Publications

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preferential binding of 4-hydroxynonenal to lysine residues in specific parasite proteins in plakortin-treated plasmodium falciparum-parasitized red blood cells.the data show the frequencies by which the amino acid residues lysine, histidine and cysteine of six proteins of the malaria parasite plasmodium falciparum are post-translationally modified by the lipoperoxydation endproduct 4-hydroxynonenal after challenging the parasitized red blood cell with plakortin. plakortin is an antimalarial endoperoxide whose molecular anti-parasitic effect is described in skorokhod et al. (2015) [1]. plakortin did not elicit hemoglobin leakage from host red blood cell ...201526702418
visualization and quantification of plasmodium falciparum intraerythrocytic merozoites.malaria, a leading parasitic killer, is caused by plasmodium spp. the pathology of the disease starts when plasmodium merozoites infect erythrocytes to form rings, that matures through a large trophozoite form and develop into schizonts containing multiple merozoites. the number of intra-erythrocytic merozoites is a key-determining factor for multiplication rate of the parasite. counting of intraerythrocytic merozoites by classical 2-d microscopy method is error prone due to insufficient represe ...201526702305
in silico analysis of calcium binding pocket of perforin like protein 1: insights into the regulation of pore formation.plasmodium falciparum perforin like proteins (pfplps) are an important arsenal for the entry and exit of malaria parasites. these proteins bind and oligomerize on the membrane in calcium dependent manner and form an open pore. the calcium dependent pore forming activity of plps is usually conferred by their c2 like c-terminal domain. here, we have tried to elucidate the calcium binding residues in the c-terminal domain of pfplp1, a member of p. falciparum plps, playing a crucial role in calcium ...201526702304
in silico characterization of plasmodium falciparum purinergic receptor: a novel chemotherapeutic target.serpentine receptors with g-protein coupled receptor like seven transmembrane (7 tm) topology are identified in plasmodium. a class of 7 tm receptors known as purinergic receptors binds to purines such as adp, atp and utp and mediates important physiological functions including regulation of calcium signaling. here we performed in silico analysis of plasmodium falciparum serpentine receptors and found that one of the p. falciparum serpentine receptors, pfsr12 possess nucleotide binding consensus ...201526702303
an ultrasensitive reverse transcription polymerase chain reaction assay to detect asymptomatic low-density plasmodium falciparum and plasmodium vivax infections in small volume blood samples.highly sensitive, scalable diagnostic methods are needed to guide malaria elimination interventions. while traditional microscopy and rapid diagnostic tests (rdts) are suitable for the diagnosis of symptomatic malaria infection, more sensitive tests are needed to screen for low-density, asymptomatic infections that are targeted by interventions aiming to eliminate the entire reservoir of malaria infection in humans.201526701778
computer-vision-based technology for fast, accurate and cost effective diagnosis of malaria.microscopy has long been considered to be the gold standard for diagnosis of malaria despite the introduction of newer assays. however, it has many challenges like requirement of trained microscopists and logistic issues. a vision based device that can diagnose malaria, provide speciation and estimate parasitaemia was evaluated.201526714633
a prospective study from south india to compare the severity of malaria caused by plasmodium vivax, p. falciparum and dual infection.traditionally, plasmodium falciparum has been attributed to cause severe malaria, whereas p. vivax is considered to cause "benign" tertian malaria. recently, there has been an increasing body of evidence challenging this conviction. however, the spectrum and degree of severity of the disease caused by p. vivax, as per world health organization (2012) remains unclear. thus, in this prospective study, we aimed at comparing the severity of malaria caused by p. vivax, p. falciparum and dual infectio ...201526714506
mapping residual transmission for malaria elimination.eliminating malaria from a defined region involves draining the endemic parasite reservoir and minimizing local malaria transmission around imported malaria infections . in the last phases of malaria elimination, as universal interventions reap diminishing marginal returns, national resources must become increasingly devoted to identifying where residual transmission is occurring. the needs for accurate measures of progress and practical advice about how to allocate scarce resources require new ...201526714110
evasion of immunity to plasmodium falciparum: rosettes of blood group a impair recognition of pfemp1.the abo blood group antigens are expressed on erythrocytes but also on endothelial cells, platelets and serum proteins. notably, the abo blood group of a malaria patient determines the development of the disease given that blood group o reduces the probability to succumb in severe malaria, compared to individuals of groups a, b or ab. p. falciparum rosetting and sequestration are mediated by pfemp1, rifin and stevor, expressed at the surface of the parasitized red blood cell (prbc). antibodies t ...201526714011
