathogenic role of p-selectin in experimental cerebral malaria: importance of the endothelial compartment.	p-selectin is a leukocyte adhesion receptor expressed on the surface of activated platelets and endothelial cells. its role in the pathogenesis of cerebral malaria was explored in a murine model of cerebral malaria. infection of mice with plasmodium berghei anka led to p-selectin up-regulation in brain vessels of cerebral malaria-susceptible mice but not of cerebral malaria-resistant mice. treatment of susceptible mice with anti-mouse p-selectin mab failed to prevent the development of the neuro ...	2004	14982832
laboratory evaluation of the ict malaria p.f./p.v. immunochromatographic test for detecting the panmalarial antigen using a rodent malaria model.	we evaluated the ict malaria p.f./p.v. immunochromatographic test for the detection of the panmalarial antigen (pma) using a rodent malaria model. mice were infected with plasmodium berghei by mosquito bite, and blood was examined by microscopy and the ict test. treatment with artemether was started when the parasite density exceeded 70,000/microl. the ict pma band appeared when the parasite density was more than 2,000/microl, but it continued to be positive after the parasitemia became negative ...	2004	14993624
orally active antimalarials: hydrolytically stable derivatives of 10-trifluoromethyl anhydrodihydroartemisinin.	new fluoroartemisinin derivatives containing polar or water-soluble functionalities at c-16 (11a-j, 12a-g) were synthesized using the key intermediate 16-bromo-10-trifluoromethyl anhydrodihydroartemisinin 10. the substitution reaction from 10 was more selective than that from the nonfluorinated parent bromide; the allylic bromide 10 underwent no allylic rearrangement and provided only nucleophilic substitution products in high yields with n-, o-, and c-nucleophiles. among them, amines 11a-c appe ...	2004	14998331
ptramp; a conserved plasmodium thrombospondin-related apical merozoite protein.	a gene encoding a 352 amino acid protein with a putative signal sequence, transmembrane domain and thrombospondin structural homology repeat was identified in the genome of the human malaria parasite, plasmodium falciparum and the rodent malaria parasite, plasmodium berghei. the protein localises in the apical organelles of p. falciparum and p. berghei merozoites within intraerythrocytic schizonts and has, therefore, been termed the plasmodium thrombospondin-related apical merozoite protein (ptr ...	2004	15003842
brain gene expression, metabolism, and bioenergetics: interrelationships in murine models of cerebral and noncerebral malaria.	malaria infection can cause cerebral symptoms without parasite invasion of brain tissue. we examined the relationships between brain biochemistry, bioenergetics, and gene expression in murine models of cerebral (plasmodium berghei anka) and noncerebral (p. berghei k173) malaria using multinuclear nmr spectroscopy, neuropharmacological approaches, and real-time rt-pcr. in cerebral malaria caused by p. berghei anka infection, we found biochemical changes consistent with increased glutamatergic act ...	2004	15003995
complement-like protein tep1 is a determinant of vectorial capacity in the malaria vector anopheles gambiae.	anopheles mosquitoes are major vectors of human malaria in africa. large variation exists in the ability of mosquitoes to serve as vectors and to transmit malaria parasites, but the molecular mechanisms that determine vectorial capacity remain poorly understood. we report that the hemocyte-specific complement-like protein tep1 from the mosquito anopheles gambiae binds to and mediates killing of midgut stages of the rodent malaria parasite plasmodium berghei. the dsrna knockdown of tep1 in adults ...	2004	15006349
plasmodium berghei parasite transformed with green fluorescent protein for screening blood schizontocidal agents.	high priority has been given to new assays that facilitate and accelerate the development of novel antimalarial compounds. unlike evaluation of drugs in vitro, in which new approaches have been used to expedite identification of parasites, the conventional in vivo murine assay requires determination of parasitemia by light microscopy, an incompatible technique to test large numbers of drugs. we have investigated the possibility of using an autonomously fluorescent plasmodium berghei strain, stab ...	2004	15013738
isonicotinic acid hydrazide: an anti-tuberculosis drug inhibits malarial transmission in the mosquito gut.	we studied the transmission-blocking effect of isonicotinic acid hydrazide (inh), a widely used anti-tuberculosis drug, against plasmodium gallinaceum and plasmodium berghei. inh-treatment of infected animals did not inhibit parasite development in the blood of the vertebrate host, but did inhibit exflagellation, ookinete formation, and oocyst development in the mosquito. oocyst development was inhibited in a dose-dependent manner. the ed(50) in the p. gallinaceum/chicken/aedes aegypti model and ...	2004	15013786
transcriptional profiling reveals suppressed erythropoiesis, up-regulated glycolysis, and interferon-associated responses in murine malaria.	the primary pathophysiological events contributing to fatal malaria are the cerebral syndrome, anemia, and lactic acidosis. the molecular basis of each event has been unclear. in the present study, microarray analysis of murine transcriptional responses during the development of severe disease revealed temporal, organ-specific, and pathway-specific patterns. more than 400 genes in the brain and 600 genes in the spleen displayed transcriptional changes. dominant patterns revealed strongly suppres ...	2004	15031794
parasitology. new ways to control malaria.		2004	15044794
effects of mosquito genes on plasmodium development.	malaria parasites must complete a complex developmental cycle in an anopheles mosquito vector before transmission to a vertebrate host. sexual development of the parasite in the midgut is initiated in the lumen immediately after the mosquito ingests infected blood, and the resulting ookinetes must traverse the surrounding epithelial layer before transforming into oocysts. the innate immune system of the mosquito is activated during midgut invasion, but to date, no evidence has been published ide ...	2004	15044804
efficacy and pharmacokinetics of intravenous nanocapsule formulations of halofantrine in plasmodium berghei-infected mice.	the efficacy and pharmacokinetics of a new parenteral formulation of halofantrine were studied in mice infected with plasmodium berghei. the formulation consisted of nanocapsules with an oily core, prepared from either poly(d,l-lactide) (pla) homopolymer or pla that was surface modified with grafted polyethylene glycol chains. they were compared with a previously described intravenous halofantrine preparation. no toxic effects were observed with halofantrine in form of nanocapsules after intrave ...	2004	15047523
