Publications

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application of spect/ct imaging system and radiochemical analysis for investigation of blood kinetics and tissue distribution of radiolabeled plumbagin in healthy and plasmodium berghei-infected mice.plumbagin is a derivative of napthoquinone which is isolated from the roots of plants in several families. these compound exhibits a wide range of biological and pharmacological activities including antimalarial, antibacterial, antifungal, and anticancer activities. the aim of the study was to investigate blood kinetics and tissue distribution of plumbagin in healthy and plasmodium berghei-infected mice using single-photon emission computed tomography/computed tomography (spect/ct) and radiochem ...201626713669
evaluation of the use of ocimum suave willd. (lamiaceae), plectranthus barbatus andrews (lamiaceae) and zanthoxylum chalybeum engl. (rutaceae) as antimalarial remedies in kenyan folk medicine.crude extracts from the leaves of ocimum suave willd (lamiaceae) and the root barks of plectranthus barbatus andrews (lamiaceae) and zanthoxylum chalybeum engl. (rutaceae) were studied to ascertain the ethnopharmacological standing of their antimalarial usage in kenyan folk medicine.201626705665
tap-mediated processing of exoerythrocytic antigens is essential for protection induced with radiation-attenuated plasmodium sporozoites.mhc class i dependent cd8(+) t cells are essential for protection induced by radiation-attenuated plasmodium sporozoites (ras) in murine malaria models. apart from the mechanism of activation of cd8(+) t cells specific for the circumsporozoite protein, the major sporozoite antigen (ag), cd8(+) t cells specific for other exoerythrocytic ags that have been shown to mediate protection have not been thoroughly investigated. specifically, mechanisms of processing and presentation of exoerythrocytic a ...201626703789
mutation tendency of mutator plasmodium berghei with proofreading-deficient dna polymerase δ.in this study, we investigated the mutation tendency of a mutator rodent malaria parasite, plasmodium berghei, with proofreading-deficient dna polymerase δ. wild-type and mutator parasites were maintained in mice for over 24 weeks, and the genome-wide accumulated mutations were determined by high-throughput sequencing. the mutator p. berghei had a significant preference for c/g to a/t substitutions; thus, its genome had a trend towards a higher at content. the mutation rate was influenced by the ...201627845384
a neuroprotective effect of the glutamate receptor antagonist mk801 on long-term cognitive and behavioral outcomes secondary to experimental cerebral malaria.cerebral malaria (cm) is a life-threatening complication of plasmodium falciparum infection, which can result in long-term cognitive and behavioral deficits despite successful anti-malarial therapy. due to the substantial social and economic burden of cm, the development of adjuvant therapies is a scientific goal of highest priority. apart from vascular and immune responses, changes in glutamate system have been reported in cm pathogenesis suggesting a potential therapeutic target. based on that ...201627796746
route of administration of attenuated sporozoites is instrumental in rendering immunity against plasmodia infection.whole sporozoite vaccine (wsv) approach has been shown to induce efficient cd8(+) t cell response, critical for developing of long-lasting sterile protection against plasmodium. although wsv was initiated over four decades ago, we still do not fully understand about the absolute requirements for the generation of liver-stage specific cd8(+) t memory cells. for more than a decade intravenous (iv) route of immunization has been shown to be protective in pre-clinical studies. however, the intraderm ...201627160038
identifying antimalarial compounds targeting dihydrofolate reductase-thymidylate synthase (dhfr-ts) by chemogenomic profiling.the mode of action of many antimalarial drugs is unknown. chemogenomic profiling is a powerful method to address this issue. this experimental approach entails disruption of gene function and phenotypic screening for changes in sensitivity to bioactive compounds. here, we describe the application of reverse genetics for chemogenomic profiling in plasmodium. plasmodium falciparum parasites harbouring a transgenic insertion of the glms ribozyme downstream of the dihydrofolate reductase-thymidylate ...201627150044
cysteamine broadly improves the anti-plasmodial activity of artemisinins against murine blood stage and cerebral malaria.the potential emergence and spread of resistance to artemisinins in the plasmodium falciparum malaria parasite constitutes a major global health threat. hence, improving the efficacy of artemisinins and of artemisinin-based combination therapy (act) represents a major short-term goal in the global fight against malaria. mice defective in the enzyme pantetheinase (vnn3) show increased susceptibility to blood-stage malaria (increased parasitaemia, reduced survival), and supplementation of vnn3 mut ...201627150250
development of artemether and lumefantrine co-loaded nanostructured lipid carriers: physicochemical characterization and in vivo antimalarial activity.artemether and lumefantrine combination therapy is well-accepted for uncomplicated malaria treatment. however, the current available formulation has several pharmacokinetic mismatches such as drug degradation in gastrointestinal tract, erratic absorption, etc. hence, need of the hour is the injectable formulation, which can overcome the pharmacokinetic mismatch associated with current available formulation in the market.201624786480
asiatic acid influences glucose homeostasis in p. berghei murine malaria infected sprague-dawley rats.glucose homeostasis derangement is a common pathophysiology of malaria whose aetiology is still controversial. the plasmodium parasite, immunological and inflammatory responses, as well as chemotherapeutics currently used cause hypoglycaemia in malaria. anti-parasitic and anti-disease drugs are required to combat malaria while ameliorating the pathophysiology of the infection. asiatic acid has anti-hyperglycaemic, antioxidant, pro-oxidant properties useful in glucose homeostasis but its influenc ...201628487899
host cell autophagy contributes to plasmodium liver development.autophagy plays an important role in the defence against intracellular pathogens. however, some microorganisms can manipulate this host cell pathway to their advantage. in this study, we addressed the role of host cell autophagy during plasmodium berghei liver infection. we show that vesicles containing the autophagic marker lc3 surround parasites from early time-points after invasion and throughout infection and colocalize with the parasitophorous vacuole membrane. moreover, we show that the lc ...201626399761
multiple short windows of calcium-dependent protein kinase 4 activity coordinate distinct cell cycle events during plasmodium gametogenesis.malaria transmission relies on the production of gametes following ingestion by a mosquito. here, we show that ca(2+)-dependent protein kinase 4 controls three processes essential to progress from a single haploid microgametocyte to the release of eight flagellated microgametes in plasmodium berghei. a myristoylated isoform is activated by ca(2+) to initiate a first genome replication within twenty seconds of activation. this role is mediated by a protein of the saps-domain family involved in s- ...201728481199