a comparative study of natural immune responses against plasmodium vivax c-terminal merozoite surface protein-1 (pvmsp-1) and apical membrane antigen-1 (pvama-1) in two endemic settings.the mechanisms of cellular and humoral immune responses against p. vivax parasite remain poorly understood. several malaria immunological studies have been conducted in endemic regions where both p. falciparum and p. vivax parasites co-exist. in this study, a comparative analysis of immunity to plasmodium vivax antigens in different geography and incidence of plasmodium spp. infection was performed. we characterised antibodies against two p. vivax antigens, pvmsp-1 and pvama-1, and the cross-rea ...201526713085
imidazopyridazine inhibitors of plasmodium falciparum calcium-dependent protein kinase 1 also target cyclic gmp-dependent protein kinase and heat shock protein 90 to kill the parasite at different stages of intracellular development.imidazopyridazine compounds are potent, atp-competitive inhibitors of calcium-dependent protein kinase 1 (cdpk1) and of plasmodium falciparum parasite growth in vitro. here, we show that these compounds can be divided into two classes depending on the nature of the aromatic linker between the core and the r2 substituent group. class 1 compounds have a pyrimidine linker and inhibit parasite growth at late schizogony, whereas class 2 compounds have a nonpyrimidine linker and inhibit growth in the ...201526711771
atovaquone-proguanil remains a potential stopgap therapy for multidrug-resistant plasmodium falciparum in areas along the thai-cambodian border.our recent report of dihydroartemisinin-piperaquine failure to treat plasmodium falciparum infections in cambodia adds new urgency to the search for alternative treatments. despite dihydroartemisinin-piperaquine failure, and higher piperaquine 50% inhibitory concentrations (ic50s) following reanalysis than those previously reported, p. falciparum remained sensitive to atovaquone (atq) in vitro. there were no point mutations in the p. falciparum cytochrome b atq resistance gene. mefloquine, artem ...201526711753
methods to investigate the regulatory role of small rnas and ribosomal occupancy of plasmodium falciparum.the genetic variation responsible for the sickle cell allele (hbs) enables erythrocytes to resist infection by the malaria parasite, p. falciparum. the molecular basis of this resistance, which is known to be multifactorial, remains incompletely understood. recent studies found that the differential expression of erythrocyte micrornas, once translocated into malaria parasites, affect both gene regulation and parasite growth. these mirnas were later shown to inhibit mrna translation by forming a ...201526709459
delayed haemolysis after artesunate therapy in a cohort of patients with severe imported malaria due to plasmodium falciparum.delayed haemolytic anaemia is one of the more frequent events after treatment with intravenous artesunate in patients with severe malaria. little is known about its frequency and the outcomes of patients with this condition.201526708338
an attempt to estimate the minimal number of poles infected and treated for malaria in poland and abroad.malaria is one of the three most dangerous infectious diseases in the world. according to official statistics, there are a few dozen cases in poland annually while the number of poles treated abroad or self-treating remains unknown. poland has been declared to be malaria-free since 1963 and nowadays all cases are imported. the aim of the study is to determine the minimal number of malaria cases in poles at home and abroad in the last decade.201526726894
the il17f and il17ra genetic variants increase risk of cerebral malaria in two african populations.cerebral malaria (cm) is a neurological complication of infection with plasmodium falciparum that is partly caused by cytokine-mediated inflammation. it is not known whether interleukin-17 (il-17) cytokines, which regulate inflammation, control the development of cm. to evaluate the involvement of il-17 cytokines in cm, we analyzed 46 common polymorphisms in il17a, il17f, and il17ra (which encodes the common receptor chain of the members of the il-17 family) in two independent african population ...201526667835
genome-wide transcriptome profiling reveals functional networks involving the plasmodium falciparum drug resistance transporters pfcrt and pfmdr1.the acquisition of multidrug resistance by plasmodium falciparum underscores the need to understand the underlying molecular mechanisms so as to counter their impact on malaria control. for the many antimalarials whose mode of action relates to inhibition of heme detoxification inside infected erythrocytes, the digestive vacuole transporters pfcrt and pfmdr1 constitute primary resistance determinants.201526689807