ctla-4-dependent mechanisms prevent t cell induced-liver pathology during the erythrocyte stage of plasmodium berghei malaria.	during the course of malaria several organs develop pathology. frequently also signs of hepatocyte damage are found. in the present work we studied the mechanisms leading to liver pathology during the erythrocyte stage of plasmodium berghei malaria. during infection, mice developed an inflammation of the liver, associated with infiltration of t cells, although only little tissue damage could be observed. histological analysis revealed the presence of ctl-associated antigen-4 (ctla-4)-positive t ...	2004	15048707
fitness of anopheline mosquitoes expressing transgenes that inhibit plasmodium development.	one potential strategy for the control of malaria and other vector-borne diseases is the introduction into wild vector populations of genetic constructs that reduce vectorial capacity. an important caveat of this approach is that the genetic construct should have minimal fitness cost to the transformed vector. previously, we produced transgenic anopheles stephensi expressing either of two effector genes, a tetramer of the sm1 dodecapeptide or the phospholipase a2 gene (pla2) from honeybee venom. ...	2004	15082552
contribution of cd1d-unrestricted hepatic dx5+ nkt cells to liver injury in plasmodium berghei-parasitized erythrocyte-injected mice.	inoculation with erythrocytes infected with plasmodium berghei, a protozoan causing mouse lethal malaria, induces liver injury in mice, although the parasite cannot invade host hepatocytes at this infectious stage. as previously reported, hepatic infiltrates participate in this liver injury by exerting their perforin-dependent killing action. here, we have investigated the cellular mechanisms underlying p. berghei-induced incidental liver injury. hepatic lymphocytes from p. berghei-infected mice ...	2004	15096477
comparative study of brain cd8+ t cells induced by sporozoites and those induced by blood-stage plasmodium berghei anka involved in the development of cerebral malaria.	to obtain insight into the mechanisms that contribute to the pathogenesis of plasmodium infections, we developed an improved rodent model that mimics human malaria closely by inducing cerebral malaria (cm) through sporozoite infection. we used this model to carry out a detailed study on isolated t cells recruited from the brains of mice during the development of cm. we compared several aspects of the immune response related to the experimental model of plasmodium berghei anka infection induced b ...	2004	15102792
analysis of the plasmodium and anopheles transcriptomes during oocyst differentiation.	understanding the life cycle of the malaria parasite in its mosquito vector is essential for developing new strategies to combat this disease. subtractive hybridization cdna libraries were constructed that are enriched for plasmodium berghei and anopheles stephensi genes expressed during oocyst differentiation on the midgut. sequencing of 1485 random clones led to the identification of 1137 unique expressed sequence tags. of the 608 expressed sequence tags with data base hits, 320 (53%) had sign ...	2004	14627711
analysis of the plasmodium and anopheles transcriptional repertoire during ookinete development and midgut invasion.	plasmodium, the causative agent of malaria, has to undergo sexual differentiation and development in anopheline mosquitoes for transmission to occur. to isolate genes specifically induced in both organisms during the early stages of plasmodium differentiation in the mosquito, two cdna libraries were constructed, one enriched for sequences expressed in differentiating plasmodium berghei ookinetes and another enriched for sequences expressed in anopheles stephensi guts containing invading ookinete ...	2004	14627712
selection and reversal of plasmodium berghei resistance in the mouse model following repeated high doses of artemether.	artemether, a derivative of artemisinin, is effectively used for the treatment of malaria without any clinically relevant resistance to date. artemether has also been developed as an antischistosomal agent, exhibiting highest activity against immature parasites. here, we employ a rodent model and investigate whether the proposed artemether treatment schedule to prevent schistosome-attributable morbidity might select for plasmodium berghei resistance. mice infected with an anka strain of p. bergh ...	2004	14677058
gene targeting demonstrates that the plasmodium berghei subtilisin pbsub2 is essential for red cell invasion and reveals spontaneous genetic recombination events.	the plasmodium merozoite proteases involved in the crucial process of erythrocyte invasion are promising targets for novel malaria control strategies. we report here the characterization of the subtilisin-like protease sub2 from the rodent parasites plasmodium berghei and plasmodium yoelii, leading the way to in vivo functional studies of this enzyme. the kinetics of expression and subcellular localization imply a central role for sub2 in erythrocyte invasion. through the use of gene targeting s ...	2004	14678331
mice deficient in interleukin-4 (il-4) or il-4 receptor alpha have higher resistance to sporozoite infection with plasmodium berghei (anka) than do naive wild-type mice.	balb/c interleukin-4 (il-4(-/-)) or il-4 receptor-alpha (il-4ralpha(-/-)) knockout (ko) mice were used to assess the roles of the il-4 and il-13 pathways during infections with the blood or liver stages of plasmodium in murine malaria. intraperitoneal infection with the blood-stage erythrocytes of plasmodium berghei (anka) resulted in 100% mortality within 24 days in balb/c mice, as well as in the mutant mouse strains. however, when infected intravenously with the sporozoite liver stage, 60 to 8 ...	2004	14688111
effects of bisphosphonates on the growth of entamoeba histolytica and plasmodium species in vitro and in vivo.	the effects of a series of 102 bisphosphonates on the inhibition of growth of entamoeba histolytica and plasmodium falciparum in vitro have been determined, and selected compounds were further investigated for their in vivo activity. forty-seven compounds tested were active (ic(50) < 200 microm) versus e. histolytica growth in vitro. the most active compounds (ic(50) approximately 4-9 microm) were nitrogen-containing bisphosphonates with relatively large aromatic side chains. simple n-alkyl-1-hy ...	2004	14695831
folate-synthesizing enzyme system as target for development of inhibitors and inhibitor combinations against candida albicans-synthesis and biological activity of new 2,4-diaminopyrimidines and 4'-substituted 4-aminodiphenyl sulfones.	the paper describes the design, synthesis, and testing of inhibitors of folate-synthesizing enzymes and of whole cell cultures of candida albicans. the target enzymes used were dihydropteroic acid synthase (syn) and dihydrofolate reductase (dhfr). several series of new 2,4-diaminopyrimidines were synthesized and tested as inhibitors of dhfr and compared with their activity against dhfr derived from mycobacteria and escherichia coli. to test for selectivity, also rat dhfr was used. a series of su ...	2004	14695838