identification of protective b-cell epitopes within the novel malaria vaccine candidate plasmodium falciparum schizont egress antigen 1.naturally acquired antibodies to plasmodium falciparum schizont egress antigen 1 (pfsea-1a) are associated with protection against severe malaria in children. vaccination of mice with sea-1a from plasmodium berghei (pbsea-1a) decreases parasitemia and prolongs survival following p. berghei anka challenge. to enhance the immunogenicity of pfsea-1a, we identified five linear b-cell epitopes using peptide microarrays probed with antisera from nonhuman primates vaccinated with recombinant pfsea-1a ( ...201728468980
icam-1 is a key receptor mediating cytoadherence and pathology in the plasmodium chabaudi malaria model.parasite cytoadherence within the microvasculature of tissues and organs of infected individuals is implicated in the pathogenesis of several malaria syndromes. multiple host receptors may mediate sequestration. the identity of the host receptor(s), or the parasite ligand(s) responsible for sequestration of plasmodium species other than plasmodium falciparum is largely unknown. the rodent malaria parasites may be useful to model interactions of parasite species, which lack the var genes with the ...201728468674
expression of negative immune regulatory molecules, pro-inflammatory chemokine and cytokines in immunopathology of ecm developing mice.the pathological events in human cerebral malaria are mimicked in the experimental cerebral malaria (ecm) in plasmodium berghei anka (pba)-infected c57bl/6 mice. although previously implied in ecm, the kinetics of cytokines and chemokines expression-an essential functional feature for defining causality in ecm development-remained untested. herein, we characterized the immunopathological changes and the expression of negative immune regulatory molecules, cytokines and chemokines through asymptom ...201728454880
il-33 receptor st2 regulates the cognitive impairments associated with experimental cerebral malaria.cerebral malaria (cm) is associated with a high mortality rate and long-term neurocognitive impairment in survivors. the murine model of experimental cerebral malaria (ecm) induced by plasmodium berghei anka (pba)-infection reproduces several of these features. we reported recently increased levels of il-33 protein in brain undergoing ecm and the involvement of il-33/st2 pathway in ecm development. here we show that pba-infection induced early short term and spatial memory defects, prior to bloo ...201728448579
antimalarial efficacy of mmv390048, an inhibitor of plasmodium phosphatidylinositol 4-kinase.as part of the global effort toward malaria eradication, phenotypic whole-cell screening revealed the 2-aminopyridine class of small molecules as a good starting point to develop new antimalarial drugs. stemming from this series, we found that the derivative, mmv390048, lacked cross-resistance with current drugs used to treat malaria. this compound was efficacious against all plasmodium life cycle stages, apart from late hypnozoites in the liver. efficacy was shown in the humanized plasmodium fa ...201728446690
apolipophorin-iii acts as a positive regulator of plasmodium development in anopheles stephensi.apolipophorin iii (apolp-iii) is a well-known hemolymph protein having a functional role in lipid transport and immune responses of insects. here we report the molecular and functional characterization of anopheles stephensi apolipophorin-iii (asapolp-iii) gene. this gene consists of 679 nucleotides arranged into two exons of 45 and 540 bp that give an orf encoding 194 amino acid residues. excluding a putative signal peptide of the first 19 amino acid residues, the 175-residues in mature asapolp ...201728439240
rapid inducible protein displacement in plasmodiumin vivo and in vitro using knocksideways technology.a deeper understanding of the biology of the plasmodium parasite is essential in order to identify targets for interventions, with the ultimate aim of eliminating malaria. determining the function(s) of essential proteins in plasmodium has, until recently, been hampered by the lack of efficient conditional systems to abrogate proteins. we report the adaptation of a conditional technology, knocksideways (ks), for use in plasmodium berghei, which can potentially rapidly inactivate proteins of inte ...201728428983
lccl protein complex formation in plasmodium is critically dependent on lap1.successful sporogony of plasmodium berghei in vector mosquitoes requires expression of a family of six modular proteins named lccl lectin domain adhesive-like proteins (laps). the laps share a subcellular localization in the crystalloid, a unique parasite organelle that forms during ookinete development. here, lap interactions in p. berghei were studied using a series of parasite lines stably expressing reporter-tagged laps combined with affinity purification and high accuracy label free quantit ...201728414172
in vivo antimalarial activity of synthetic hepcidin against plasmodium berghei in mice.the present study was designed to investigate the antimalarial activity of synthetic hepcidin and its effect on cytokine secretion in mice infected with plasmodium berghei. the mice were infected with p. berghei intravenously and treated with hepcidin according to 4-day suppression test and rane's test. the serum levels of interleukins (il-1β, il-2, il-6, il-10, il-12p70, and il-17a), tumor necrosis factor-α (tnf-α), and interferon-γ (ifn-γ) in the experimental mice were determined using a cytom ...201728411684
manipulation of the host cell membrane during plasmodium liver stage egress.a crucial step in the life cycle of plasmodium parasites is the transition from the liver stage to the blood stage. hepatocyte-derived merozoites reach the blood vessels of the liver inside host cell-derived vesicles called merosomes. the molecular basis of merosome formation is only partially understood. here we show that plasmodium berghei liver stage merozoites, upon rupture of the parasitophorous vacuole membrane, destabilize the host cell membrane (hcm) and induce separation of the host cel ...201728400525
host resistance to plasmodium-induced acute immune pathology is regulated by interleukin-10 receptor signaling.the resolution of malaria infection is dependent on a balance between proinflammatory and regulatory immune responses. while early effector t cell responses are required for limiting parasitemia, these responses need to be switched off by regulatory mechanisms in a timely manner to avoid immune-mediated tissue damage. interleukin-10 receptor (il-10r) signaling is considered to be a vital component of regulatory responses, although its role in host resistance to severe immune pathology during acu ...201728396319
bioluminescence method for in vitro screening of plasmodium transmission-blocking compounds.the sporogonic stage of the life cycle of plasmodium spp., the causative agents of malaria, occurs inside the parasite's mosquito vector, where a process of fertilization, meiosis, and mitotic divisions culminates in the generation of large numbers of mammalian-infective sporozoites. efforts to cultivate plasmodium mosquito stages in vitro have proved challenging and yielded only moderate success. here, we describe a methodology that simplifies the in vitro screening of much-needed transmission- ...201728348156