maintenance of phenotypic diversity within a set of virulence encoding genes of the malaria parasite plasmodium falciparum.infection by the human malaria parasite plasmodium falciparum results in a broad spectrum of clinical outcomes, ranging from severe and potentially life-threatening malaria to asymptomatic carriage. in a process of naturally acquired immunity, individuals living in malaria-endemic regions build up a level of clinical protection, which attenuates infection severity in an exposure-dependent manner. underlying this shift in the immunoepidemiology as well as the observed range in malaria pathogenesi ...201526674193
[analysis of msp1 allelotypes in imported cases of plasmodium falciparum malaria from africa].to understand the allelotype characteristics of the merozoite surface protein 1 (msp1) in imported plasmodium falciparum.201526672211
a geostatistical analysis of the association between armed conflicts and plasmodium falciparum malaria in africa, 1997-2010.the absence of conflict in a country has been cited as a crucial factor affecting the operational feasibility of achieving malaria control and elimination, yet mixed evidence exists on the influence that conflicts have had on malaria transmission. over the past two decades, africa has seen substantial numbers of armed conflicts of varying length and scale, creating conditions that can disrupt control efforts and impact malaria transmission. however, very few studies have quantitatively assessed ...201526670739
evaluation of artemether-lumefantrine efficacy in the treatment of uncomplicated malaria and its association with pfmdr1, pfatpase6 and k13-propeller polymorphisms in luanda, angola.drug resistance in plasmodium falciparum has posed an obstacle to effective treatment and challenges many malaria control programmes in endemic areas. in angola, until 2003, chloroquine (cq) was used as first-line therapy for uncomplicated malaria. it was replaced initially by amodiaquine and, in 2006, by artemisinin-based combination therapy (act) with artemether-lumefantrine (al, coartem(®)). efficacy study of act, conducted in angola between 2004 and 2005, showed a baseline efficacy of ≈99%.201526670642
no polymorphism in plasmodium falciparum k13 propeller gene in clinical isolates from kolkata, india.molecular markers associated with artemisinin resistance in plasmodium falciparum are yet to be well defined. recent studies showed that polymorphisms in k13 gene are associated with artemisinin resistance. the present study was designed to know the pattern of polymorphisms in propeller region of k13 gene among the clinical isolates collected from urban kolkata after five years of act implementation. we collected 59 clinical isolates from urban kolkata and sequenced propeller region of k13 gene ...201526688755
single-target high-throughput transcription analyses reveal high levels of alternative splicing present in the fpps/ggpps from plasmodium falciparum.malaria is a tropical disease with significant morbidity and mortality. a better understanding of the metabolism of its most important etiological agent, plasmodium falciparum, is paramount to the development of better treatment and other mitigation measures. farnesyldiphosphate synthase/geranylgeranyldiphosphate synthase (fpps/ggpps) is a key enzyme in the synthesis of isoprenic chains present in many essential structures. in p. falciparum, as well as a handful of other organisms, fpps/ggpps ha ...201526688062
effect of red blood cell variants on childhood malaria in mali: a prospective cohort study.red blood cell variants protect african children from severe falciparum malaria. however, their individual and interactive effects on mild disease and parasite density, and their modification by age-dependent immunity, are poorly understood. in this study, we address these knowledge gaps in a prospective cohort study of malaria risk and plasmodium falciparum densities in malian children.201526687956
glucose-6-phosphate dehydrogenase deficiency and the risk of malaria and other diseases in children in kenya: a case-control and a cohort study.the global prevalence of x-linked glucose-6-phosphate dehydrogenase (g6pd) deficiency is thought to be a result of selection by malaria, but epidemiological studies have yielded confusing results. we investigated the relationships between g6pd deficiency and both malaria and non-malarial illnesses among children in kenya.201526686045
isolation of invasive plasmodium yoelii merozoites with a long half-life to evaluate invasion dynamics and potential invasion inhibitors.malaria symptoms and pathogenesis are caused by blood stage parasite burdens of plasmodium spp., for which invasion of red blood cells (rbcs) by merozoites is essential. successful targeting by either drugs or vaccines directed against the whole merozoite or its antigens during its transient extracellular status would contribute to malaria control by impeding rbc invasion. to understand merozoite invasion biology and mechanisms, it is desired to obtain merozoites that retain their invasion activ ...201526684675
placental malaria: decreased transfer of maternal antibodies directed to plasmodium falciparum and impact on the incidence of febrile infections in infants.the efficacy of mother-to-child placental transfer of antibodies specific to malaria blood stage antigens was investigated in the context of placental malaria infection, taking into account igg specificity and maternal hypergammaglobulinemia. the impact of the resulting maternal antibody transfer on infections in infants up to the age of 6 months was also explored. this study showed that i) placental malaria was associated with a reduced placental transfer of total and specific igg, ii) antibody ...201526698578
