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plasmodium infection is associated with impaired hepatic dimethylarginine dimethylaminohydrolase activity and disruption of nitric oxide synthase inhibitor/substrate homeostasis.inhibition of nitric oxide (no) signaling may contribute to pathological activation of the vascular endothelium during severe malaria infection. dimethylarginine dimethylaminohydrolase (ddah) regulates endothelial no synthesis by maintaining homeostasis between asymmetric dimethylarginine (adma), an endogenous no synthase (nos) inhibitor, and arginine, the nos substrate. we carried out a community-based case-control study of gambian children to determine whether adma and arginine homeostasis is ...201526407009
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
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
vascular endothelial growth factor (vegf) and lovastatin suppress the inflammatory response to plasmodium berghei infection and protect against experimental cerebral malaria.cerebral malaria (cm) is a severe complication of plasmodium falciparum infection, which is associated with high mortality and long-term cognitive impairment even when effective anti-parasitic treatment is administered. (1 , 2) supportive therapy is needed to improve both morbidity and mortality associated with this condition. in an accompanying paper, we have demonstrated that in the plasmodium berghei anka (pba) rodent model, cm can be effectively prevented by a treatment combining sub-lethal ...201526392164
vegf and lps synergistically silence inflammatory response to plasmodium berghei infection and protect against cerebral malaria.malaria infection induces, alongside endothelial damage and obstruction hypoxia, a potent inflammatory response similar to that observed in other systemic diseases caused by bacteria and viruses. accordingly, it is increasingly recognised that cerebral malaria (cm), the most severe and life threatening complication of plasmodium falciparum infection, bears a number of similarities with sepsis, an often fatal condition associated with a misregulated inflammatory response triggered by systemic mic ...201526392042
phytochemical screening and in vivo antimalarial activity of extracts from three medicinal plants used in malaria treatment in nigeria.the use of plant to meet health-care needs has greatly increased worldwide in the recent times. the search for new plant-derived bioactive agents that can be explored for the treatment of drug-resistant malaria infection is urgently needed. thus, we evaluated the antimalarial activity of three medicinal plants used in nigerian folklore for the treatment of malaria infection. a modified peter's 4-day suppressive test was used to evaluate the antimalarial activity of the plant extracts in a mouse ...201626391173
dynamic control of hepatic plasmodium numbers by hepcidin despite elevated liver iron during iron supplementation.treatment of iron deficiency anemia in malaria endemic areas is complicated as iron supplementation increases malaria risk while malaria decreases iron absorption. here we measured the influence of hepcidin expression and non-heme iron during iron supplementation on hepatic plasmodium berghei numbers in anemic and non-anemic mice. despite elevated hepatic non-heme iron on the high iron diet, elevated hepcidin expression is associated with less parasite bioavailable iron and lower hepatic parasit ...201626384816
protective effect of aqueous crude extract of neem (azadirachta indica) leaves on plasmodium berghei-induced renal damage in mice.malaria is a major public health problem in the world because it can cause of death in patients. malaria-associated renal injury is associated with 45% of mortality in adult patients hospitalized with severe form of the disease. therefore, new plant extracts to protect against renal injury induced by malaria infection are urgently needed. in this study, we investigated the protective effect of aqueous crude extract of azadirachta indica (neem) leaves on renal injury induced by plasmodium berghei ...201526379714
no-donor dihydroartemisinin derivatives as multitarget agents for the treatment of cerebral malaria.hybrid products in which the dihydroartemisinin scaffold is combined with no-donor furoxan and nonoate moieties have been synthesized and studied as potential tools for the treatment of cerebral malaria (cm). the designed products were able to dilate rat aorta strips precontracted with phenylephrine with a no-dependent mechanism. all hybrid compounds showed preserved antiplasmodial activity in vitro and in vivo against plasmodium berghei anka, comparable to artesunate and artemether. hybrid 10, ...201526367273
the plasmodium translocon of exported proteins component exp2 is critical for establishing a patent malaria infection in mice.export of most malaria proteins into the erythrocyte cytosol requires the plasmodium translocon of exported proteins (ptex) and a cleavable plasmodium export element (pexel). in contrast, the contribution of ptex in the liver stages and export of liver stage proteins is unknown. here, using the flp/frt conditional mutatagenesis system, we generate transgenic plasmodium berghei parasites deficient in exp2, the putative pore-forming component of ptex. our data reveal that exp2 is important for par ...201626347246
multidrug atp-binding cassette transporters are essential for hepatic development of plasmodium sporozoites.multidrug resistance-associated proteins (mrps) belong to the c-family of atp-binding cassette (abc) transport proteins and are known to transport a variety of physiologically important compounds and to be involved in the extrusion of pharmaceuticals. rodent malaria parasites encode a single abc transporter subfamily c protein, whereas human parasites encode two: mrp1 and mrp2. although associated with drug resistance, their biological function and substrates remain unknown. to elucidate the rol ...201626332724
naghibione; a novel sesquiterpenoid with antiplasmodial effect from dorema hyrcanum koso-pol. root, a plant used in traditional medicine.some dorema species are used in persian traditional medicine. in the present study the total extract from the roots of dorema hyrcanum koso-pol. was investigated for its in-vitro (pldh assay) and in-vivo (peters' 4-days suppressive test) antiplasmodial effects and assessed for cytotoxicity against the normal cell line mdbk (mtt test). the ic50 values for a chloroquine- sensitive (3d7) and a chloroquine- resistant (k1) strain of plasmodium falciparum were 28.64 and 9.79 µg/ml, respectively. the i ...201526330887
structure-activity relationship studies of orally active antimalarial 2,4-diamino-thienopyrimidines.based on the initial optimization of orally active antimalarial 2,4-diamino-thienopyrimidines and with the help of metabolite identification studies, a second generation of derivatives involving changes at the 2- and 4-positions of the thienopyrimidine core were synthesized. improvements in the physiochemical properties resulted in the identification of 15a, 17a, 32, and 40 as lead molecules with improved in vivo exposure. furthermore, analogue 40 exhibited excellent in vivo antimalarial activit ...201526322748