within-host selection of drug resistance in a mouse model reveals dose-dependent selection of atovaquone resistance mutations.the evolutionary selection of malaria parasites within an individual host plays a critical role in the emergence of drug resistance. we have compared the selection of atovaquone resistance mutants in mouse models reflecting two different causes of failure of malaria treatment, an inadequate subtherapeutic dose and an incomplete therapeutic dose. the two models are based on cycles of insufficient treatment of plasmodium berghei-infected mice: repeated inadequate treatment associated with a subthe ...201728193656
yeast lysates carrying the nucleoprotein from measles virus vaccine as a novel subunit vaccine platform to deliver plasmodium circumsporozoite antigen.yeast cells represent an established bioreactor to produce recombinant proteins for subunit vaccine development. in addition, delivery of vaccine antigens directly within heat-inactivated yeast cells is attractive due to the adjuvancy provided by the yeast cell. in this study, pichia pastoris yeast lysates carrying the nucleoprotein (n) from the measles vaccine virus were evaluated as a novel subunit vaccine platform to deliver the circumsporozoite surface antigen (cs) of plasmodium. when expres ...201728662722
virus-like particle (vlp) plus microcrystalline tyrosine (mct) adjuvants enhance vaccine efficacy improving t and b cell immunogenicity and protection against plasmodium berghei/vivax.vaccination is the most effective prophylactic tool against infectious diseases. despite continued efforts to control malaria, the disease still generally represents a significant unmet medical need. microcrystalline tyrosine (mct) is a well described depot used in licensed allergy immunotherapy products and in clinical development. however, its proof of concept in prophylactic vaccines has only recently been explored. mct has never been used in combination with virus-like particles (vlps), whic ...201728468322
in vivo imaging of pathogen homing to the host tissues.hematogenous dissemination followed by tissue tropism is a characteristic of the infectious process of many pathogens including those transmitted by blood-feeding vectors. after entering into the blood circulation, these pathogens must arrest in the target organ before they infect a specific tissue. here, we describe a non-invasive method to visualize and quantify the homing of pathogens to the host tissues. by using in vivo bioluminescence imaging we quantify the accumulation of luciferase-expr ...201728522323
antecedent nippostrongylus infection alters the lung immune response to plasmodium berghei.in endemic regions, it is not uncommon for patients to be co-infected with soil-transmitted helminths and malaria. although both malaria and many helminth species use the lungs as a site of development, little attention has been paid to the impact that pulmonary immunity induced by one parasite has on the lung response to the other. to model the consequences of a prior hookworm exposure on the development of immunity to malaria in the lungs, mice were infected with nippostrongylus brasiliensis a ...201728475238
a plasmodium plasma membrane reporter reveals membrane dynamics by live-cell microscopy.during asexual replication within the anopheles mosquito and their vertebrate host, plasmodium parasites depend on the generation of a massive amount of new plasma membrane to produce thousands of daughter parasites. how the parasite plasma membrane (ppm) is formed has mostly been studied by electron microscopy, which does not allow an insight into the dynamics of this process. we generated a plasmodium berghei reporter parasite line by gfp-tagging of a non-essential ppm-localized protein, and f ...201728851956
multifunctional involvement of a c2h2 zinc finger protein (pbzfp) in malaria transmission, histone modification, and susceptibility to dna damage response.in sexually reproducing organisms, meiosis is an essential step responsible for generation of haploid gametes from diploid somatic cells. the quest for understanding regulatory mechanisms of meiotic recombination in plasmodium led to identification of a gene encoding a protein that contains 11 copies of c2h2 zinc fingers (znf). reverse genetic approaches were used to create plasmodium berghei parasites either lacking expression of full-length plasmodium berghei zinc finger protein (pbzfp) (knock ...201728851851
preparation and in vivo evaluation of anti-plasmodial properties of artemisinin loaded pcl-peg-pcl nanoparticles.artemisinin (art) has anti-inflammatory, antimicrobial, antioxidant, anti-amyloid, and anti-malarial effects, but its application is limited due to its low water solubility and poor oral bioavailability. in this study, the bioavailability, water solubility and anti-plasmodial property of art were improved by pcl-peg-pcl triblock copolymers.201728851256
antioxidant defense system induced by cysteine-stabilized peptide fraction of aqueous extract of morinda lucida leaf in selected tissues of plasmodium berghei-infected mice.this study evaluated the responses of some antioxidant parameters in selected tissues of plasmodium berghei-infected mice treated with cysteine-stabilized peptide fraction (cspf) of aqueous extract of morinda lucida leaf.201728844216
chemopreventive and remediation effect of adansonia digitata l. baobab (bombacaceae) stem bark extracts in mouse model malaria.adansonia digitata l. baobab (bombacaceae) solvent extracts have been reported to possess medicinal properties and are currently been used traditionally for the treatment of malaria and several other diseases and infection; however few reports exist in literature that provides supportive scientific evidence in favour of its medicinal use.201728843893
perillyl alcohol exhibits in vitro inhibitory activity against plasmodium falciparum and protects against experimental cerebral malaria.the development of new drugs is one of the strategies to control malaria. isoprenoid biosynthesis in plasmodium falciparum is an essential pathway for parasite survival, and therefore a potential target for new antimalarial drugs. indeed, plant-derived secondary metabolites such as terpenes exhibit antimalarial activity in vitro by inhibiting isoprenoid biosynthesis in p. falciparum. in this study, the in vitro antiplasmodial activity of perillyl alcohol (poh) was evaluated, along with its in vi ...201728843818
dysregulation of limk-1/cofilin-1 pathway: a possible basis for alteration of neuronal morphology in experimental cerebral malaria.loss of cognition even after survival is the salient feature of cerebral malaria (cm). currently, the fate of neuronal morphology is not studied at the ultra-structural level in cm. recent studies suggest that maintenance of neuronal morphology and dendritic spine density (actin dynamics in particular) are essential for proper cognitive functions. limk-1/cofilin-1signaling pathway is known to involve in the maintenance of actin dynamics through regulation of cofilin-1, in executing learning and ...201728843047
plasmodium berghei cap93, a novel oocyst capsule-associated protein, plays a role in sporozoite development. 201728841886