evaluation of the 2-aminomethylphenol jpc-2997 in aotus monkeys infected with plasmodium falciparum. 201526666945
artemether-lumefantrine pharmacokinetics and clinical response are minimally altered in pregnant ugandan women treated for uncomplicated falciparum malaria.artemether-lumefantrine is a first-line regimen for the treatment of uncomplicated malaria during the second and third trimesters of pregnancy. previous studies have reported changes in the pharmacokinetics and clinical outcomes following treatment with artemether-lumefantrine in pregnant women compared to nonpregnant adults; however, the results are inconclusive. we conducted a study in rural uganda to compare the pharmacokinetics of artemether-lumefantrine and the treatment responses between 3 ...201526666942
prevalence of plasmodium falciparum malaria among pregnant students in dodoma region, tanzania: no cases have been detected.malaria in pregnancy, being often asymptomatic, is a major problem in endemic african countries. it is characterized by anemia and placental malaria leading to poor pregnancy outcomes. in 2001 tanzania adopted an intermittent-preventive treatment of malaria in pregnancy (iptp) policy, which recommends receiving doses of antimalarial drugs every planned visit to the antenatal care centre (anc), starting from the second trimester. currently the policy is valid across the whole country, regardless ...201526664761
identification of immunodominant responses to the plasmodium falciparum antigens pfuis3, pflsa1 and pflsap2 in multiple strains of mice.malaria, caused by the plasmodium parasite, remains a serious global public health concern. a vaccine could have a substantial impact on eliminating this disease, alongside other preventative measures. we recently described the development of three novel, viral vectored vaccines expressing either of the antigens pfuis3, pflsa1 and pflsap2. each vaccination regimen provided high levels of protection against chimeric parasite challenge in a mouse model, largely dependent on cd8+ t cells. in this s ...201526659715
modulation of malaria phenotypes by pyruvate kinase (pklr) variants in a thai population.pyruvate kinase (pklr) is a critical erythrocyte enzyme that is required for glycolysis and production of atp. we have shown that pklr deficiency in mice reduces the severity (reduced parasitemia, increased survival) of blood stage malaria induced by infection with plasmodium chabaudi as. likewise, studies in human erythrocytes infected ex vivo with p. falciparum show that presence of host pk-deficiency alleles reduces infection phenotypes. we have characterized the genetic diversity of the pklr ...201526658699
differential plasmodium falciparum surface antigen expression among children with malarial retinopathy.retinopathy provides a window into the underlying pathology of life-threatening malarial coma ("cerebral malaria"), allowing differentiation between 1) coma caused by sequestration of plasmodium falciparum-infected erythrocytes in the brain and 2) coma with other underlying causes. parasite sequestration in the brain is mediated by pfemp1; a diverse parasite antigen that is inserted into the surface of infected erythrocytes and adheres to various host receptors. pfemp1 sub-groups called "dc8" an ...201526657042
contrasting patterns of serologic and functional antibody dynamics to plasmodium falciparum antigens in a kenyan birth cohort.igg antibodies to plasmodium falciparum are transferred from the maternal to fetal circulation during pregnancy, wane after birth, and are subsequently acquired in response to natural infection. we examined the dynamics of malaria antibody responses of 84 kenyan infants from birth to 36 months of age by (i) serology, (ii) variant surface antigen (vsa) assay, (iii) growth inhibitory activity (gia), and (iv) invasion inhibition assays (iia) specific for merozoite surface protein 1 (msp1) and siali ...201526656119
aspidosperma species as sources of anti-malarials: uleine is the major anti-malarial indole alkaloid from aspidosperma parvifolium (apocynaceae).several species of the genus aspidosperma (apocynaceae) are used for the treatment of human malaria in brazil and other meso- and south american countries.201526655827
clonal population expansion in an outbreak of plasmodium falciparum on the northwest coast of ecuador.determining the source of malaria outbreaks in ecuador and identifying remaining transmission foci will help in malaria elimination efforts. in this study, the genetic signatures of plasmodium falciparum isolates, obtained from an outbreak that occurred in northwest ecuador from 2012 to 2013, were characterized.201526651993
rotenoids, flavonoids, and chalcones from the root bark of millettia usaramensis.five new compounds, 4-o-geranylisoliquiritigenin (1), 12-dihydrousararotenoid b (2), 12-dihydrousararotenoid c (3), 4'-o-geranyl-7-hydroxyflavanone (4), and 4'-o-geranyl-7-hydroxydihydroflavanol (5), along with 12 known natural products (6-17) were isolated from the ch2cl2/meoh (1:1) extract of the root bark of millettia usaramensis ssp. usaramensis by chromatographic separation. the purified metabolites were identified by nmr spectroscopic and mass spectrometric analyses, whereas their absolute ...201526651537