in vivo evaluation of isolated triterpenes and semi-synthetic derivatives as antimalarial agents.the triterpenes balsaminoside b (1) and karavilagenin c (2) were isolated from the african medicinal plant momordica balsamina l. karavoates b (3) and d (4) were synthesized by diacylation of 2 with acetic and propionic anhydrides, respectively. in previous work, derivatives 3 and 4 exhibited submicromolar median inhibitory concentrations (ic50) in vitro against plasmodium falciparum welch (human malaria parasite) strains 20 to 25 times lower than those of natural product 2. the main objective o ...201526301556
the hfe genotype and a formulated diet controlling for iron status attenuate experimental cerebral malaria in mice.plasmodium falciparum infects approximately 500million individuals each year. a small but significant number of infections lead to complications such as cerebral malaria. cerebral malaria is associated with myelin damage and neurological deficits in survivors, and iron status is thought to impact the outcome of infection. we evaluated whether a mouse model of experimental cerebral malaria with plasmodium berghei anka strain was altered by dietary iron deficiency or genetic iron overload (h67d hf ...201526296689
antimalarial benzoheterocyclic 4-aminoquinolines: structure-activity relationship, in vivo evaluation, mechanistic and bioactivation studies.a novel class of benzoheterocyclic analogues of amodiaquine designed to avoid toxic reactive metabolite formation was synthesized and evaluated for antiplasmodial activity against k1 (multidrug resistant) and nf54 (sensitive) strains of the malaria parasite plasmodium falciparum. structure-activity relationship studies led to the identification of highly promising analogues, the most potent of which had ic50s in the nanomolar range against both strains. the compounds further demonstrated good in ...201526264839
effect of mushroom agaricus blazei on immune response and development of experimental cerebral malaria.cerebral malaria (cm) is debilitating and sometimes fatal. disease severity has been associated with poor treatment access, therapeutic complexity and drug resistance and, thus, alternative therapies are increasingly necessary. in this study, the effect of the administration of agaricus blazei, a mushroom of brazilian origin in a model of cm caused by plasmodium berghei, strain anka, was investigated in mice.201526260055
plasmodium berghei anka infection results in exacerbated immune responses from c57bl/6 mice displaying hypothalamic obesity. 201526239414
mouse models of uncomplicated and fatal malaria.mouse models have demonstrated utility in delineating the mechanisms underlying many aspects of malaria immunology and physiology. the most common mouse models of malaria employ the rodent-specific parasite species plasmodium berghei, p. yoelii, and p. chabaudi, which elicit distinct pathologies and immune responses and are used to model different manifestations of human disease. in vitro culture methods are not well developed for rodent plasmodium parasites, which thus require in vivo maintenan ...201526236758
global expression profiling reveals shared and distinct transcript signatures in arrested act2(-) and cdpk4(-) plasmodium berghei gametocytes.gametocytogenesis and gametogenesis in malaria parasites are complex processes of cell differentiation and development likely involving many gene products. gametocytes develop in the blood of the vertebrate host but mature gametocytes are not activated until taken up by the mosquito vector. several distinct mutants have been described that block gametogenesis but the detailed molecular causes for the mutant phenotypes are not understood. to investigate whether a block in gametogenesis also resul ...201526222913
anti-plasmodium falciparum activity of quinoline-sulfonamide hybrids.fifteen quinoline-sulfonamide hybrids, with a 7-chloroquinoline moiety connected by a linker group to arylsulfonamide moieties with different substituents in the 4-position were synthesized and assayed against plasmodium falciparum. the compounds displayed high schizonticidal blood activity in vitro, with ic50 values ranging from 0.05 to 1.63 μm, in the anti-hpr2 assay against clone w2-chloroquine-resistant; ten of them showed an ic50 (ranging from 0.05 to 0.40 μm) lower than that of chloroquine ...201526190461
kix domain specific immunoglobulin a can protect from adverse lung and cerebral pathology induced by plasmodium berghei anka.plasmodium specific iga has been detected in serum and breast milk among the endemic population but the role it can play in vivo is not clear. in this report, we demonstrate the utility of malaria specific iga, elicited by peptide sequences (referred as mpep3 and mpep4) of region vi of eba-175 (pfrvi). immunization of mice with klh tagged or untagged peptides of mpep3, mpep4 or with pfrvi have resulted in specific iga response that inhibits the in vitro invasion of plasmodium falciparum merozoit ...201526188504
antiplasmodial activity and cytotoxicity of plants used in traditional medicine of iran for the treatment of fever.malaria is the most serious parasitic disease and one of the oldest recorded diseases in the world. because of the resistance of malaria parasites to current drugs, it is necessary to discover new antiplasmodial drugs. traditional medicine is one of the important sources of new antiplasmodial drugs. in this study, twenty methanolic extracts from different parts of sixteen medicinal plants used in traditional medicine of iran for the treatment of "nobeh fever" and/ or fever were screened for in-v ...201526185511
in vivo antimalarial activity of the crude root and fruit extracts of croton macrostachyus (euphorbiaceae) against plasmodium berghei in mice.euphorbiaceae (croton macrostachyus h.; bā dòu) is used in ethiopian folklore medicine for the treatment of malaria, gonorrhea, diabetes, wounds, fungal infections, and helminths. no scientific investigations have been performed to substantiate these claims. this study aimed to investigate the in vivo antiplasmodial activity of 80% methanol extract of the fruit and the root of croton macrostachyus h. in a rodent model of malaria. the rodent malaria parasite plasmodium berghei was used to inocula ...201526151030
protective activity of biflavanones from garcinia kola against plasmodium infection.garcinia kola is a medicinal plant traditionally used for malaria therapy in central africa.201526129936
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
metabolic signature profiling as a diagnostic and prognostic tool in pediatric plasmodium falciparum malaria.background.  accuracy in malaria diagnosis and staging is vital to reduce mortality and post infectious sequelae. in this study, we present a metabolomics approach to diagnostic staging of malaria infection, specifically plasmodium falciparum infection in children. methods.  a group of 421 patients between 6 months and 6 years of age with mild and severe states of malaria with age-matched controls were included in the study, 107, 192, and 122, individuals, respectively. a multivariate design was ...201526110164