8-quinolinamines conjugated with amino acids are exhibiting potent blood-schizontocidal antimalarial activities.	alanine, lysine, ornithine and valine conjugated to primaquine and other 8-quinolinamine antimalarials were prepared for blood-schizontocidal antimalarial activity evaluation. the analogues were examined in vivo against plasmodium berghei (drug-sensitive strain) and plasmodium yoelii nigeriensis (highly virulent multi-drug-resistant strain) infected mice models. n(1)-[4-(5-butoxy-4-ethyl-6-methoxy-8-quinolylamino)pentyl]-(2s)-2,6-diaminohexanamide (20) which showed curative activity at 5mg/kg in ...	2004	14697789
discovery of a bulky 2-tert-butyl group containing primaquine analogue that exhibits potent blood-schizontocidal antimalarial activities and complete elimination of methemoglobin toxicity.	to eliminate an unwarranted metabolic pathway of the quinoline ring, a set of two compounds, where c-2 position of the antimalarial drug primaquine is blocked by metabolically stable bulky alkyl group are synthesized. compound 2 [r = c(ch(3))(3)] of the series has produced excellent antimalarial efficacy against p. berghei and highly virulent multidrug-resistant p. yoelii nigeriensis strain in vivo. compound 2 was also evaluated for methemoglobin (methb) toxicity. this study describes the discov ...	2004	14711300
cell-passage activity is required for the malarial parasite to cross the liver sinusoidal cell layer.	liver infection is an obligatory step in malarial transmission, but it remains unclear how the sporozoites gain access to the hepatocytes, which are separated from the circulatory system by the liver sinusoidal cell layer. we found that a novel microneme protein, named sporozoite microneme protein essential for cell traversal (spect), is produced by the liver-infective sporozoite of the rodent malaria parasite, plasmodium berghei. targeted disruption of the spect gene greatly reduced sporozoite ...	2004	14737184
the pharmacodynamic study of a potent new antimalarial (mc1).	2,3-bis(trifluoromethyl)-4-(3-hydroxyquinuclidinylquinoline) or mc(1) is a new synthetic compound with potent antimalarial activity in vitro and in vivo studies. the ic(50) values of mc(1) and chloroquine in in vitro culture of plasmodium falciparum are 7.0x10(-8) and 6.06x10(-7)m, respectively. in an in vivo study using plasmodium berghei infected mice as the test model, the survival time of the infected mice without drug treatment was 6.00+0.58 days. chloroquine and mc(1) at an equal dose of 7 ...	2004	14744560
naphthoquine phosphate and its combination with artemisinine.	naphthoquine phosphate and artemisinine are two antimalarials developed in china. both drugs have proven to be efficacious and well tolerated as monotherapy as well as in combination in patients suffering from malaria. the co-naphthoquine, a novel antimalarial combination, is an oral fixed combination tablet of the naphthoquine phosphate and artemisinine. artemisinin is characterised by a rapid onset of schizonticidal action and a short half-life. parasite clearance is, however, often incomplete ...	2004	14744564
a new modular protein of cryptosporidium parvum, with ricin b and lccl domains, expressed in the sporozoite invasive stage.	the recombinant sa35 peptide has been described as an antigenic portion of a larger cryptosporidium parvum protein. we identified and characterized the encoding cpa135 gene and the entire protein, cpa135. the cpa135 gene was found to consist of a single exon of 4671 bp, and the mrna transcribed in the sporozoites was identified. the predicted 1556 amino-acid protein showed the presence of domains which are widely conserved also in other unrelated phylogenetic groups (i.e. a ricin b and a lccl mo ...	2004	14747151
protection of mice infected with plasmodium berghei by bacillus thuringiensis crystal proteins.	eight bacillus thuringiensis strains were used to test their activity against plasmodium berghei. when crystal proteins extracted from strains 007, 017, 020, 021, 030, 032, and 037 were injected into plasmodium-infected mice through the tail vein at a rate of 0.45-1.5 mg per mouse, the lengths of survival for the mice were extended up to 5 days (from 8.5 days to 13.5-15 days). blood-cell staining demonstrated that normal erythrocytes were lightly stained and regularly shaped while the erythrocyt ...	2004	14600831
identification and expression analysis of abc genes in plasmodium yoelii and p. berghei.	the atp-binding cassette (abc) proteins are one of the largest evolutionarily conserved families. they are characterized by the presence of highly conserved nucleotide-binding sites (nbs). in the present study, we identified abc genes in rodent plasmodia. we queried the plasmodium yoelii genome with the abc signature motif and retrieved 15 contigs. sequences were classified into seven abc families by blast comparison. conservation of the five signature abc motifs in the p. yoelii contigs was exa ...	2004	14564508
invariant valpha14 chain nkt cells promote plasmodium berghei circumsporozoite protein-specific gamma interferon- and tumor necrosis factor alpha-producing cd8+ t cells in the liver after poxvirus vaccination of mice.	understanding the protective mechanism in the liver induced by recombinant vaccines against the pre-erythrocytic stages of malaria is important for vaccine development. most studies in mice have focused on splenic and peripheral blood t cells and identified gamma interferon (ifn-gamma)-producing cd8+ t cells as correlates of protection, which can be induced by prime-boost vaccination with recombinant poxviruses. invariant natural killer t (valpha14inkt) cells can also protect against liver stage ...	2005	15664925
synergistic antimalarial activity of ketones with rufigallol and vitamin c.	malaria remains a major cause of human morbidity and mortality worldwide. plasmodium falciparum, the most virulent of the 4 human plasmodium species causing malaria, is potentially life threatening, is increasing in prevalence and is becoming even more resistant to in-use drugs. in light of the growing problem of multi-drug resistance to malarial parasites, the development of new drugs or the use of a combination therapy is of primary importance. a previous report describes a remarkable synergis ...	2005	16174410
plasmodium berghei resists killing by reactive oxygen species.	reactive oxygen species (ros) are widely believed to kill malarial parasites. c57bl/6 mice injected with p. berghei inocula incubated with supraphysiological doses of no (< or =150 microm) or with peroxynitrite (220 microm), however, exhibited parasitemia similar to that seen with those given control inocula, and there was no difference in disease development. only treatment of inocula with no doses nearing saturation (> or =1.2 mm) resulted in no detectable parasitemia in the recipients; flow c ...	2005	16177347
curcumin for malaria therapy.	malaria remains a major global health concern. new, inexpensive, and effective antimalarial agents are urgently needed. here we show that curcumin, a polyphenolic organic molecule derived from turmeric, inhibits chloroquine-resistant plasmodium falciparum growth in culture in a dose dependent manner with an ic(50) of approximately 5 microm. additionally, oral administration of curcumin to mice infected with malaria parasite (plasmodium berghei) reduces blood parasitemia by 80-90% and enhances th ...	2005	15582601