beninese children with cerebral malaria do not develop humoral immunity against the it4-var19-dc8 pfemp1 variant linked to epcr and brain endothelial binding.malaria is still one of the most prevalent infectious diseases in the world. sequestration of infected erythrocytes (ies) is the prime mediator of disease. cytoadhesion of ies is mediated by members of the highly diverse plasmodium falciparum erythrocyte membrane protein 1 (pfemp1). a restricted sub-set of var genes encoding for pfemp1s possessing the domain cassettes dc8 and dc13 were found to bind to the endothelial protein c receptor (epcr). these var genes were shown to be highly expressed b ...201526646943
antimalarial and insecticidal activities of newly synthesized derivatives of benzimidazole.the bioactive benzimidazole and corresponding substituted phenacyl halides has been synthesized (11) new derivatives out of three compounds 8, 10 and 11 were found to inhibit the plasmodium falciparum moderately after 72 hours of incubation hence acting as antimalarial agents. while these derivatives were exhibited negligible insecticidal activity too when analyzed by impregnated filter paper method.201526639510
characterization of the 26s proteasome network in plasmodium falciparum.in eukaryotic cells, the ubiquitin-proteasome system as a key regulator of protein quality control is an excellent drug target. we therefore aimed to analyze the 26s proteasome complex in the malaria parasite plasmodium falciparum, which still threatens almost half of the world's population. first, we established an affinity purification protocol allowing for the isolation of functional 26s proteasome complexes from the parasite. subunit composition of the proteasome and component stoichiometry ...201526639022
plant expression and characterization of the transmission-blocking vaccine candidate pfgap50.despite the limited success after decades of intensive research and development efforts, vaccination still represents the most promising strategy to significantly reduce the disease burden in malaria endemic regions. besides the ultimate goal of inducing sterile protection in vaccinated individuals, the prevention of transmission by so-called transmission blocking vaccines (tbvs) is being regarded as an important feature of an efficient malaria eradication strategy. recently, plasmodium falcipar ...201526625934
an improved sybr green-1-based fluorescence method for the routine monitoring of plasmodium falciparum resistance to anti-malarial drugs.the recently introduced sybr green1 (sg) assay for testing parasites susceptibility to anti-malarial drugs needs further improvement. this has been necessitated by various setbacks, the major one being the low fluorescence intensity associated with it use. this shortcoming diminishes the anticipated hope that this novel method was going to replace the more traditional ones, such as the isotopic and microscopy. in order to restore confidence in its use, series of experiments to determine conditio ...201526625907
structures of plasmepsin ii from plasmodium falciparum in complex with two hydroxyethylamine-based inhibitors.plasmepsin ii (pmii) is one of the ten plasmepsins (pms) identified in the genome of plasmodium falciparum, the causative agent of the most severe and deadliest form of malaria. owing to the emergence of p. falciparum strains that are resistant to current antimalarial agents such as chloroquine and sulfadoxine/pyrimethamine, there is a constant pressure to find new and lasting chemotherapeutic drug therapies. previously, the crystal structure of pmii in complex with nu655, a potent antimalarial ...201526625296
pfcrt gene in plasmodium falciparum field isolates from muzaffargarh, pakistan.the aim of the study was to identify the prevalence of different species of plasmodium and haplotypes of pfcrt in plasmodium falciparum from the selected area.201526623432
reported incidence of fever for under-5 children in zambia: a longitudinal study.childhood fever is the most common clinical sign of plasmodium falciparum infection. it is used as a measure of burden of the disease and the effectiveness of control programs for malaria. this study aimed to determine the incidence of fever in under-5 children of magoye and chivuna rural areas of mazabuka district, zambia.201526623009
haplotypes of the endothelial protein c receptor (epcr) gene are not associated with severe malaria in tanzania.endothelial protein c receptor (epcr) was recently identified as a key receptor for plasmodium falciparum erythrocyte membrane protein 1 mediating sequestration of p. falciparum-infected erythrocytes in patients suffering from severe malaria. soluble epcr (sepcr) inhibits binding of p. falciparum to epcr in vitro and increased levels of sepcr have been associated with the h3 haplotype of the epcr encoding procr gene. it has been hypothesized that elevated sepcr levels, possibly linked to the pro ...201526620701