synthesis, β-hematin inhibition studies and antimalarial evaluation of dehydroxy isotebuquine derivatives against plasmodium berghei.diverse dehydroxy-isotebuquine derivatives were prepared by using a five step synthetic sequence in good yields. all these new 4-aminoquinolines were evaluated as inhibitors of haemozoin formation, where most of them showed a significant inhibition value (% ihf >97). the best inhibitors were tested in vivo as potential antimalarials in mice infected with plasmodium berghei anka chloroquine susceptible strain, three of them (11b, 11d and 11h) displayed an antimalarial activity comparable to that ...201526081761
effect of crude leaf extract of osyris quadripartita on plasmodium berghei in swiss albino mice.continuous emergence of multi-drug-resistant malaria parasites and their rapid spread across the globe warrant urgent search for new anti-malarial chemotherapeutics. traditional medicinal plants have been the main sources for screening active phytochemicals against malaria. accordingly, this study was aimed at evaluating the anti-malarial activity of osyris quadripartita salzm. ex decne., a plant which is used for traditional malaria treatment by local people in different parts of ethiopia.201526077462
p-selectin is a host receptor for plasmodium msp7 ligands.plasmodium parasites typically elicit a non-sterile but protective immune response in human host populations, suggesting that the parasites actively modulate normal immunological mechanisms. p-selectin is a cell surface receptor expressed in mammals, that is a known component of the inflammatory response against pathogens and has been previously identified as a host factor that influences malaria-associated pathology both in human patients and rodent infection models.201526045295
n-cinnamoylation of antimalarial classics: effects of using acyl groups other than cinnamoyl toward dual-stage antimalarials.in a follow-up study to our reports of n-cinnamoylated chloroquine and quinacrine analogues as promising dual-stage antimalarial leads with high in vitro potency against both blood-stage plasmodium falciparum and liver-stage plasmodium berghei, we decided to investigate the effect of replacing the cinnamoyl moiety with other acyl groups. thus, a series of n-acylated analogues were synthesized, and their activities against blood- and liver-stage plasmodium spp. were assessed along with their in v ...201526038181
evaluation of the ex vivo antimalarial activity of organotin (iv) ethylphenyldithiocarbamate on erythrocytes infected with plasmodium berghei nk 65.malaria is the most destructive and dangerous parasitic disease. the commonness of this disease is getting worse mainly due to the increasing resistance of plasmodium falciparum against antimalarial drugs. therefore, the search for new antimalarial drug is urgently needed. this study was carried out to evaluate the effects of dibutyltin (iv) ethylphenyldithiocarbamate (dbep), diphenyltin (iv) ethylphenyldithiocarbamate (dpep) and triphenyltin (iv) ethylphenyldithiocarbamate (tpep) compounds as a ...201426035957
study of the antimalarial properties of hydroxyethylamine derivatives using green fluorescent protein transformed plasmodium berghei.a rapid decrease in parasitaemia remains the major goal for new antimalarial drugs and thus, in vivo models must provide precise results concerning parasitaemia modulation. hydroxyethylamine comprise an important group of alkanolamine compounds that exhibit pharmacological properties as proteases inhibitors that has already been proposed as a new class of antimalarial drugs. herein, it was tested the antimalarial property of new nine different hydroxyethylamine derivatives using the green fluore ...201526018449
from mets to malaria: rrx-001, a multi-faceted anticancer agent with activity in cerebral malaria.the survival of malaria parasites, under substantial haem-induced oxidative stress in the red blood cells (rbcs) is dependent on the pentose phosphate pathway (ppp). the ppp is the only source of nadph in the rbc, essential for the production of reduced glutathione (gsh) and for protection from oxidative stress. glucose-6-phosphate dehydrogenase (g6pd) deficiency, therefore, increases the vulnerability of erythrocytes to oxidative stress. in plasmodium, g6pd is combined with the second enzyme of ...201526017006
implications of glutathione levels in the plasmodium berghei response to chloroquine and artemisinin.malaria is one of the most devastating parasitic diseases worldwide. plasmodium drug resistance remains a major challenge to malaria control and has led to the re-emergence of the disease. chloroquine (cq) and artemisinin (art) are thought to exert their anti-malarial activity inducing cytotoxicity in the parasite by blocking heme degradation (for cq) and increasing oxidative stress. besides the contribution of the cq resistance transporter (pfcrt) and the multidrug resistant gene (pfmdr), cq re ...201526010448
protein phosphorylation during plasmodium berghei gametogenesis.plasmodium gametogenesis within the mosquito midgut is a complex differentiation process involving signaling mediated by phosphorylation, which modulate metabolic routes and protein synthesis required to complete this development. however, the mechanisms leading to gametogenesis activation are poorly understood. we analyzed protein phosphorylation during plasmodium berghei gametogenesis in vitro in serum-free medium using bidimensional electrophoresis (2-de) combined with immunoblotting (ib) and ...201526008612
phenylhydrazine administration accelerates the development of experimental cerebral malaria.phenylhydrazine (phz) treatment is generally used to enhance parasitemia in infected mice models. transient reticulocytosis is commonly observed in iron-deficient anemic hosts after treatment with iron supplementation, and is also associated with short-term hemolysis caused by phz treatment. in this study, we investigated the relationship between reticulocytosis and cerebral malaria (cm) in a murine model induced by phz administration before plasmodium berghei anka (pba) infection. mortality and ...201526005191
in vivo study on splenomegaly inhibition by genistein in plasmodium berghei-infected mice.spleen plays an important role in removing old and damaged red blood cells and malaria-infected erythrocytes. when malaria parasites invade the spleen and induce splenomegaly, splenic function tends to be impaired. thus, the inhibition of splenomegaly is strongly required to protect the spleen. in this study, malaria-induced splenomegaly is inhibited by injecting genistein into a plasmodium berghei-infected icr mouse. to explain this phenomenon, the effect of genistein in spleen and liver of mal ...201526004668
plasmodium berghei induced priming in anopheles albimanus independently of bacterial co-infection.priming in invertebrates is the acquired capacity to better combat a pathogen due to a previous exposure to sub-lethal doses of the same organism. it is proposed to be functionally analogous to immune memory in vertebrates. previous studies with anopheles gambiae mosquitoes provide evidence that the inhibitory response to a second challenge by the malaria parasite plasmodium berghei resulted from a sustained activation of hemocytes by midgut bacteria. these bacteria probably accessed the hemolym ...201526004500