inverted recruitment of autophagy proteins to the plasmodium berghei parasitophorous vacuole membrane.selective autophagy and related mechanisms can act as variable defense mechanisms against pathogens and can therefore be considered as intracellular immune responses. when in hepatocytes, plasmodium parasites reside in a parasitophorous vacuole (pv) and the pv membrane (pvm) is the main contact site between host cell and parasite. early in infection, the pvm is directly labeled with host cell autophagy proteins lc3b and p62 (nucleoporin 62). we investigated the recruitment of different selective ...201728841718
phenotypic approach artemisinin resistance in malaria rodent as in vivo model.the aim of this study is to prove the development of artemisinin resistance phenotypically in malaria rodent as an in vivo resistance development model in humans.201728831224
immunological memory to blood-stage malaria infection is controlled by the histamine releasing factor (hrf) of the parasite.while most subunit malaria vaccines provide only limited efficacy, pre-erythrocytic and erythrocytic genetically attenuated parasites (gap) have been shown to confer complete sterilizing immunity. we recently generated a plasmodium berghei (pbnk65) parasite that lacks a secreted factor, the histamine releasing factor (hrf) (pbnk65 hrfδ), and induces in infected mice a self-resolving blood stage infection accompanied by a long lasting immunity. here, we explore the immunological mechanisms underl ...201728831137
down-regulation of tim-3 in monocytes and macrophages in plasmodium infection and its association with parasite clearance.t-cell immunoglobulin and mucin-domain-containing molecule 3 (tim-3) has complicated roles in regulating monocytes and macrophages in various diseases and it tends to be an inhibitory molecule to facilitate the immune escape of parasites in malaria. however, the mechanisms of tim-3 mediated responses in monocytes and macrophages in malaria have not been clear. in this study, we found that plasmodium infection down-regulated tim-3 expression in peripheral monocytes of patients suffering from plas ...201728824565
tlr4-mediated placental pathology and pregnancy outcome in experimental malaria.malaria-associate pregnancy has a significant impact on infant morbidity and mortality. the detrimental effects of malaria infection during pregnancy have been shown to correlate with immune activation in the placental tissue. herein we sought to evaluate the effect of toll-like receptors (tlrs) activation on placental malaria (pm) development by using the plasmodium berghei nk65(gfp) infection model. we observed that activation of the innate immune system by parasites leads to pm due to local i ...201728819109
hexahydroquinolines are antimalarial candidates with potent blood-stage and transmission-blocking activity.antimalarial compounds with dual therapeutic and transmission-blocking activity are desired as high-value partners for combination therapies. here, we report the identification and characterization of hexahydroquinolines (hhqs) that show low nanomolar potency against both pathogenic and transmissible intra-erythrocytic forms of the malaria parasite plasmodium falciparum. this activity translates into potent transmission-blocking potential, as shown by in vitro male gamete formation assays and re ...201728808258
reduction of mosquito survival in mice vaccinated with anopheles stephensi glucose transporter.despite the fact that recent efforts to control/eradicate malaria have contributed to a significant decrease in the number of cases and deaths, the disease remains a global health challenge. vaccines based on mosquito salivary gland antigens are a potential approach for reducing vector populations and malaria parasites. the anopheles agap007752 gene encodes for a glucose transporter that is upregulated during plasmodium infection, and its knockdown decreases the number of sporozoites in mosquito ...201728804714
antimalarial evaluation of selected medicinal plant extracts used in iranian traditional medicine.in an attempt to discover new natural active extracts against malaria parasites, the present study evaluated the antiplasmodial properties of selected plants based on iranian traditional medicine.201728804611
structured illumination microscopy reveals actin i localization in discreet foci in plasmodium berghei gametocytes.actin has important roles in plasmodium parasites but its exact function in different life stages is not yet fully elucidated. here we report the localization of ubiquitous actin i in gametocytes of the rodent model parasite p. berghei. using an antibody specifically recognizing f-actin and deconvolution microscopy we detected actin i in a punctate pattern in gametocytes. 3d-structured illumination microscopy which allows sub-diffraction limit imaging resolved the signal into structures of less ...201728803903
differential modulation of glial cell mediated neuroinflammation in plasmodium berghei anka infection by tgf β and il 6.modulation of pro-inflammatory and anti-inflammatory axis and orientation of glial cell function towards neuroinflammation, were hallmark signs of cerebral malaria (cm). cm pathogenesis was concerned with the circulating levels of interleukin 6 (il 6) and transforming growth factor β (tgf β). definite roles of these two cytokines in brain related pathology remained largely unexplored. to study the effect of these two cytokines, we have examined changes in morphology and in activation profile of ...201728803696
an integrated approach to explore composition and dynamics of cholesterol-rich membrane microdomains in sexual stages of malaria parasite.membrane microdomains that include lipid rafts, are involved in key physiological and pathological processes and participate in the entry of endocellular pathogens. these assemblies, enriched in cholesterol and sphingolipids, form highly dynamic, liquid-ordered phases that can be separated from the bulk membranes thanks to their resistance to solubilization by non-ionic detergents. to characterize complexity and dynamics of detergent-resistant membranes of sexual stages of the rodent malaria par ...201728798222
assessment of liver antioxidant status and mitochondrial membrane composition of plasmodium berghei-infected mice treated with selected antimalarials.the present study was aimed at determining and comparing the effects of artecxin (art), p - alaxin (p-ala), lonart (lon) and chloroquine (cq) on oxidative stress parameters and mitochondrial membrane composition in the course of malaria infection. six groups of five mice each categorized as healthy control (non-parasitized non-treated group), parasitized-non-treated (pnt), parasitized-chloroquine-treated (positive control), parasitized-artecxin, -lonart and -p-alaxin-treated groups were used for ...201728787466
late-phase immune responses limiting oocyst survival are independent of tep1 function yet display strain specific differences in anopheles gambiae.there is emerging evidence that mosquito anti-plasmodium immunity is multimodal with distinct mechanisms for killing malaria parasites at either the ookinete or oocyst stages. early-phase responses targeting the ookinete require complement-like components circulating in the mosquito hemolymph that result in tep1-mediated lysis or melanization. additional responses mediated by the ll3 and stat pathways limit oocyst survival through unknown mechanisms that require mosquito hemocyte function. while ...201728764765