erratum to: cd14 hi cd16+ monocytes phagocytose antibody-opsonised plasmodium falciparum infected erythrocytes more efficiently than other monocyte subsets, and require cd16 and complement to do so. 201526619830
temperature and population density determine reservoir regions of seasonal persistence in highland malaria.a better understanding of malaria persistence in highly seasonal environments such as highlands and desert fringes requires identifying the factors behind the spatial reservoir of the pathogen in the low season. in these 'unstable' malaria regions, such reservoirs play a critical role by allowing persistence during the low transmission season and therefore, between seasonal outbreaks. in the highlands of east africa, the most populated epidemic regions in africa, temperature is expected to be in ...201526631558
health systems readiness and management of febrile outpatients under low malaria transmission in vanuatu.vanuatu, an archipelago country in western pacific harbouring low plasmodium falciparum and plasmodium vivax malaria transmission, has been implementing a malaria case management policy, recommending parasitological testing of patients with fever and anti-malarial treatment for test-positive only patients. a health facility survey to evaluate the health systems readiness to implement the policy and the quality of outpatient management for patients with fever was undertaken.201526630927
transfection with thymidine kinase permits bromodeoxyuridine labelling of dna replication in the human malaria parasite plasmodium falciparum.plasmodium falciparum, the causative agent of severe human malaria, is an early-diverging protozoan whose lifecycle has many unusual features, including its modes of replication. research on the plasmodium cell cycle, which occurs primarily via schizogony instead of canonical binary fission, has been hampered by a lack of tools and markers that can be transferred from cell cycle studies in model organisms. a common tool used to study dna replication and the cell cycle in human cells is the label ...201526630917
an integrative analysis of small molecule transcriptional responses in the human malaria parasite plasmodium falciparum.transcriptional responses to small molecules can provide insights into drug mode of action (moa). the capacity of the human malaria parasite, plasmodium falciparum, to respond specifically to transcriptional perturbations has been unclear based on past approaches. here, we present the most extensive profiling to date of the parasite's transcriptional responsiveness to thirty-one chemically and functionally diverse small molecules.201526637195
clinical variation of plasmodium falciparum eba-175, ama-1, and msp-3 genotypes in young children living in a seasonally high malaria transmission setting in burkina faso.the association between p. falciparum eba-175, ama-1, and msp-3 polymorphism in the pathogenicity of malaria disease was investigated. we therefore compared the prevalence of different alleles between symptomatic and asymptomatic malarial children under five years of age living in burkina faso. blood filter papers were collected during the 2008 malaria transmission season from 228 symptomatic and 199 asymptomatic children under five years of age. all patients were living in the rural area of sap ...201526634149
assessing the impact of next-generation rapid diagnostic tests on plasmodium falciparum malaria elimination strategies.mass-screen-and-treat and targeted mass-drug-administration strategies are being considered as a means to interrupt transmission of plasmodium falciparum malaria. however, the effectiveness of such strategies will depend on the extent to which current and future diagnostics are able to detect those individuals who are infectious to mosquitoes. we estimate the relationship between parasite density and onward infectivity using sensitive quantitative parasite diagnostics and mosquito feeding assays ...201526633771
comparison of diagnostics for the detection of asymptomatic plasmodium falciparum infections to inform control and elimination strategies.the global burden of malaria has been substantially reduced over the past two decades. future efforts to reduce malaria further will require moving beyond the treatment of clinical infections to targeting malaria transmission more broadly in the community. as such, the accurate identification of asymptomatic human infections, which can sustain a large proportion of transmission, is becoming a vital component of control and elimination programmes. we determined the relationship across common diag ...201526633770
challenges in antimalarial drug treatment for vivax malaria control.plasmodium vivax is the most widespread human malaria parasite, but has received much less attention than plasmodium falciparum during the past 50 years of research. plasmodium vivax was historically seen as causing only benign disease, but this view has recently changed, with increased recognition of the burden of vivax malaria, as well as numerous case reports of severe malaria or death caused by this parasite. the complexity of p. vivax biology is characteristic of specific features of the pa ...201526611336