mesenchymal stromal cell therapy attenuated lung and kidney injury but not brain damage in experimental cerebral malaria.malaria is the most relevant parasitic disease worldwide, and still accounts for 1 million deaths each year. since current antimalarial drugs are unable to prevent death in severe cases, new therapeutic strategies have been developed. mesenchymal stromal cells (msc) confer host resistance against malaria; however, thus far, no study has evaluated the therapeutic effects of msc therapy on brain and distal organ damage in experimental cerebral malaria.201525998168
the cytoplasmic prolyl-trna synthetase of the malaria parasite is a dual-stage target of febrifugine and its analogs.the emergence of drug resistance is a major limitation of current antimalarials. the discovery of new druggable targets and pathways including those that are critical for multiple life cycle stages of the malaria parasite is a major goal for developing next-generation antimalarial drugs. using an integrated chemogenomics approach that combined drug resistance selection, whole-genome sequencing, and an orthogonal yeast model, we demonstrate that the cytoplasmic prolyl-trna (transfer rna) syntheta ...201525995223
advances in molecular genetic systems in malaria.robust tools for analysing gene function in plasmodium parasites, which are the causative agents of malaria, are being developed at an accelerating rate. two decades after genetic technologies for use in plasmodium spp. were first described, a range of genetic tools are now available. these include conditional systems that can regulate gene expression at the genome, transcriptional or protein level, as well as more sophisticated tools for gene editing that use piggybac transposases, integrases, ...201525978707
n-acetyl cysteine and mushroom agaricus sylvaticus supplementation decreased parasitaemia and pulmonary oxidative stress in a mice model of malaria.malaria infection can cause high oxidative stress, which could lead to the development of severe forms of malaria, such as pulmonary malaria. in recent years, the role of reactive oxygen species in the pathogenesis of the disease has been discussed, as well as the potential benefit of antioxidants supplementation. the aim of this study was to investigate the effects of n-acetyl cysteine (nac) or mushroom agaricus sylvaticus supplementation on the pulmonary oxidative changes in an experimental mo ...201525971771
in vivo antiplasmodial and toxicological effect of crude ethanol extract of echinops kebericho traditionally used in treatment of malaria in ethiopia.medicinal plants have contributed significantly to current malaria treatment. emergence of resistance to currently available drugs has necessitated the search for new plant-based anti-malarial agents and several plant-based, pharmacologically active anti-malarial compounds have been isolated. this study was conducted to validate the traditional usage of echinops kebericho for treating malaria in the traditional health care system of ethiopia.201525958112
effects of 5,8-dimethylthieno[2,3-b]quinoline-2-carboxylic acid on the antioxidative defense and lipid membranes in plasmodium berghei-infected erythrocytes.plasmodium parasites degrade hemoglobin producing reactive oxygen species as toxic byproducts which are detoxified by a series of antioxidant mechanisms. quinoline compounds have demonstrated activity against hemoglobin degradation with 5,8-dimethylthieno[2,3-b]quinoline-2-carboxylic acid (tqca) representing a recent compound inhibiting this process. thus, this study was undertaken to determine the ability of tqca to modify the oxidative status in plasmodium berghei-infected erythrocytes. after ...201525956945
trafficking of the signature protein of intra-erythrocytic plasmodium berghei-induced structures, ibis1, to p. falciparum maurer's clefts.remodeling of the host red blood cell by plasmodium falciparum is well established and crucial for infection and parasite virulence. host cell modifications are not exclusive to human plasmodium parasites and also occur in hepatocytes and erythrocytes infected with murine plasmodium parasites. the recently described intra-erythrocytic p. berghei-induced structures (ibis) share similarities to p. falciparum maurer's clefts. it is shown here that a potential candidate ibis1 homologue in p. falcipa ...201525956941
in vivo antimalarial activity of α-mangostin and the new xanthone δ-mangostin.based on the previously reported in vitro antiplasmodial activity of several xanthones from garcinia mangostana, two xanthones, α-mangostin and a new compound, δ-mangostin, were isolated from mangosteen husk, and the in vitro antiplasmodial and cytotoxic effects were determined. α-mangostin was more active against the resistant plasmodium falciparum chloroquine-resistant (fcr3) strain (ic50  = 0.2 ± 0.01 μm) than δ-mangostin (ic50  = 121.2 ± 1.0 μm). furthermore, the therapeutic response accordi ...201525943035
l-arginine exacerbates experimental cerebral malaria by enhancing pro-inflammatory responses.l-arginine (l-arg), the substrate for nitric oxide (no) synthase, has been used to treat malaria to reverse endothelial dysfunction in adults. however, the safety and efficacy of l-arg remains unknown in malaria patients under the age of five, who are at the greatest risk of developing cerebral malaria (cm), a severe malaria complication. here, we tested effects of l-arg treatment on the outcomes of cm using a mouse model. experimental cerebral malaria (ecm) was induced in female c57bl/6 mice in ...201525925198
low fetal weight is directly caused by sequestration of parasites and indirectly by il-17 and il-10 imbalance in the placenta of pregnant mice with malaria.the sequestration of infected erythrocytes in the placenta can activate the syncytiotrophoblast to release cytokines that affect the micro-environment and influence the delivery of nutrients and oxygen to fetus. the high level of il-10 has been reported in the intervillous space and could prevent the pathological effects. there is still no data of th17 involvement in the pathogenesis of placental malaria. this study was conducted to reveal the influence of placental il-17 and il-10 levels on fet ...201525925177
new quinoline derivatives demonstrate a promising antimalarial activity against plasmodium falciparum in vitro and plasmodium berghei in vivo.malaria continues to be an important public health problem in the world. nowadays, the widespread parasite resistance to many drugs used in antimalarial therapy has made the effective treatment of cases and control of the disease a constant challenge. therefore, the discovery of new molecules with good antimalarial activity and tolerance to human use can be really important in the further treatment of the disease. in this study we have investigated the antiplasmodial activity of 10 synthetic com ...201525920564
disruption of parasite hmgb2 gene attenuates plasmodium berghei anka pathogenicity.eukaryotic high-mobility-group-box (hmgb) proteins are nuclear factors involved in chromatin remodeling and transcription regulation. when released into the extracellular milieu, hmgb1 acts as a proinflammatory cytokine that plays a central role in the pathogenesis of several immune-mediated inflammatory diseases. we found that the plasmodium genome encodes two genuine hmgb factors, plasmodium hmgb1 and hmgb2, that encompass, like their human counterparts, a proinflammatory domain. given that th ...201525916985