generation of transgenic rodent malaria parasites by transfection of cell culture-derived merozoites.malaria research is greatly dependent on and has drastically advanced with the possibility of genetically modifying plasmodium parasites. the commonly used transfection protocol by janse and colleagues utilizes blood stage-derived plasmodium berghei schizonts that have been purified from a blood culture by density gradient centrifugation. naturally, this transfection protocol depends on the availability of suitably infected mice, constituting a time-based variable. in this study, the potential o ...201728764716
quantitative real-time pcr analysis of anopheles dirus tep1 and nos during plasmodium berghei infection, using three reference genes.quantitative reverse transcription pcr (qrt-pcr) has been an integral part of characterizing the immunity of anopheles mosquitoes towards plasmodium invasion. two anti-plasmodium factors of anopheles, thioester-containing protein 1 (tep1) and nitric oxide synthase (nos), play a role in the refractoriness of anopheles towards plasmodium infection and are generally expressed during infection. however, these are less studied in anopheles dirus, a dominant malaria vector in southeast asia. furthermo ...201728761783
antiplasmodial activity and cytotoxicity of ethanol extract of zea mays root.zea mays root decoction that has been traditionally used for the treatment of malaria by various tribes in nigeria, was evaluated for antimalarial potential against malaria parasites using in vivo and in vitro models.201728748174
young sprague dawley rats infected by plasmodium berghei: a relevant experimental model to study cerebral malaria.cerebral malaria (cm) is the most severe manifestation of human malaria yet is still poorly understood. mouse models have been developed to address the subject. however, their relevance to mimic human pathogenesis is largely debated. here we study an alternative cerebral malaria model with an experimental plasmodium berghei keyberg 173 (k173) infection in sprague dawley rats. as in human, not all infected subjects showed cerebral malaria, with 45% of the rats exhibiting experimental cerebral mal ...201728742109
solute carriers affect anopheles stephensi survival and plasmodium berghei infection in the salivary glands.malaria is caused by mosquito-borne plasmodium spp. parasites that must infect and survive within mosquito salivary glands (sgs) prior to host transmission. recent advances in transcriptomics and the complete genome sequencing of mosquito vectors have increased our knowledge of the sg genes and proteins involved in pathogen infection and transmission. membrane solute carriers are key proteins involved in drug transport and are useful in the development of new interventions for transmission block ...201728733628
plasmodium berghei p47 is essential for ookinete protection from the anopheles gambiae complement-like response.malaria is a mosquito-borne disease affecting millions of people every year. the rodent parasite plasmodium berghei has served as a model for human malaria transmission studies and played a pivotal role in dissecting the mosquito immune response against infection. the 6-cysteine protein p47, known to be important for p. berghei female gamete fertility, is shown to serve a different function in plasmodium falciparum, protecting ookinetes from the mosquito immune response. here, we investigate the ...201728729672
protein tyrosine phosphatase inhibition prevents experimental cerebral malaria by precluding cxcr3 expression on t cells.cerebral malaria induced by plasmodium berghei anka infection is dependent on the sequestration of cytotoxic t cells within the brain and augmentation of the inflammatory response. herein, we demonstrate that inhibition of protein tyrosine phosphatase (ptp) activity significantly attenuates t cell sequestration within the brain and prevents the development of neuropathology. mechanistically, the initial upregulation of cxcr3 on splenic t cells upon t cell receptor stimulation was critically decr ...201728710387
functional profiling of a plasmodium genome reveals an abundance of essential genes.the genomes of malaria parasites contain many genes of unknown function. to assist drug development through the identification of essential genes and pathways, we have measured competitive growth rates in mice of 2,578 barcoded plasmodium berghei knockout mutants, representing >50% of the genome, and created a phenotype database. at a single stage of its complex life cycle, p. berghei requires two-thirds of genes for optimal growth, the highest proportion reported from any organism and a probabl ...201728708996
[fe-s] cluster assembly in the apicoplast and its indispensability in mosquito stages of the malaria parasite.the relict plastid (apicoplast) of the malaria parasite is the site for important biochemical pathways and is essential for parasite survival. the sulfur mobilization (suf) pathway of iron-sulfur [fe-s] cluster assembly in the apicoplast of plasmodium spp. is of interest due to its absence in the human host suggesting the possibility of antimalarial intervention through apicoplast [fe-s] biogenesis. we report biochemical characterization of components of the plasmodium falciparum apicoplast suf ...201728695709
enantioselective synthesis and in vivo evaluation of regioisomeric analogues of the antimalarial arterolane.we describe the first systematic study of antimalarial 1,2,4-trioxolanes bearing a substitution pattern regioisomeric to that of arterolane. conformational analysis suggested that trans-3″-substituted trioxolanes would exhibit fe(ii) reactivity and antiparasitic activity similar to that achieved with canonical cis-4″ substitution. the chiral 3″ analogues were prepared as single stereoisomers and evaluated alongside their 4″ congeners against cultured malaria parasites and in a murine malaria mod ...201728692297
an exported protein-interacting complex involved in the trafficking of virulence determinants in plasmodium-infected erythrocytes.the malaria parasite, plasmodium falciparum, displays the p. falciparum erythrocyte membrane protein 1 (pfemp1) on the surface of infected red blood cells (rbcs). we here examine the physical organization of pfemp1 trafficking intermediates in infected rbcs and determine interacting partners using an epitope-tagged minimal construct (pfemp1b). we show that parasitophorous vacuole (pv)-located pfemp1b interacts with components of the ptex (plasmodium translocon of exported proteins) as well as a ...201728691708
s-nitrosoglutathione reductase deficiency confers improved survival and neurological outcome in experimental cerebral malaria.artesunate remains the mainstay of treatment for cerebral malaria, but it is less effective in later stages of disease when the host inflammatory response and blood-brain barrier integrity dictate clinical outcomes. nitric oxide (no) is an important regulator of inflammation and microvascular integrity, and impaired no bioactivity is associated with fatal outcomes in malaria. endogenous no bioactivity in mammals is largely mediated by s-nitrosothiols (snos). based on these observations, we hypot ...201728674030
host-mediated impairment of parasite maturation during blood-stage plasmodium infection.severe malaria and associated high parasite burdens occur more frequently in humans lacking robust adaptive immunity to plasmodium falciparum nevertheless, the host may partly control blood-stage parasite numbers while adaptive immunity is gradually established. parasite control has typically been attributed to enhanced removal of parasites by the host, although in vivo quantification of this phenomenon remains challenging. we used a unique in vivo approach to determine the fate of a single coho ...201728673996