plasmodium berghei: effect of protease inhibitors during gametogenesis and early zygote development.	plasmodium berghei: the effect of five protease inhibitors, tpck, tlck, pmsf, leupeptin, and 1,10-phenanthroline on in vitro gametogenesis and early zygote development of p. berghei was investigated. pmsf and leupeptin showed no effect. cysteine/serine protease inhibitors tpck/tlck at concentrations of 75 and 100 microm were effective on inhibiting exflagellation center formation, and this effect was reversible with the addition of l-cysteine. exflagellation center formation was most effectively ...	2005	16198343
mutational analysis of the gpi-anchor addition sequence from the circumsporozoite protein of plasmodium.	the plasma membrane of plasmodium sporozoites is uniformly covered by the glycosylphosphatidylinositol (gpi)-anchored circumsporozoite (cs) protein. sporozoites form in the mosquito midgut through a budding process that occurs within a multinucleate oocyst underneath the basal lamina of the gut. earlier genetic studies established that normal sporozoite development requires cs. mutant parasites lacking cs [cs (-)] do not form sporozoites. ultrastructural analysis of the oocysts from these parasi ...	2005	16207248
the liver stage of plasmodium berghei inhibits host cell apoptosis.	plasmodium berghei is the causative agent of rodent malaria and is widely used as a model system to study the liver stage of plasmodium parasites. the entry of p. berghei sporozoites into hepatocytes has extensively been studied, but little is known about parasite-host interaction during later developmental stages of the intracellular parasite. growth of the parasite far beyond the normal size of the host cell is an important stress factor for the infected cell. cell stress is known to trigger p ...	2005	16238623
antimalarial drug synergism and antagonism: mechanistic and clinical significance.	interactions between antimicrobial agents provide clues as to their mechanisms of action and influence the combinations chosen for therapy of infectious diseases. in the treatment of malaria, combinations of drugs, in many cases acting synergistically, are increasingly important in view of the frequency of resistance to single agents. the study of antimalarial drug interactions is therefore of great significance to both treatment and research. it is therefore worrying that the analysis of drug-i ...	2005	16243458
an immune-responsive serpin, srpn6, mediates mosquito defense against malaria parasites.	we have functionally analyzed the orthologous srpn6 genes from anopheles stephensi and anopheles gambiae using phylogenetic, molecular, reverse genetic, and cell biological tools. the results strongly implicate srpn6 in the innate immune response against plasmodium. this gene belongs to a mosquito-specific gene cluster including three additional anopheles serpins. srpn6 expression is induced by escherichia coli and both rodent and human malaria parasites. the gene is specifically expressed in mi ...	2005	16260729
towards systematic identification of plasmodium essential genes by transposon shuttle mutagenesis.	after the deciphering of the genome sequences of several plasmodium species, efforts must turn to elucidating gene function and identifying essential gene products. however, random approaches are lacking and gene targeting is inefficient in plasmodium. here, we established shuttle transposon mutagenesis in plasmodium berghei. we constructed a mini-tn5 derivative that can transpose into parasite genes cloned in escherichia coli, providing an efficient means of generating knockout fragments. a 10( ...	2005	16284199
cell- rather than antibody-mediated immunity leads to the development of profound thrombocytopenia during experimental plasmodium berghei malaria.	experimental malarial thrombocytopenia can reach life-threatening levels and is believed to be due to abs targeting platelets for destruction by the reticuloendothelial system. however, we report that abs account for at most 15% of platelet destruction as plasmodium berghei-infected b cell-deficient mice exhibited profound thrombocytopenia (83%) as did c57bl/6 controls (98%). further, no significant increase in abs bound to intact platelets was observed during infection. p. berghei infection can ...	2005	16301680
antimalarial activities of new pyrrolo[3,2-f]quinazoline-1,3-diamine derivatives.	wr227825 is an antimalarial pyrroloquinazolinediamine derivative with a high potency but a low therapeutic index. a series of carbamate, carboxamide, succinimide, and alkylamine derivatives of wr227825 were prepared to search for compounds with an improved therapeutic index. the new acetamides and imide showed potent cell growth inhibition against four clones of plasmodium falciparum (d-6, rcs, w-2, and tm91c235), with a 50% inhibitory concentration of approximately 0.01 ng/ml, and were highly a ...	2005	16304154
an atypical mitogen-activated protein kinase controls cytokinesis and flagellar motility during male gamete formation in a malaria parasite.	the transmission of malaria parasites to the mosquito depends critically on the rapid initiation of sexual reproduction in response to triggers from the mosquito midgut environment. we here identify an essential function for an atypical mitogen-activated protein kinase of the rodent malaria parasite plasmodium berghei, pbmap-2, in male sexual differentiation and parasite transmission to the mosquito. a deletion mutant no longer expressing the pbmap-2 protein develops as wild type throughout the ...	2005	16313614
synthesis and antimalarial activity of new 3-arylquinoxaline-2-carbonitrile derivatives.	new series of 3-arylquinoxaline-carbonitrile derivatives have been synthesized from various 5-substituted or 5,6-disubstituted benzofuroxanes and tested for their in vitro and in vivo activity against the erythrocytic development of plasmodium falciparum strain with different chloroquine-resistance status. quinoxaline 1,4-dioxide derivatives showed superior antimalarial activity in respect to reduced quinoxaline analogues. the best activity was observed with nonsubstituted quinoxaline 1,4-dioxid ...	2005	16430030
[recent advances in the study of artemisinin-related 1,2,4-trioxanes and ozonides (1,2,4-trioxolanes) as antimalarials].		2005	16496665
synthesis of 2-azabicyclo[3.2.2]nonanes from bicyclo[2.2.2]octan-2-ones and their activities against trypanosoma brucei rhodesiense and plasmodium falciparum k1.	new 2-azabicyclo[3.2.2]nonanes were prepared from antiprotozoal bicyclo[2.2.2]octan-2-ones to investigate the influence of the replacement of the rigid bicyclo-octane structure by the more flexible bicyclo-nonane system on the antiplasmodial and antitrypanosomal activity.	2005	16401404