targeting the cell stress response of plasmodium falciparum to overcome artemisinin resistance.successful control of falciparum malaria depends greatly on treatment with artemisinin combination therapies. thus, reports that resistance to artemisinins (arts) has emerged, and that the prevalence of this resistance is increasing, are alarming. art resistance has recently been linked to mutations in the k13 propeller protein. we undertook a detailed kinetic analysis of the drug responses of k13 wild-type and mutant isolates of plasmodium falciparum sourced from a region in cambodia (pailin). ...201525901609
antimalarial properties of saabmal (®): an ethnomedicinal polyherbal formulation for the treatment of uncomplicated malaria infection in the tropics.malaria is a serious problem in the countries of the developing world. as the malaria parasite has become resistant to most of the antimalaria drugs available currently, there is a need to search for newer drugs. this study reports the pharmaceutical quality and in vivo antimalarial activities of a polyherbal formulation (saabmal ® ) used as malarial remedy in nigeria.201525900958
in vivo antiplasmodial and toxicological effect of maytenus senegalensis traditionally used in the treatment of malaria in tanzania.in tanzania and elsewhere, medicinal plants, including maytenus senegalensis, are still widely used in the treatment of malaria and other ailments. the aim of the present study was to investigate the in vivo antiplasmodial and toxic effects in mice.201525890324
anti-malarial activity and toxicity assessment of himatanthus articulatus, a plant used to treat malaria in the brazilian amazon.plasmodium falciparum has become resistant to some of the available drugs. several plant species are used for the treatment of malaria, such as himatanthus articulatus in parts of brazil. the present paper reports the phyto-chemistry, the anti-plasmodial and anti-malarial activity, as well as the toxicity of h. articulatus.201525888719
effect of chronic khat (catha edulis, forsk) use on outcome of plasmodium berghei anka infection in swiss albino mice.the objective of this study was to explore effects of khat (catha edulis) on outcome of rodent malaria infection and its anti-plasmodial activities on plasmodium berghei anka (pba).201525886020
specific depletion of ly6c(hi) inflammatory monocytes prevents immunopathology in experimental cerebral malaria.plasmodium berghei anka (pba) infection of c57bl/6 mice leads to experimental cerebral malaria (ecm) that is commonly associated with serious t cell mediated damage. in other parasitic infection models, inflammatory monocytes have been shown to regulate th1 responses but their role in ecm remains poorly defined, whereas neutrophils are reported to contribute to ecm immune pathology. making use of the recent development of specific monoclonal antibodies (mab), we depleted in vivo ly6c(hi) inflamm ...201525884830
the t-cell inhibitory molecule butyrophilin-like 2 is up-regulated in mild plasmodium falciparum infection and is protective during experimental cerebral malaria.plasmodium falciparum infection can result in severe disease that is associated with elevated inflammation and vital organ dysfunction; however, malaria-endemic residents gain protection from lethal outcomes and manifest only mild symptoms during infection. to characterize host responses associated with this more effective antimalarial response, we characterized whole-blood transcriptional profiles in rwandan adults during a mild malaria episode and compared them with findings from a convalescen ...201525883389
sex hormones modulate the immune response to plasmodium berghei anka in cba/ca mice.susceptibility to malaria differs between females and males, and this sexual dimorphism may have important implications for the effects of vaccines and drugs. however, little is known about the mechanisms mediating these sexual differences. because the main differences between sexes are dictated by sex hormones, we studied the effect of gonadal steroids on immune responses to malaria in cba/ca mice. we decreased sex hormones levels by gonadectomy and evaluated the splenic index and the cells inv ...201525876048
antiplasmodial activity of aqueous extract of berberis aristata roots against plasmodium berghei-infected balb/c mice.the rising problem of resistance to present antimalarial drugs stresses the need to look for newer antiplasmodial components with effective modes of action. the roots of berberis aristata dc. (berberidaceae) are used in the traditional medicine for malaria in various parts of india.201525858288
induction of cd8(+) t cell responses and protective efficacy following microneedle-mediated delivery of a live adenovirus-vectored malaria vaccine.there is an urgent need for improvements in vaccine delivery technologies. this is particularly pertinent for vaccination programmes within regions of limited resources, such as those required for adequate provision for disposal of used needles. microneedles are micron-sized structures that penetrate the stratum corneum of the skin, creating temporary conduits for the needle-free delivery of drugs or vaccines. here, we aimed to investigate immunity induced by the recombinant simian adenovirus-ve ...201525839104
changes in brain metabolites in experimental cerebral malaria infection with plasmodium berghei anka: a literature review.in this paper, we have collected the findings of available literature focusing on brain metabolites by spectroscopy in the murine model of cerebral malaria disease. the literature search for experimental cerebral malaria (ecm) and spectroscopy using national institute of health's pubmed database provided us with 9 peer-reviewed publications. these publications have used mice infected with plasmodium berghei (pba) antwerpen-kasapa (anka) strain to mimic the human infection with plasmodium falcipa ...201425823161
in vivo function of ptex88 in malaria parasite sequestration and virulence.malaria pathology is linked to remodeling of red blood cells by eukaryotic plasmodium parasites. central to host cell refurbishment is the trafficking of parasite-encoded virulence factors through the plasmodium translocon of exported proteins (ptex). much of our understanding of its function is based on experimental work with cultured plasmodium falciparum, yet direct consequences of ptex impairment during an infection remain poorly defined. using the murine malaria model parasite plasmodium be ...201525820521
in vivo antimalarial activity and mechanisms of action of 4-nerolidylcatechol derivatives.4-nerolidylcatechol (1) is an abundant antiplasmodial metabolite that is isolated from piper peltatum roots. o-acylation or o-alkylation of compound 1 provides derivatives exhibiting improved stability and significant in vitro antiplasmodial activity. the aim of this work was to study the in vitro inhibition of hemozoin formation, inhibition of isoprenoid biosynthesis in plasmodium falciparum cultures, and in vivo antimalarial activity of several 4-nerolidylcatechol derivatives. 1,2-o,o-diacetyl ...201525801563