dispensing and determinants of non-adherence to treatment for non complicated malaria caused by plasmodium vivax and plasmodium falciparum in high-risk municipalities in the brazilian amazon.in brazil, 99.7 % of malaria cases occur in the amazon region. although the number of cases is decreasing, the country accounted for almost 60 % of cases in the americas region, in 2013. novel approaches for malaria treatment open the possibility of eliminating the disease, but suboptimal dispensing and lack of adherence influence treatment outcomes. the aim of this paper is to show the results on dispensing practices, non-adherence and determinants of non-adherence to treatment of non-complicat ...201526611324
summary of anti-malarial prophylactic efficacy of tafenoquine from three placebo-controlled studies of residents of malaria-endemic countries.tafenoquine is a long half-life primaquine analog being developed for malaria prophylaxis. the us army recently performed a unified analysis of efficacy in preparation for a regulatory submission, utilizing legacy data from three placebo-controlled studies conducted in the late 1990s and early 2000s. the subjects were residents of africa who were naturally exposed to plasmodium falciparum for 12-26 weeks.201526610844
efficacy and safety of fixed dose combination of arterolane maleate and piperaquine phosphate dispersible tablets in paediatric patients with acute uncomplicated plasmodium falciparum malaria: a phase ii, multicentric, open-label study.the world health organization (who) recommends artemisinin combination therapy (act) for the treatment of uncomplicated plasmodium falciparum malaria. the present study investigated the efficacy and safety of fixed dose combination (fdc) of arterolane maleate 37.5 mg and piperaquine phosphate (pqp) 187.5 mg dispersible tablets in paediatric patients aged 6 months to 12 years.201526608469
analysis of nucleosome positioning landscapes enables gene discovery in the human malaria parasite plasmodium falciparum.plasmodium falciparum, the deadliest malaria-causing parasite, has an extremely at-rich (80.7 %) genome. because of high at-content, sequence-based annotation of genes and functional elements remains challenging. in order to better understand the regulatory network controlling gene expression in the parasite, a more complete genome annotation as well as analysis tools adapted for at-rich genomes are needed. recent studies on genome-wide nucleosome positioning in eukaryotes have shown that nucleo ...201526607328
antiplasmodial activity of iron(ii) and ruthenium(ii) organometallic complexes against plasmodium falciparum blood parasites.this work reports the in vitro activity against plasmodium falciparum blood forms (w2 clone, chloroquine-resistant) of tamoxifen-based compounds and their ferrocenyl (ferrocifens) and ruthenocenyl (ruthenocifens) derivatives, as well as their cytotoxicity against hepg2 human hepatoma cells. surprisingly with these series, results indicate that the biological activity of ruthenocifens is better than that of ferrocifens and other tamoxifen-like compounds. the synthesis of a new metal-based compoun ...201526602875
evidence of il-17, ip-10, and il-10 involvement in multiple-organ dysfunction and il-17 pathway in acute renal failure associated to plasmodium falciparum malaria.plasmodium falciparum malaria in india is characterized by high rates of severe disease, with multiple organ dysfunction (mod)-mainly associated with acute renal failure (arf)-and increased mortality. the objective of this study is to identify cytokine signatures differentiating severe malaria patients with mod, cerebral malaria (cm), and cerebral malaria with mod (cm-mod) in india. we have previously shown that two cytokines clusters differentiated cm from mild malaria in maharashtra. hence, we ...201526602091
role of s180l polymorphism in etiology of malaria caused by plasmodium falciparum in a small group of pakistani population.the aim of our study was to investigate the role of s180l polymorphism in modulation of acquisition of malaria caused by plasmodium falciparum in a small group of pakistani population. a total of 133 individuals including 60 controls and 73 patients of malaria, caused by plasmodium falciparum, were genotyped using allele-specific pcr. ninety-two samples successfully demonstrated the pcr amplification results, while forty-one samples could not be genotyped due to failure in pcr amplification. the ...201526614847
quantitative analysis of drug effects at the whole-body level: a case study for glucose metabolism in malaria patients.we propose a hierarchical modelling approach to construct models for disease states at the whole-body level. such models can simulate effects of drug-induced inhibition of reaction steps on the whole-body physiology. we illustrate the approach for glucose metabolism in malaria patients, by merging two detailed kinetic models for glucose metabolism in the parasite plasmodium falciparum and the human red blood cell with a coarse-grained model for whole-body glucose metabolism. in addition we use a ...201526614654