immunopathological consequences of the loss of engulfment genes: the case of abca1.	programmed cell death plays a crucial role in the maintenance of cell homeostasis. an initial, effector phase leads to the generation of apoptotic corpses and is closely followed by a swift clearance by professional or amateur phagocytes. several aspects distinguish this latter process of engulfment of dying cells from the classical forms of phagocytosis. they concern all aspects of the process from the recognition of the prey to the final outcome, i.e. immunological silence. the engulfment of d ...	2005	16471259
midgut epithelial responses of different mosquito-plasmodium combinations: the actin cone zipper repair mechanism in aedes aegypti.	in vivo responses of midgut epithelial cells to ookinete invasion of three different vector-parasite combinations, aedes aegypti-plasmodium gallinaceum, anopheles stephensi-plasmodium berghei, and a. stephensi-p. gallinaceum, were directly compared by using enzymatic markers and immunofluorescence stainings. our studies indicate that, in a. aegypti and a. stephensi ookinetes traverse the midgut via an intracellular route and inflict irreversible damage to the invaded cells. these two mosquito sp ...	2005	15753303
genome update: base skews in 200+ bacterial chromosomes.		2005	15758208
hgf/met signalling protects plasmodium-infected host cells from apoptosis.	plasmodium, the causative agent of malaria, migrates through several hepatocytes before initiating a malaria infection. we have previously shown that this process induces the secretion of hepatocyte growth factor (hgf) by traversed cells, which renders neighbour hepatocytes susceptible to infection. the signalling initiated by hgf through its receptor met has multifunctional effects on various cell types. our results reveal a major role for apoptosis protection of host cells by hgf/met signallin ...	2005	15760460
chemosensitizing action of cepharanthine against drug-resistant human malaria, plasmodium falciparum.	we have established a system of in vitro and in vivo assays to prioritize plant extracts that can serve as a source of drug candidates for the treatment of malaria, an infectious disease that affects nearly 40% of the world's population. in the present study, we have investigated the biological potential of one such plant-derived drug lead, cepharanthine. in vitro growth inhibition studies indicated this compound possessed good antiplasmodial activity without mediating a cytotoxic response. base ...	2005	15763374
a strong cd8+ t cell response is elicited using the synthetic polypeptide from the c-terminus of the circumsporozoite protein of plasmodium berghei together with the adjuvant qs-21: quantitative and phenotypic comparison with the vaccine model of irradiated sporozoites.	stable protective immunity can be achieved against malaria by the injection of radiation-attenuated sporozoites (gamma-spz) and is mediated by ifn-gamma producing cd8+ t cells targeting the pre-erythrocytic stages. an efficient malaria vaccine should mimic this immunity. we compared the immune response specific for the circumsporozoite protein (csp) of plasmodium berghei (p. berghei), an important target of this protective response, elicited in mice immunized with the long synthetic polypeptide ...	2005	15780728
the natural killer complex regulates severe malarial pathogenesis and influences acquired immune responses to plasmodium berghei anka.	the natural killer complex (nkc) is a genetic region of highly linked genes encoding several receptors involved in the control of nk cell function. the nkc is highly polymorphic, and allelic variability of various nkc loci has been demonstrated in inbred mice. making use of balb.b6-cmv1r congenic mice, in which the nkc from disease-susceptible c57bl/6 mice has been introduced into the disease-resistant balb/c background, we show here that during murine malaria infection, the nkc regulates a rang ...	2005	15784573
synthesis of some cryptolepine analogues, assessment of their antimalarial and cytotoxic activities, and consideration of their antimalarial mode of action.	a series of analogues of cryptolepine (1) have been synthesized and evaluated for their in vitro antiplasmodial and cytotoxic properties. the ic(50) values of several compounds (11a, 11k-m, 11o, 13) against plasmodium falciparum (strain k1) were <0.1 mum, 5-10-fold lower than that of 1 but their cytotoxicities were only 2-4 times greater than that of 1. compounds with a halogen in the quinoline ring and a halogen or a nitro group in the indole ring have enhanced antiplasmodial activity. in mice ...	2005	15801861
convenient access both to highly antimalaria-active 10-arylaminoartemisinins, and to 10-alkyl ethers including artemether, arteether, and artelinate.	an economical phase-transfer method is used to prepare 10-arylaminoartemisinins from dha and arylamines, and artemether, arteether, and artelinate from the corresponding alcohols. in vivo sc screens against plasmodium berghei and p. yoelii in mice reveal that the p-fluorophenylamino derivative 5 g is some 13 and 70 times, respectively, more active than artesunate; this reflects the very high sc activity of 10-alkylaminoartemisinins. however, through the po route, the compounds are less active th ...	2005	15812783
thalidomide influences the function of macrophages and increases the survival of plasmodium berghei-infected cba mice.	malaria remains a major cause of morbidity and mortality in vast areas of the world, mainly due to the severe forms of plasmodium falciparum infection. the exacerbated immune response, with increased production of tnf and reactive nitrogen and oxygen intermediates, plays a role in the complex pathogenesis of the disease. it is recognised that thalidomide decreases tnf production and may modulate several functions of the immune system. this work evaluated the influence of thalidomide on macrophag ...	2005	15817259
arrest in the liver--a genetically defined malaria vaccine?		2005	15829544
apoptotic plasmodium-infected hepatocytes provide antigens to liver dendritic cells.	malaria starts with infection of the host liver by plasmodium sporozoites. inoculation with radiation-attenuated plasmodium sporozoites induces complete protection against malaria. protection is mediated by dendritic cells (dcs) and cd8(+) t cells, but the source of parasite antigens mediating this response remains unclear. here, we show that hepatocytes infected with irradiated plasmodium sporozoites undergo apoptosis shortly after infection. infection with irradiated sporozoites induces the re ...	2005	15838783
motility and infectivity of plasmodium berghei sporozoites expressing avian plasmodium gallinaceum circumsporozoite protein.	avian and rodent malaria sporozoites selectively invade different vertebrate cell types, namely macrophages and hepatocytes, and develop in distantly related vector species. to investigate the role of the circumsporozoite (cs) protein in determining parasite survival in different vector species and vertebrate host cell types, we replaced the endogenous cs protein gene of the rodent malaria parasite plasmodium berghei with that of the avian parasite p. gallinaceum and control rodent parasite p. y ...	2005	15839899