dendritic cells subsets mediated immune response during plasmodium berghei anka and plasmodium yoelii infection.the roles of dendritic cells (dcs) in mediating immunity against plasmodium infection have been extensively investigated, but immune response during pathogenesis of malaria is still poorly understood. in the present study, we compared the splenic dcs phenotype and function during p. berghei anka (pba) or p. yoelii (p. yoelii) infection in swiss mice. we observed that pba-infected mice developed more myeloid and mature dcs capable of secreting il-12, while p. yoelii-infected mice had more plasmac ...201525792277
towards genome-wide experimental genetics in the in vivo malaria model parasite plasmodium berghei.plasmodium berghei was identified as a parasite of thicket rats (grammomys dolichurus) and anopheles dureni mosquitoes in african highland forests. successful adaptation to a range of rodent and mosquito species established p. berghei as a malaria model parasite. the introduction of stable transfection technology, permitted classical reverse genetics strategies and thus systematic functional profiling of the gene repertoire. in the past 10 years following the publication of the p. berghei genome ...201525789828
phosphatidylinositol 3-kinase γ is required for the development of experimental cerebral malaria.experimental cerebral malaria (ecm) is characterized by a strong immune response, with leukocyte recruitment, blood-brain barrier breakdown and hemorrhage in the central nervous system. phosphatidylinositol 3-kinase γ (pi3kγ) is central in signaling diverse cellular functions. using pi3kγ-deficient mice (pi3kγ-/-) and a specific pi3kγ inhibitor, we investigated the relevance of pi3kγ for the outcome and the neuroinflammatory process triggered by plasmodium berghei anka (pba) infection. infected ...201525775137
pathogenic cd8+ t cells in experimental cerebral malaria.cerebral malaria (cm) is one the major complications occurring during malaria infection. the mechanisms leading to this syndrome are still not completely understood. although it is clear that parasite sequestration is the key initiation factor, the downstream pathological processes are still highly debated. the experimental cerebral malaria (ecm) model, in which susceptible mice are infected with plasmodium berghei anka, has led to the identification of cd8(+) t cells as the major mediator of ec ...201525772948
oral lipid-based nanoformulation of tafenoquine enhanced bioavailability and blood stage antimalarial efficacy and led to a reduction in human red blood cell loss in mice.tafenoquine (tq), a new synthetic analog of primaquine, has relatively poor bioavailability and associated toxicity in glucose-6-phosphate dehydrogenase (g6pd)-deficient individuals. a microemulsion formulation of tq (mtq) with sizes <20 nm improved the solubility of tq and enhanced the oral bioavailability from 55% to 99% in healthy mice (area under the curve 0 to infinity: 11,368±1,232 and 23,842±872 min·μmol/l) for reference tq and mtq, respectively. average parasitemia in plasmodium berghei- ...201525759576
synthesis of 3-azabicyclo[3.2.2]nonanes and their antiprotozoal activities.several bicyclic compounds, 3-azabicyclo[3.2.2]nonanes, have been prepared. the new compounds were tested for their activities against one strain of the causative organism of malaria tropica, plasmodium falciparum k1, which is resistant against chloroquine and pyrimethamine. in addition, their cytotoxicity and their activity against the pathogen of the east african form of sleeping sickness, trypanosoma brucei rhodesiense, were investigated. structure-activity relationships are discussed conside ...201525746816
amodiaquine-ciprofloxacin: a potential combination therapy against drug resistant malaria.emergence of malaria parasites resistant to artemisinin necessitates the need for development of new antimalarial therapies. ciprofloxacin (cfx) a second generation quinolone antibiotic possesses some antimalarial activities. we investigated the in vivo antimalarial activities of cfx in combination with amodiaquine in mice infected with chloroquine-resistant plasmodium berghei anka. animals were treated orally with 80 or 160 mg kg-1 body weight of cfx alone given twice daily or in combination wi ...201525736371
a genome-scale vector resource enables high-throughput reverse genetic screening in a malaria parasite.the genome-wide identification of gene functions in malaria parasites is hampered by a lack of reverse genetic screening methods. we present a large-scale resource of barcoded vectors with long homology arms for effective modification of the plasmodium berghei genome. cotransfecting dozens of vectors into the haploid blood stages creates complex pools of barcoded mutants, whose competitive fitness can be measured during infection of a single mouse using barcode sequencing (barseq). to validate t ...201525732065
montanide, poly i:c and nanoparticle based vaccines promote differential suppressor and effector cell expansion: a study of induction of cd8 t cells to a minimal plasmodium berghei epitope.the development of practical and flexible vaccines to target liver stage malaria parasites would benefit from an ability to induce high levels of cd8 t cells to minimal peptide epitopes. herein we compare different adjuvant and carrier systems in a murine model for induction of interferon gamma (ifn-γ) producing cd8 t cells to the minimal immuno-dominant peptide epitope from the circumsporozoite protein (csp) of plasmodium berghei, pb9 (syipsaeki, referred to as ki). two pro-inflammatory adjuvan ...201525705207
critical role of il-33 receptor st2 in experimental cerebral malaria development.cerebral malaria, a severe complication of plasmodium falciparum infection, can be modeled in murine plasmodium berghei anka (pba) infection. pba-induced experimental cerebral malaria (ecm) is cd8(+) t-cell mediated, and influenced by th 1/th 2 balance. here, we show that il-33 expression is increased in brain undergoing ecm and we address the role of the il-33/st2 pathway in ecm development. st2-deficient mice were resistant to pba-induced neuropathology. they survived >20 days with no ecm neur ...201525682948
host erythrocyte environment influences the localization of exported protein 2, an essential component of the plasmodium translocon.malaria parasites replicating inside red blood cells (rbcs) export a large subset of proteins into the erythrocyte cytoplasm to facilitate parasite growth and survival. ptex, the parasite-encoded translocon, mediates protein transport across the parasitophorous vacuolar membrane (pvm) in plasmodium falciparum-infected erythrocytes. proteins exported into the erythrocyte cytoplasm have been localized to membranous structures, such as maurer's clefts, small vesicles, and a tubovesicular network. c ...201525662767
il-33-mediated protection against experimental cerebral malaria is linked to induction of type 2 innate lymphoid cells, m2 macrophages and regulatory t cells.cerebral malaria (cm) is a complex parasitic disease caused by plasmodium sp. failure to establish an appropriate balance between pro- and anti-inflammatory immune responses is believed to contribute to the development of cerebral pathology. using the blood-stage pba (plasmodium berghei anka) model of infection, we show here that administration of the pro-th2 cytokine, il-33, prevents the development of experimental cerebral malaria (ecm) in c57bl/6 mice and reduces the production of inflammator ...201525659095