efficacy and safety evaluation of a novel trioxaquine in the management of cerebral malaria in a mouse model.the emergence of multidrug-resistant strains of plasmodium falciparum poses a great threat of increased fatalities in cases of cerebral and other forms of severe malaria infections in which parenteral artesunate monotherapy is the current drug of choice. the study aimed to investigate in a mouse model of human cerebral malaria whether a trioxaquine chemically synthesized by covalent linking of a 4,7-dichloroquinoline pharmacophore to artesunate through a recent drug development approach termed ' ...201728673299
examination of the antimalarial potential of experimental aminoquinolines: poor in vitro effect does not preclude in vivo efficacy.malaria remains a major disease in the developing world and globally is the most important parasitic disease causing significant morbidity and mortality. because of widespread resistance to conventional antimalarials, including chloroquine (cq), new drugs are urgently needed. here we report on the antimalarial efficacy, both in vitro and in vivo, of a series of aminoquinoline derivatives with adamantane or benzothiophene as a carrier. in vitro efficacy was evaluated by a lactate dehydrogenase (l ...201728668677
conditional knock-out of lipoic acid protein ligase 1 reveals redundancy pathway for lipoic acid metabolism in plasmodium berghei malaria parasite.lipoic acid is a cofactor for α-keto acid dehydrogenase system that is involved in the central energy metabolism. in the apicomplexan parasite, plasmodium, lipoic acid protein ligase 1 (lpla1) and lpla2 catalyse the ligation of acquired lipoic acid to the dehydrogenase complexes in the mitochondrion. the enzymes lipb and lipa mediate lipoic acid synthesis and ligation to the enzymes in the apicoplast. these enzymes in the lipoic acid metabolism machinery have been shown to play important roles i ...201728655332
3-hydroxy-n'-arylidenepropanehydrazonamides with halo-substituted phenanthrene scaffolds cure p. berghei infected mice when administered perorally.structural optimization of 3-hydroxy-n'-arylidenepropanehydrazonamides provided new analogs with nanomolar to subnanomolar antiplasmodial activity against asexual blood stages of plasmodium falciparum, excellent parasite selectivity, and nanomolar activity against the earliest forms of gametocyte development. particularly, derivatives with a 1,3-dihalo-6-trifluoromethylphenanthrene moiety showed outstanding in vivo properties and demonstrated in part curative activity in the plasmodium berghei m ...201728653845
high efficacy in vitro selection procedure for generating transgenic parasites of plasmodium berghei using an antibiotic toxic to rodent hosts.the malaria parasite plasmodium berghei is one of the main rodent malaria models. a shortcoming of this model parasite is its low flexibility in genetic manipulation. as this parasite cannot be continuously propagated in cell cultures, in vivo drug selection procedures are necessary to isolate genetic mutants. drugs harmful to rodents therefore cannot be used for drug selection, which restricts the range of genetic manipulation. in this study, we addressed this problem by establishing a novel in ...201728638105
engineering of genetically arrested parasites (gaps) for a precision malaria vaccine.continuous stage conversion and swift changes in the antigenic repertoire in response to acquired immunity are hallmarks of complex eukaryotic pathogens, including plasmodium species, the causative agents of malaria. efficient elimination of plasmodium liver stages prior to blood infection is one of the most promising malaria vaccine strategies. here, we describe different genetically arrested parasites (gaps) that have been engineered in plasmodium berghei, p. yoelii and p. falciparum and compa ...201728620583
a novel genetic technique in plasmodium berghei allows liver stage analysis of genes required for mosquito stage development and demonstrates that de novo heme synthesis is essential for liver stage development in the malaria parasite.the combination of drug resistance, lack of an effective vaccine, and ongoing conflict and poverty means that malaria remains a major global health crisis. understanding metabolic pathways at all parasite life stages is important in prioritising and targeting novel anti-parasitic compounds. the unusual heme synthesis pathway of the rodent malaria parasite, plasmodium berghei, requires eight enzymes distributed across the mitochondrion, apicoplast and cytoplasm. deletion of the ferrochelatase (fc ...201728617870
in-vivo antimalarial activity of aqueous leaf and bark extracts of trema orientalis against plasmodium berghei in mice.the control of malaria relies on the use of chemical antimalarial, but the development of resistance necessitates research into alternatives. trema orientalis (l.) blume is used in nigerian folklore medicine for the treatment of malaria. this study investigates the in vivo antiplasmodial activity of aqueous leaf and bark extracts of t. orientalis in rodent model. swiss albino mice weighing 23-27 g were intraperitoneally infected with plasmodium berghei. the lethal dose in mice was estimated to b ...201728615849
suppression of experimental cerebral malaria by disruption of malate:quinone oxidoreductase.aspartate, which is converted from oxaloacetate (oaa) by aspartate aminotransferase, is considered an important precursor for purine salvage and pyrimidine de novo biosynthesis, and is thus indispensable for the growth of plasmodium parasites at the asexual blood stages. oaa can be produced in malaria parasites via two routes: (i) from phosphoenolpyruvate (pep) by phosphoenolpyruvate carboxylase (pepc) in the cytosol, or (ii) from fumarate by consecutive reactions catalyzed by fumarate hydratase ...201728606087
menoctone resistance in malaria parasites is conferred by m133i mutations in cytochrome b that are transmissible through mosquitoes.malaria-related mortality has slowly decreased over the past decade; however, eradication of malaria requires the development of new antimalarial chemotherapies that target liver stages of the parasite and combat the emergence of drug resistance. the diminishing arsenal of anti-liver-stage compounds sparked our interest in reviving the old and previously abandoned compound menoctone. in support of these studies, we developed a new convergent synthesis method that was facile, required fewer steps ...201728584157
lc3-association with the parasitophorous vacuole membrane of plasmodium berghei liver stages follows a noncanonical autophagy pathway.eukaryotic cells can employ autophagy to defend themselves against invading pathogens. upon infection by plasmodium berghei sporozoites, the host hepatocyte targets the invader by labelling the parasitophorous vacuole membrane (pvm) with the autophagy marker protein lc3. until now, it has not been clear whether lc3 recruitment to the pvm is mediated by fusion of autophagosomes or by direct incorporation. to distinguish between these possibilities, we knocked out genes that are essential for auto ...201728573684