the in vitro and in vivo antimalarial activity of cardiospermum halicacabum l. and momordica foetida schumch. et thonn.	two plants cardiospermum halicacabum l. and momordica foetida schumch. et thonn traditionally used to treat symptoms of malaria in parts of east and central africa were screened for in vitro and in vivo antimalarial activity. using the nitro tetrazolium blue-based parasite lactate dehydrogenase assay as used by [makler, m.t., ries, j.m., williams, j.a., bancroft, j.e., piper, r.c., gibbins, b.l., hinrichs, d.j., 1993. parasite lactate dehydrogenase as an assay for plasmodium falciparum drug sens ...	2005	15848033
[automatic analysis of micronuclei by flow cytometry using anti-cd71-fitc and pi staining].	to explore flow cytometry (fcm) based method for automatic analysis of micronuclei (mn) in cells staining with anti-cd71-fitc and pi.	2005	15862014
a mitogen-activated protein kinase regulates male gametogenesis and transmission of the malaria parasite plasmodium berghei.	differentiation of malaria parasites into sexual forms (gametocytes) in the vertebrate host and their subsequent development into gametes in the mosquito vector are crucial steps in the completion of the parasite's life cycle and transmission of the disease. the molecular mechanisms that regulate the sexual cycle are poorly understood. although several signal transduction pathways have been implicated, a clear understanding of the pathways involved has yet to emerge. here, we show that a plasmod ...	2005	15864297
direct processing and presentation of antigen from malaria sporozoites by professional antigen-presenting cells in the induction of cd8 t-cell responses.	irradiated malaria sporozoites induce better protection than viable untreated sporozoites. we observed early differences between irradiated and viable untreated sporozoites in priming responses in vivo to a protective cd8 t-cell epitope, pb9, of the circumsporozoite protein of plasmodium berghei. sporozoites were processed for mhc class i presentation by dendritic cells (dc) to prime pb9-specific ifn-gamma-producing cd8 t cells. dc pulsed with untreated and irradiated sporozoites were similarly ...	2005	15877610
synthesis and antimalarial activity of e-2-quinolinylbenzocycloalcanones.	a series of e-2-quinolinylbenzocycloalcanones 5-21 were prepared and evaluated for their activity to inhibit beta-hematin formation and the hydrolysis of hemoglobin in vitro. positive compounds for both assays were also tested for their efficacy in rodent plasmodium berghei. compounds 6, 16, 19, and 20, were the most promising. inhibition of beta-hematin formation was minimal when a hydrogen or methoxy groups were present on the position 8 of the quinoline and position 4' of the indanone ring as ...	2005	15878218
brain macrophage activation in murine cerebral malaria precedes accumulation of leukocytes and cd8+ t cell proliferation.	although the activation of brain macrophages is associated with both human and mouse cerebral malaria (cm) the relative contributions of the heterogeneous populations of brain macrophages to the disease are unknown. in this work, we dissociate for the first time inflammatory monocytes from resident brain macrophages in mice developing cm when infected with plasmodium berghei. based on the differential expression of cd45 in brain macrophage cell populations and by using bone-marrow (bm) chimeras ...	2005	15885309
synthesis and evaluation of new antimalarial phenylurenyl chalcone derivatives.	phenylurenyl chalcone derivatives have been synthesized and tested as inhibitors of in vitro development of a chloroquine-resistant strain of plasmodium falciparum, activity of the cysteine protease falcipain-2, in vitro globin hydrolysis, beta-hematin formation, and murine plasmodium berghei malaria. the most active antimalarial compound was 1-[3'-n-(n'-phenylurenyl)phenyl]-3(3,4,5-trimethoxyphenyl)-2-propen-1-one 49, with an ic(50) of 1.76 microm for inhibition of p. falciparum development. re ...	2005	15887974
ookinete-induced midgut peroxidases detonate the time bomb in anopheline mosquitoes.	previous analysis of the temporal-spatial relationship between ookinete migration and the cellular localization of genes mediating midgut immune defense responses suggested that, in order to survive, parasites must complete invasion before toxic chemicals ("a bomb") are generated by the invaded cell. recent studies indicate that ookinete invasion induces tyrosine nitration as a two-step reaction, in which nos induction is followed by a localized increase in peroxidase activity. peroxidases utili ...	2005	15894189
fas has a role in cerebral malaria, but not in proliferation or exclusion of the murine parasite in mice.	we examined the susceptibility of murine fas-deficient mutants to malaria infection in order to investigate the role of fas in an experimental murine model of cerebral malaria (cm). we infected mice of b6 and cba wild-type and mutant backgrounds with plasmodium berghei anka. the incidence of cm in the mutant mice (b6-lpr, cba-lprcg) was decreased by about 50% compared with wild-type control strains at 2 weeks after infection. we did not observe significant differences of parasitemia during a mur ...	2005	15900502
intravital observation of plasmodium berghei sporozoite infection of the liver.	plasmodium sporozoite invasion of liver cells has been an extremely elusive event to study. in the prevailing model, sporozoites enter the liver by passing through kupffer cells, but this model was based solely on incidental observations in fixed specimens and on biochemical and physiological data. to obtain direct information on the dynamics of sporozoite infection of the liver, we infected live mice with red or green fluorescent plasmodium berghei sporozoites and monitored their behavior using ...	2005	15901208
transcriptome analysis of anopheles stephensi-plasmodium berghei interactions.	simultaneous microarray-based transcription analysis of 4987 anopheles stephensi midgut and plasmodium berghei infection stage specific cdnas was done at seven successive time points: 6, 20 and 40h, and 4, 8, 14 and 20 days after ingestion of malaria infected blood. the study reveals the molecular components of several anopheles processes relating to blood digestion, midgut expansion and response to plasmodium-infected blood such as digestive enzymes, transporters, cytoskeletal and structural co ...	2005	15907562
protein farnesyltransferase inhibitors exhibit potent antimalarial activity.	new therapeutics to combat malaria are desperately needed. here we show that the enzyme protein farnesyltransferase (pft) from the malaria parasite plasmodium falciparum (p. falciparum) is an ideal drug target. pft inhibitors (pftis) are well tolerated in man, but are highly cytotoxic to p. falciparum. because of their anticancer properties, pftis comprise a highly developed class of compounds. pftis are ideal for the rapid development of antimalarials, allowing "piggy-backing" on previously gar ...	2005	15916422
reduced cerebral blood flow and n-acetyl aspartate in a murine model of cerebral malaria.	cerebral malaria is an important cause of morbidity and mortality in many parts of the world. it has been suggested that cerebral malaria is associated with reduced perfusion due to the blockage of blood vessels by parasitized erythrocytes; although, no quantitative validation of this has been done. we infected c57bl/6 mice with the anka strain of plasmodium berghei and on day 6 of infection we investigated alterations in brain function using arterial spin labeling mri and proton mrs. mr images ...	2005	15918069