antimalarial activity of 4-amidinoquinoline and 10-amidinobenzonaphthyridine derivatives.chloroquine (cq) has been used as first line malaria therapeutic drug for decades. emergence of cq drug-resistant plasmodium falciparum malaria throughout endemic areas of the world has limited its clinical value. mefloquine (mq) has been used as an effective malaria prophylactic drug due to its being long-acting and having a high potency against blood stage p. falciparum (pf). however, serious cns toxicity of mq has compromised its clinical value as a prophylaxis drug. therefore, new and inexpe ...201525654185
antiplasmodial activity of eco-friendly synthesized palladium nanoparticles using eclipta prostrata extract against plasmodium berghei in swiss albino mice.malaria is an infectious disease caused by the plasmodium parasite that continues to be a health issue for humans. it is one of the most common pathogenic factors of morbidity and mortality. palladium nanoparticles (pd nps) have been used as target antimicrobial compounds, as a catalyst to manufacture pharmaceuticals, degrade harmful environmental pollutants, and as sensors for the detection of various analyses. the aim of this study was to investigate the antiplasmodial activity of synthesized ...201525653029
in vitro synergistic effect of fluoroquinolone analogues in combination with artemisinin against plasmodium falciparum; their antiplasmodial action in rodent malaria model.emergence of drug-resistant parasite strains has surfaced as a major obstacle in attempts to ameliorate malaria. current treatment regimen of malaria relies on the concept of artemisinin-based combination therapy (act).201525652883
irgm3 contributes to immunopathology and is required for differentiation of antigen-specific effector cd8+ t cells in experimental cerebral malaria.gamma interferon (ifn-γ) drives antiparasite responses and immunopathology during infection with plasmodium species. immunity-related gtpases (irgs) are a class of ifn-γ-dependent proteins that are essential for cell autonomous immunity to numerous intracellular pathogens. however, it is currently unknown whether irgs modulate responses during malaria. we have used the plasmodium berghei anka (pba) model in which mice develop experimental cerebral malaria (ecm) to study the roles of irgm1 and ir ...201525644000
prodrugs of reverse fosmidomycin analogues.fosmidomycin inhibits ispc (dxr, 1-deoxy-d-xylulose 5-phosphate reductoisomerase), a key enzyme in nonmevalonate isoprenoid biosynthesis that is essential in plasmodium falciparum. the drug has been used successfully to treat malaria patients in clinical studies, thus validating ispc as an antimalarial target. however, improvement of the drug's pharmacodynamics and pharmacokinetics is desirable. here, we show that the conversion of the phosphonate moiety into acyloxymethyl and alkoxycarbonyloxym ...201525633870
addition of histamine to subcutaneously injected plasmodium berghei sporozoites increases the parasite liver load and could facilitate whole-parasite vaccination.whole-parasite immunization remains the benchmark in malaria vaccine development. a major bottleneck in the translation of whole-parasite immunization towards routine vaccination is the mode of administration, since high degrees of protection are currently only achieved by intravenous, and not by intradermal or subcutaneous injection of viable parasites. it is known that only a small proportion of subcutaneously administered parasites reach the subsequent liver stage and low parasite liver load ...201525627880
fitness cost of resistance for lumefantrine and piperaquine-resistant plasmodium berghei in a mouse model.the evolution of drug-resistant parasites is a major hindrance to malaria control, and thus understanding the behaviour of drug-resistant mutants is of clinical relevance. the study aimed to investigate how resistance against lumefantrine (lu) and piperaquine (pq), anti-malarials used as partner drugs in artemisinin-based combination therapy (act), impacts parasite fitness. this is important since resistance to act, the first-line anti-malarial regimen is increasingly being reported.201525627576
splenic cd11c+ cells derived from semi-immune mice protect naïve mice against experimental cerebral malaria.immunity to malaria requires innate, adaptive immune responses and plasmodium-specific memory cells. previously, mice semi-immune to malaria was developed. three cycles of infection and cure ('three-cure') were required to protect mice against plasmodium berghei (anka strain) infection.201525626734
cannabidiol increases survival and promotes rescue of cognitive function in a murine model of cerebral malaria.cerebral malaria (cm) is a severe complication resulting from plasmodium falciparum infection that might cause permanent neurological deficits. cannabidiol (cbd) is a nonpsychotomimetic compound of cannabis sativa with neuroprotective properties. in the present work, we evaluated the effects of cbd in a murine model of cm. female mice were infected with plasmodium berghei anka (pba) and treated with cbd (30mg/kg/day - 3 or 7days i.p.) or vehicle. on 5th day-post-infection (dpi), at the peak of t ...201525595981
plasmogem, a database supporting a community resource for large-scale experimental genetics in malaria parasites.the plasmodium genetic modification (plasmogem) database (http://plasmogem.sanger.ac.uk) provides access to a resource of modular, versatile and adaptable vectors for genome modification of plasmodium spp. parasites. plasmogem currently consists of >2000 plasmids designed to modify the genome of plasmodium berghei, a malaria parasite of rodents, which can be requested by non-profit research organisations free of charge. plasmogem vectors are designed with long homology arms for efficient genome ...201525593348
lipoxin a4 attenuates endothelial dysfunction during experimental cerebral malaria.a breakdown of the brain-blood barrier (bbb) due to endothelial dysfunction is a primary feature of cerebral malaria (cm). lipoxins (lx) are specialized pro-resolving mediators that attenuate endothelial dysfunction in different vascular beds. it has already been shown that lxa4 prolonged plasmodium berghei-infected mice survival by a mechanism that depends on inhibiting il-12 production and cd8(+)ifn-γ(+) t cells in brain tissue; however, the effects of this treatment on endothelial dysfunction ...201525576659
efficacy and pharmacokinetic evaluation of a novel anti-malarial compound (np046) in a mouse model.even though malaria is a completely preventable and treatable disease, it remains a threat to human life and a burden to the global economy due to the emergence of multiple-drug resistant malaria parasites. according to the world malaria report 2013, in 2012 there were an estimated 207 million malaria cases and 627,000 deaths. thus, the discovery and development of new, effective anti-malarial drugs are required. to achieve this goal, the department of chemistry at the university of the free sta ...201525563929