plasmodium berghei pimms2 promotes ookinete invasion of the anopheles gambiae mosquito midgut.mosquito midgut stages of the malaria parasite present an attractive biological system to study host-parasite interactions and develop interventions to block disease transmission. mosquito infection ensues upon oocyst development that follows ookinete invasion and traversal of the mosquito midgut epithelium. here, we report the characterization of pimms2 (plasmodium invasion of mosquito midgut screen candidate 2), a plasmodium berghei protein with structural similarities to subtilisin-like prote ...201728559405
a unique profilin-actin interface is important for malaria parasite motility.profilin is an actin monomer binding protein that provides atp-actin for incorporation into actin filaments. in contrast to higher eukaryotic cells with their large filamentous actin structures, apicomplexan parasites typically contain only short and highly dynamic microfilaments. in apicomplexans, profilin appears to be the main monomer-sequestering protein. compared to classical profilins, apicomplexan profilins contain an additional arm-like β-hairpin motif, which we show here to be criticall ...201728552953
the fibrinogen-like domain of frep1 protein is a broad-spectrum malaria transmission-blocking vaccine antigen.frep1 in mosquito midguts facilitates plasmodium falciparum parasite transmission. the fibrinogen-like (fbg) domain of frep1 is highly conserved (>90% identical) among anopheles species from different continents, suggesting that anti-fbg antibodies may block malaria transmission to all anopheline mosquitoes. using standard membrane-feeding assays, anti-frep1 polyclonal antibodies significantly blocked transmission of plasmodium berghei and plasmodium vivax to anopheles gambiae and anopheles diru ...201728533429
artesunate and erythropoietin synergistically improve the outcome of experimental cerebral malaria.cerebral malaria (cm) is a severe neurological syndrome in humans and the main fatal cause of malaria. in malaria epidemic regions, despite appropriate anti-malarial treatment, 10-20% of deaths still occur during the acute phase. this is largely attributable to poor treatment access, therapeutic complexity and drug resistance; thus, developing additional clinical adjunctive therapies is an urgent necessity. in this study, we investigated the effect of artesunate (ast) and recombinant human eryth ...201728531845
experimental evaluation of cryopreservative solutions to maintain in vitro and in vivo infectivity of p. berghei sporozoites.the rodent malaria parasite plasmodium berghei is an excellent model organism for laboratory-based experimental evaluation of anti-malarial therapeutics prior to studies with human malaria parasites. the rodent model is especially important for evaluation of pre-erythrocytic (pe) stage therapies, especially as current efforts to develop new pe vaccines and drugs is limited by access to p. falciparum and p. vivax sporozoites. developing a more effective method for cryopreservation of sporozoites ...201728531172
shedding of host autophagic proteins from the parasitophorous vacuolar membrane of plasmodium berghei.the hepatic stage of the malaria parasite plasmodium is accompanied by an autophagy-mediated host response directly targeting the parasitophorous vacuolar membrane (pvm) harbouring the parasite. removal of the pvm-associated autophagic proteins such as ubiquitin, p62, and lc3 correlates with parasite survival. yet, it is unclear how plasmodium avoids the deleterious effects of selective autophagy. here we show that parasites trap host autophagic factors in the tubovesicular network (tvn), an exp ...201728526861
malaria parasite limp protein regulates sporozoite gliding motility and infectivity in mosquito and mammalian hosts.gliding motility allows malaria parasites to migrate and invade tissues and cells in different hosts. it requires parasite surface proteins to provide attachment to host cells and extracellular matrices. here, we identify the plasmodium protein limp (the name refers to a gliding phenotype in the sporozoite arising from epitope tagging of the endogenous protein) as a key regulator for adhesion during gliding motility in the rodent malaria model p. berghei. transcribed in gametocytes, limp is tran ...201728525314
synthesis and in vivo antimalarial activity of novel naphthoquine derivatives with linear/cyclic structured pendants.naphthoquine (nq) was discovered by our institute as an antimalarial candidate in 1980s, and currently employed as an artemisinin-based combination therapy partner drug. resistance to nq was found in mouse model in laboratory, and might emerge in future as widely used.201728513196
antiplasmodial activity of indigofera spicata root extract against plasmodium berghei infection in mice.in addition to pharmacovigilance and pharmaco-economic concerns, resistance to anti-malarial medicines has been documented in all classes of anti-malarials and this is further worsened by resistance to common insecticides by malaria vector, which is a major threat to malaria control. as a means of facing the challenges of searching for new anti-malarial agents, the current study focused on evaluation of anti-malarial activity of root extract of indigofera spicata.201728511659
anti-plasmodial assessment of four different iranian propolis extracts.eradication of malaria will depend on discovery of new intervention tools such as anti-malarial drugs. due to the increasing interest in the application of propolis against significant clinical pathogenic agents, the aim of the present investigation was to evaluate the anti-plasmodial effect of iranian propolis extracts against chloroquine (cq)-sensitive plasmodium falciparum 3d7 and plasmodium berghei (anka strain).201728510462
adaptation and optimization of a fluorescence-based assay for in vivo antimalarial drug screening.the in vivo efficacy of potential antimalarials is usually evaluated by direct microscopic determination of the parasitaemia of plasmodium-infected mice on giemsa-stained blood smears. this process is time-consuming, requires experienced technicians and is not automatable. therefore, we optimized a sybr green i (sybrg i) fluorescence-based assay to fluorometers commonly available in many research laboratories. this technique was originally developed to assess parasitaemia in humans by cytometry. ...201728508922
the peptidoglycan recognition proteins pgrpla and pgrplb regulate anopheles immunity to bacteria and affect infection by plasmodium.peptidoglycan recognition proteins (pgrps) form a family of immune regulators that is conserved from insects to mammals. in the malaria vector mosquito anophelescoluzzii, the peptidoglycan receptor pgrplc activates the immune-deficiency (imd) pathway limiting both the microbiota load and plasmodium infection. here, we carried out an rna interference screen to examine the role of all 7 anopheles pgrps in infections with plasmodium berghei and p. falciparum. we show that, in addition to pgrplc, pg ...201728494453
in vivo antiplasmodial activity evaluation of the leaves of balanites rotundifolia (van tiegh.) blatter (balanitaceae) against plasmodium berghei.balanites rotundifolia (br) (van tiegh.) blatter (balanitaceae) has been used in ethiopian folk medicine to treat malaria, despite the lack of scientific validation. therefore, the present study was carried out to evaluate the antiplasmodial activity of 80% methanol leaf extract of br in mice. both the 4-day suppressive test and rane's test were employed. three extract doses (br100 mg/kg, br200 mg/kg, and br400 mg/kg/d) were given orally, and chloroquine was the standard drug administered throug ...201728490906