cassane- and norcassane-type diterpenes from caesalpinia crista of indonesia and their antimalarial activity against the growth of plasmodium falciparum.	the ch2cl2 extract of the seed kernels of caesalpinia crista, which exhibited promising antimalarial activity against plasmodium berghei-infected mice in vivo, was examined and resulted in the isolation of seven new furanocassane-type diterpenes [caesalpinins c-g (1-5) and norcaesalpinins d and e (6, 7)] together with norcaesalpinins a-c (8-10) and 11 known compounds (norcaesalpinins a-c, 2-acetoxy-3-deacetoxycaesaldekarin e, caesalmin b, caesaldekarin e, caesalpin f, 14(17)-dehydrocaesalpin f, ...	2005	15921414
genetically modified plasmodium highlights the potential of whole parasite vaccine strategies.	a genetically modified malaria sporozoite might breathe new life into the traditional approach to vaccine development, that of using whole organisms. mueller and colleagues recently knocked out a gene, uis3, from the rodent parasite, plasmodium berghei, and demonstrated that the sporozoite forms could not develop beyond the stage of the life cycle in the liver (thus not giving rise to clinical disease, which is associated with blood infection) but could induce protection against subsequent chall ...	2005	15922944
driving midgut-specific expression and secretion of a foreign protein in transgenic mosquitoes with agaper1 regulatory elements.	the anopheles gambiae adult peritrophic matrix protein 1 (agaper1) regulatory elements were used to drive the expression of phospholipase a2 (pla2), a protein known to disrupt malaria parasite development in mosquitoes. these agaper1 regulatory elements were sufficient to promote the accumulation of pla2 in midgut epithelial cells before a blood meal and its release into the lumen upon blood ingestion. plasmodium berghei oocyst formation was reduced by approximately 80% (74-91% range) in transge ...	2005	15926896
synthesis and evaluation of beta-carbolinium cations as new antimalarial agents based on pi-delocalized lipophilic cation (dlc) hypothesis.	several beta-carbolines including naturally occurring substances and their corresponding cationic derivatives were synthesized and evaluated for antimalarial (antiplasmodial) activity in vitro and in vivo. a tetracyclic carbolinium salt was elucidated for antileishmanial and antitrypanosomal activities in vitro as well as antiplasmodial activity. quarternary carbolinium cations showed much higher potencies in vitro than electronically neutral beta-carbolines and a good correlation was observed b ...	2005	15930777
revealing the molecular determinants of gender in malaria parasites.	malaria parasites have a complex life cycle with asexual multiplication in a vertebrate host and obligate sexual reproduction in the mosquito; however, commitment to sexual development begins in the vertebrate with differentiation of female and male gametocytes. in this issue of cell, khan et al. (2005) used elegant approaches to purify male and female gametocytes and elucidated their respective proteome, providing the basis for understanding sexual development in this pathogen.	2005	15935749
proteome analysis of separated male and female gametocytes reveals novel sex-specific plasmodium biology.	gametocytes, the precursor cells of malaria-parasite gametes, circulate in the blood and are responsible for transmission from host to mosquito vector. the individual proteomes of male and female gametocytes were analyzed using mass spectrometry, following separation by flow sorting of transgenic parasites expressing green fluorescent protein, in a sex-specific manner. promoter tagging in transgenic parasites confirmed the designation of stage and sex specificity of the proteins. the male proteo ...	2005	15935755
supplementation of cxcl12 (cxcl12) induces homing of cd11c+ dendritic cells to the spleen and enhances control of plasmodium berghei malaria in balb/c mice.	in malaria, parasitaemia is controlled in the spleen, a multicomponent organ that undergoes changes in its cellular constituents to control the parasite. during this process, dendritic cells (dcs) orchestrate the positioning of effector cells in a timely manner for optimal parasite clearance. we have recently demonstrated that cxcl12 [stromal cell-derived factor-1 (cxcl12)] supplementation partially restores the ability to control parasitaemia in plasmodium berghei-infected mice. in the present ...	2005	15946257
plasmodium berghei ookinetes bind to anopheles gambiae and drosophila melanogaster annexins.	using a proteomic approach we identified polypeptides from anopheles gambiae and drosophila melanogaster protein extracts that selectively bind purified plasmodium berghei ookinetes in vitro; these were two and three distinct polypeptides, respectively, with an apparent molecular weight of about 36 kda. combining two-dimensional electrophoresis and maldi-tof (matrix-associated laser desorption ionization time of flight) mass spectrometry we determined that the polypeptides correspond to isomorph ...	2005	15948958
antimalarial activities and toxicities of three plants used as traditional remedies for malaria in the democratic republic of congo: croton mubango , nauclea pobeguinii and pyrenacantha staudtii.	the antimalarial activities of crude extracts and 17 fractions from the partition of 80%-methanolic extracts of three plants (the stem bark of croton mubango, the stem bark of nauclea pobeguinii and the leaves of pyrenacantha staudtii) used as antimalarial remedies in the democratic republic of congo were studied both in vitro (against plasmodium falciparum) and in mice infected with pl. berghei berghei. the toxic effects of dried aqueous extracts of the plants were also investigated, in uninfec ...	2005	15949182
dispiro-1,2,4-trioxane analogues of a prototype dispiro-1,2,4-trioxolane: mechanistic comparators for artemisinin in the context of reaction pathways with iron(ii).	single electron reduction of the 1,2,4-trioxane heterocycle of artemisinin (1) forms primary and secondary carbon-centered radicals. the complex structure of 1 does not lend itself to a satisfactory dissection of the electronic and steric effects that influence the formation and subsequent reaction of these carbon-centered free radicals. to help demarcate these effects, we characterized the reactions of achiral dispiro-1,2,4-trioxolane 4 and dispiro-1,2,4-trioxanes 5-7 with ferrous bromide and 4 ...	2005	15960511
plasmodium berghei nk65: studies on the effect of treatment duration and inoculum size on recrudescence.	recrudescence of plasmodium berghei nk65 infection was studied to examine factors affecting recrudescence. treatment with a high dose of chloroquine did not prevent recrudescence, but an extended duration of treatment suppressed the frequency of recrudescence. infection with a larger number of parasites also resulted in more frequent recrudescences. recrudescent parasites were as sensitive to chloroquine as those before treatment. splenectomized mice were administered carbon particles, infected, ...	2005	15961077