chitosan conjugated chloroquine: proficient to protect the induction of liver apoptosis during malaria.chitosan has impelled continuous motion by its unique physicochemical and biological characteristics. in our study, chitosan-tripolyphosphate (cs-tpp) particles was conjugated with an undervalued antimalarial drug, chloroquine to find out the proficiency against ros mediated caspase activation and apoptosis in liver during plasmodium berghei nk65 infection. the transmission electron microscopic image illustrated the size range of particle was less than 50 nm and the particle showed the blood com ...201525542171
experimental study of the relationship between plasmodium gametocyte density and infection success in mosquitoes; implications for the evaluation of malaria transmission-reducing interventions.the evaluation of transmission reducing interventions (tri) to control malaria widely uses membrane feeding assays. in such assays, the intensity of plasmodium infection in the vector might affect the measured efficacy of the candidates to block transmission. gametocyte density in the host blood is a determinant of the infection success in the mosquito, however, uncertain estimates of parasite densities and intrinsic characteristics of the infected blood can induce variability. to reduce this va ...201525541384
artemisia vulgaris l. ethanolic leaf extract reverses thrombocytopenia/thrombocytosis and averts end-stage disease of experimental severe plasmodium berghei murine malaria.artemisinin isolated from artemisia annua is the most potent antimalarial against chloroquine resistant plasmodium falciparum malaria. we previously reported that the ethanolic leaf extract of artemisia vulgaris, an invasive weed and the only artemisia species in sri lanka, possess both potent and safe antimalarial activity (in terms of antiparasitic properties) in a p. berghei murine malaria model. we report here a prototype study that investigated antidisease activities of a. vulgaris ethanoli ...201425540960
plasmodium attenuation: connecting the dots between early immune responses and malaria disease severity.sterile attenuation of plasmodium parasites at the liver-stage either by irradiation or genetic modification, or at the blood-stage by chemoprophylaxis, has been shown to induce immune responses that can protect against subsequent wild-type infection. however, following certain interventions, parasite attenuation can be incomplete or non-sterile. instead parasites are rendered developmentally stunted but still capable of establishing an acute infection. in experiments involving plasmodium berghe ...201425520710
efficacy of intranasal administration of artesunate in experimental cerebral malaria.improving management of patients suffering from cerebral malaria is needed to reduce the devastating mortality and morbidity of the disease in endemic areas. intravenous artesunate is currently the first-line treatment, but the lack of material and skills in the field make it difficult to implement in endemic areas. intranasal route provides a very easy and direct gateway to blood and brain to deliver medications, by-passing the brain blood barrier. therefore, it could be helpful and suitable to ...201425516091
lambda-carrageenan treatment exacerbates the severity of cerebral malaria caused by plasmodium berghei anka in balb/c mice.there is an urgent need to develop and test novel compounds against malaria infection. carrageenans, sulphated polysaccharides derived from seaweeds, have been previously shown to inhibit plasmodium falciparum in vitro. however, they are inflammatory and alter the permeability of the blood-brain barrier, raising concerns that their use as a treatment for malaria could lead to cerebral malaria (cm), a severe complication of the disease. in this work, the authors look into the effects of the admin ...201425495520
brine shrimp cytotoxicity and antimalarial activity of plants traditionally used in treatment of malaria in msambweni district.in kenya, most people use traditional medicine and medicinal plants to treat many diseases including malaria. to manage malaria, new knowledge and products are needed. traditional herbal medicine has constituted a good basis for antimalarial lead discovery and drug development.201525495507
pharmacokinetic-pharmacodynamic analysis of spiroindolone analogs and kae609 in a murine malaria model.limited information is available on the pharmacokinetic (pk) and pharmacodynamic (pd) parameters driving the efficacy of antimalarial drugs. our objective in this study was to determine dose-response relationships of a panel of related spiroindolone analogs and identify the pk-pd index that correlates best with the efficacy of kae609, a selected class representative. the dose-response efficacy studies were conducted in the plasmodium berghei murine malaria model, and the relationship between dos ...201525487807
antihemolytic activities of green tea, safflower, and mulberry extracts during plasmodium berghei infection in mice.malaria-associated hemolysis is associated with mortality in adult patients. it has been speculated that oxidative stress and inflammation induced by malaria parasite are involved in its pathophysiology. hence, we aimed to investigate the antihemolytic effect of green tea, safflower, and mulberry extracts against plasmodium berghei infection. aqueous crude extracts of these plants were prepared using hot water method and used for oral treatment in mice. groups of icr mice were infected with 6 × ...201425485155
formulation of nanotized curcumin and demonstration of its antimalarial efficacy.the present study was conducted to overcome the disadvantages associated with the poor water solubility and low bioavailability of curcumin by synthesizing nanotized curcumin and demonstrating its efficacy in treating malaria.201425484584
antiplasmodial activity of solvent fractions of methanolic root extract of dodonaea angustifolia in plasmodium berghei infected mice.malaria is one of the most important infectious diseases in the world. the choice for the treatment is highly limited, and several of these may eventually be lost or compromised due to drug resistance. the use of plant medicine in the treatment of malaria and its various presentations is a common practice in many countries of africa where the disease is mostly endemic. dodonaea angustifolia is traditionally used in ethiopia for prophylaxis against malaria. the present study is attempted to evalu ...201425465394
the plasmodium berghei sexual stage antigen psop12 induces anti-malarial transmission blocking immunity both in vivo and in vitro.anti-malarial transmission-blocking vaccines (tbvs) aim to inhibit the transmission of plasmodium from humans to mosquitoes by targeting the sexual/ookinete stages of the parasite. successful use of such interventions will subsequently result in reduced cases of malarial infection within a human population, leading to local elimination. there are currently only five lead tbv candidates under examination. there is a consequent need to identify novel antigens to allow the formulation of new potent ...201525454088
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