in vivo antimalarial activity of extracts of tanzanian medicinal plants used for the treatment of malaria.plants used in traditional medicine have been the source of a number of currently used antimalarial medicines and continue to be a promising resource for the discovery of new classes of antimalarial compounds. the aim of this study was to evaluate in vivo antimalarial activity of four plants; erythrina schliebenii harms, holarrhena pubescens buch-ham, phyllanthus nummulariifolius poir, and caesalpinia bonducella (l.) flem used for treatment of malaria in tanzania. in vivo antimalarial activity w ...201727144154
usp15 regulates type i interferon response and is required for pathogenesis of neuroinflammation.genes and pathways in which inactivation dampens tissue inflammation present new opportunities for understanding the pathogenesis of common human inflammatory diseases, including inflammatory bowel disease, rheumatoid arthritis and multiple sclerosis. we identified a mutation in the gene encoding the deubiquitination enzyme usp15 (usp15(l749r)) that protected mice against both experimental cerebral malaria (ecm) induced by plasmodium berghei and experimental autoimmune encephalomyelitis (eae). c ...201727721430
novel metalloantimalarials: transmission blocking effects of water soluble cu(i), ag(i) and au(i) phosphane complexes on the murine malaria parasite plasmodium berghei.the water soluble phosphane complexes [m(l)4]pf6 (m=cu(i), ag(i)) and [au(l)4]cl (l=thp (tris(hydroxymethyl)phosphane) or pta (1,3,5-triaza-7-phosphaadamantane)) showed notable in vitro activity against plasmodium early sporogonic stages, the sexual forms of the malaria parasite that are responsible for infection of the mosquito vector. effects varied according to both, the type of metal and phosphane ligands. [ag(thp)4]pf6 was the best performing complex exhibiting a half inhibitory concentrati ...201727815977
tacrolimus prevents murine cerebral malaria.tacrolimus and mycophenolate mofetil are immunosuppressants frequently used in human organ transplantation. tacrolimus is also reported to inhibit plasmodium falciparum growth in vitro. here, we report that tacrolimus prevented the death from cerebral malaria of plasmodium berghei anka-infected c57bl/6j mice, but not their death from malaria due to the high parasitaemia and severe anaemia. the mycophenolate mofetil-treated mice showed higher mortality from cerebral malaria and succumbed to malar ...201727546479
antimalarial activity of fractions of aqueous extract of acacia nilotica root.the problem of resistance of malarial parasites to available antimalarial drugs makes the development of new drugs imperative, with natural plant products providing an alternative source for discovering new drugs.201727104040
in vivo antimalarial activities of russelia equisetiformis in plasmodium berghei infected mice.the rising problem of resistance to most commonly used antimalarials remains a major challenge in the control of malaria suggesting the need for new antimalarial agents. this work explores the antiplasmodial potential of ethanol extract of russelia equisetiformis in chloroquine plasmodium berghei infected mice. swiss albino mice were intraperitoneally infected with chloroquine-resistant p. berghei (anka). experimental mice were treated for four days consecutively with graded doses of plant extra ...201726664070
interleukin-18 antagonism improved histopathological conditions of malaria infection in mice.interleukin 18 (il-18) exerts pleiotropic roles in many inflammatory-related diseases including parasitic infection. previous studies have demonstrated the promising therapeutic potential of modulating il-18 bioactivity in various pathological conditions. however, its involvement during malaria infection has yet to be established. in this study, we demonstrated the effect of modulating il-18 on the histopathological conditions of malaria infected mice.201726622294
anti-plasmodial activity of ethanolic extract of root and stem back of cassia sieberiana dc on mice.this study assessed within 4 days of suppressive test in vivo antimalarial activity of ethanolic extract of root and stem bark of cassia sieberiana dc against chloroquine sensitive strain of plasmodium berghei nk65 in mice.201726401393
antimalarial evaluation of the leaf latex of aloe citrina and its major constituent.malaria is one of the major obstacles to the socioeconomic development of several developing countries. adequate treatment of the disease is becoming increasingly difficult due to the worsening problems of drug resistance in many parts of the world. therefore, increased efforts in antimalarial drug discovery are urgently needed.201726120228
anopheles stephensi heme peroxidase hpx15 suppresses midgut immunity to support plasmodium development.the heme peroxidase hpx15 is an evolutionary conserved anopheline lineage-specific gene. previously, we found that this gene is present in the genome of 19 worldwide distributed different species of anopheles mosquito and its orthologs are absent in other mosquitoes, insects, or human. in addition, 65-99% amino acid identity among these 19 orthologs permitted us to hypothesize that the functional aspects of this gene might be also conserved in different anophelines. in this study, we found that ...201728352267
plant hormone cytokinins control cell cycle progression and plastid replication in apicomplexan parasites.cytokinins are plant hormones that are involved in regulation of cell proliferation, cell cycle progression, and cell and plastid development. here, we show that the apicomplexan parasites toxoplasma gondii and plasmodium berghei, an opportunistic human pathogen and a rodent malaria agent, respectively, produce cytokinins via a biosynthetic pathway similar to that in plants. cytokinins regulate the growth and cell cycle progression of t. gondii by mediating expression of the cyclin gene tgcyc4. ...201728344153
extended protection capabilities of an immature dendritic-cell targeting malaria sporozoite vaccine.mouse studies evaluating candidate malaria vaccines have typically examined protective efficacy over the relatively short time frames of several weeks after the final of multiple immunizations. the current study examines the protective ability in a mouse model system of a novel protein vaccine construct in which the adjuvant polyinosinic polycytidilic acid (poly(i:c)) is used in combination with a vaccine in which the immature dendritic cell targeting chemokine, macrophage inflammatory protein 3 ...201728342669
the maternally inheritable wolbachia walbb induces refractoriness to plasmodium berghei in anopheles stephensi.the endosymbiont wolbachia walbb induces refractoriness to plasmodium falciparum in anopheles stephensi, the primary mosquito vector of human malaria in the middle east and south asia. however, it remains unknown whether such refractoriness can be extended to other malaria species. in particular, it was reported that under very specific conditions, walbb can enhance plasmodium infection in some hosts. here, we measured the impact of walbb on the rodent malaria parasite plasmodium berghei in a. s ...201728337184
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