laminin and the malaria parasite's journey through the mosquito midgut.	during the invasion of the mosquito midgut epithelium, plasmodium ookinetes come to rest on the basal lamina, where they transform into the sporozoite-producing oocysts. laminin, one of the basal lamina's major components, has previously been shown to bind several surface proteins of plasmodium ookinetes. here, using the recently developed rnai technique in mosquitoes, we used a specific dsrna construct targeted against the lanb2 gene (laminin gamma1) of anopheles gambiae to reduce its mrna leve ...	2005	15961736
genetic control of parasite clearance leads to resistance to plasmodium berghei anka infection and confers immunity.	unprecedented cure after infection with the lethal plasmodium berghei anka was observed in an f2 progeny generated by intercrossing the wild-derived wla and the laboratory c57bl/6 mouse strains. resistant mice were able to clear parasitaemia and establish immunity. the observed resistance was disclosed as a combinatorial effect of genetic factors derived from the two parental strains. genetic mapping of survival time showed that the wla allele at a locus on chromosome 1 (colocalizing with berghe ...	2005	15973462
the complex interplay between mosquito positive and negative regulators of plasmodium development.	the malaria parasite, plasmodium, requires sexual development in the mosquito before it can be transmitted to the vertebrate host. mosquito genes are able to substantially modulate this process, which can result in major decreases in parasite numbers. even in susceptible mosquitoes, haemolymph proteins implicated in systemic immune reactions, together with local epithelial responses, cause lysis of more than 80% of the ookinetes that cross the mosquito midgut. in a refractory mosquito strain, im ...	2005	15996894
the immune status of kupffer cells profoundly influences their responses to infectious plasmodium berghei sporozoites.	multi-factorial immune mechanisms underlie protection induced with radiation-attenuated plasmodia sporozoites (gamma-spz). spz pass through kupffer cells (kc) before invading hepatocytes but the involvement of kc in protection is poorly understood. in this study we investigated whether gamma-spz-immune kc respond to infectious spz in a manner that is distinct from the response of naive kc to infectious spz. kc were isolated from (1) naive, (2) spz-infected, (3) gamma-spz-immune, and (4) gamma-sp ...	2005	15997465
the chemotherapy of rodent malaria. lxiii. drug combinations to impede the selection of drug resistance, part 6: the potential value of chlorproguanil and dapsone in combination, and with the addition of artesunate.	resistance is readily produced in rodent malaria using the single-dose, '2%-relapse technique' (2%rt) against the individual compounds chlorproguanil (cpg), chlorcycloguanil (ccg), cycloguanil, dapsone (dds) and artesunate (asn). using the '4-day test', a low level of synergism or a simple additional action between cpg and dds was observed with multiple dosing of these two compounds in a combination. resistance to a 1 : 3 combination of cpg-dds was selected in each of three parasite lines: plasm ...	2005	16004705
functional genomic analysis of midgut epithelial responses in anopheles during plasmodium invasion.	the malaria parasite plasmodium must complete a complex developmental life cycle within anopheles mosquitoes before it can be transmitted into the human host. one day after mosquito infection, motile ookinetes traverse the midgut epithelium and, after exiting to its basal site facing the hemolymph, develop into oocysts. previously, we have identified hemolymph factors that can antagonize or promote parasite development.	2005	16005290
differences in biochemical properties of the plasmodial falcipain-2 and berghepain-2 orthologues: implications for in vivo screens of inhibitors.	falcipain-2a, the cysteine protease of plasmodium falciparum has been proposed as a good drug target. this study evaluated the suitability of plasmodium berghei as the animal model and reports the first functional expression and characterization of the falcipain-2a orthologue, berghepain-2. comparative studies revealed that the orthologues exhibited different biochemical properties. berghepain-2 demonstrated optimal activity at a narrower ph optima of 5.5-6 and a lack of preference for substrate ...	2005	16019160
a malarial cysteine protease is necessary for plasmodium sporozoite egress from oocysts.	the plasmodium life cycle is a sequence of alternating invasive and replicative stages within the vertebrate and invertebrate hosts. how malarial parasites exit their host cells after completion of reproduction remains largely unsolved. inhibitor studies indicated a role of plasmodium cysteine proteases in merozoite release from host erythrocytes. to validate a vital function of malarial cysteine proteases in active parasite egress, we searched for target genes that can be analyzed functionally ...	2005	16027235
spiro and dispiro-1,2,4-trioxolanes as antimalarial peroxides: charting a workable structure-activity relationship using simple prototypes.	this paper describes the discovery of synthetic 1,2,4-trioxolane antimalarials and how we established a workable structure-activity relationship in the context of physicochemical, biopharmaceutical, and toxicological profiling. an achiral dispiro-1,2,4-trioxolane (3) in which the trioxolane is flanked by a spiroadamantane and spirocyclohexane was rapidly identified as a lead compound. nonperoxidic 1,3-dioxolane isosteres of 3 were inactive as were trioxolanes without the spiroadamantane. the tri ...	2005	16033274
how i became a biochemist.		2005	16036582
the proteasome inhibitor mln-273 blocks exoerythrocytic and erythrocytic development of plasmodium parasites.	protein degradation is regulated during the cell cycle of all eukaryotic cells and is mediated by the ubiquitin-proteasome pathway. potent and specific peptide-derived inhibitors of the 20s proteasome have been developed recently as anti-cancer agents, based on their ability to induce apoptosis in rapidly dividing cells. here, we tested a novel small molecule dipeptidyl boronic acid proteasome inhibitor, named mln-273 on blood and liver stages of plasmodium species, both of which undergo active ...	2005	16038394
phagocyte-derived reactive oxygen species do not influence the progression of murine blood-stage malaria infections.	phagocyte-derived reactive oxygen species have been implicated in the clearance of malaria infections. we investigated the progression of five different strains of murine malaria in gp91(phox-/-) mice, which lack a functional nadph oxidase and thus the ability to produce phagocyte-derived reactive oxygen species. we found that the absence of functional nadph oxidase in the gene knockout mice had no effect on the parasitemia or total parasite burden in mice infected with either resolving (plasmod ...	2005	16041008