malaria parasite-infected erythrocytes secrete pfck1, the plasmodium homologue of the pleiotropic protein kinase casein kinase 1.casein kinase 1 (ck1) is a pleiotropic protein kinase implicated in several fundamental processes of eukaryotic cell biology. plasmodium falciparum encodes a single ck1 isoform, pfck1, that is expressed at all stages of the parasite's life cycle. we have previously shown that the pfck1 gene cannot be disrupted, but that the locus can be modified if no loss-of-function is incurred, suggesting an important role for this kinase in intra-erythrocytic asexual proliferation. here, we report on the use ...201526629826
attenuation of plasmodium falciparum in vitro drug resistance phenotype following culture adaptation compared to fresh clinical isolates in cambodia.there is currently no standardized approach for assessing in vitro anti-malarial drug susceptibility. potential alterations in drug susceptibility results between fresh immediate ex vivo (iev) and cryopreserved culture-adapted (cca) plasmodium falciparum isolates, as well as changes in parasite genotype during culture adaptation were investigated.201526626127
high resolution structures of plasmodium falciparum gst complexes provide novel insights into the dimer-tetramer transition and a novel ligand-binding site.protection from oxidative stress and efficient redox regulation are essential for malarial parasites which have to grow and multiply rapidly in pro-oxidant rich environments. therefore, redox active proteins currently belong to the most attractive antimalarial drug targets. the glutathione s-transferase from plasmodium falciparum (pfgst) is a redox active protein displaying a peculiar dimer-tetramer transition that causes full enzyme-inactivation. this distinct structural feature is absent in ma ...201526072058
strand-specific rna sequencing in plasmodium falciparum malaria identifies developmentally regulated long non-coding rna and circular rna.the human malaria parasite plasmodium falciparum has a complex and multi-stage life cycle that requires extensive and precise gene regulation to allow invasion and hijacking of host cells, transmission, and immune escape. to date, the regulatory elements orchestrating these critical parasite processes remain largely unknown. yet it is becoming increasingly clear that long non-coding rnas (lncrnas) could represent a missing regulatory layer across a broad range of organisms.201526070627
flow cytometry based detection and isolation of plasmodium falciparum liver stages in vitro.malaria, the disease caused by plasmodium parasites, remains a major global health burden. the liver stage of plasmodium falciparum infection is a leading target for immunological and pharmacological interventions. therefore, novel approaches providing specific detection and isolation of live p. falciparum exoerythrocytic forms (eefs) are warranted. utilizing a recently generated parasite strain expressing green fluorescent protein (gfp) we established a method which, allows for detection and is ...201526070149
population genetic study of plasmodium falciparum parasites pertaining to dhps gene sequence in malaria endemic areas of assam.plasmodium falciparum malaria parasite had developed resistance to almost all the currently used antimalarial drugs. the purpose of the study was to come across the genetic distances in p. falciparum dhps gene sequences circulating in assam. a partial fragment of p. falciparum dhps gene containing major single nucleotide polymorphisms associated with sulphadoxine resistance were amplified and sequenced. thereafter specific bioinformatics tools like bioedit v7.0.9, clustalw in mega 5, dnasp versi ...201526068343
benzoxaborole antimalarial agents. part 4. discovery of potent 6-(2-(alkoxycarbonyl)pyrazinyl-5-oxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaboroles.a series of 6-hetaryloxy benzoxaborole compounds was designed and synthesized for a structure-activity relationship (sar) investigation to assess the changes in antimalarial activity which result from 6-aryloxy structural variation, substituent modification on the pyrazine ring, and optimization of the side chain ester group. this sar study discovered highly potent 6-(2-(alkoxycarbonyl)pyrazinyl-5-oxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaboroles (9, 27-34) with ic50s = 0.2-22 nm against cultured pl ...201526067904
a plasmodium falciparum bromodomain protein regulates invasion gene expression.during red-blood-cell-stage infection of plasmodium falciparum, the parasite undergoes repeated rounds of replication, egress, and invasion. erythrocyte invasion involves specific interactions between host cell receptors and parasite ligands and coordinated expression of genes specific to this step of the life cycle. we show that a parasite-specific bromodomain protein, pfbdp1, binds to chromatin at transcriptional start sites of invasion-related genes and directly controls their expression. con ...201526067602
categorical complexities of plasmodium falciparum malaria in individuals is associated with genetic variations in adora2a and grk5 genes.in the erythrocytes, malaria parasite entry and infection is mediated through complex membrane sorting and signaling processes. we investigated the effects of single-locus and multilocus interactions to test the hypothesis that the members of the gpcr family genes, adenosine a2a receptor (adora2a) and g-protein coupled receptor kinase5 (grk5), may contribute to the pathogenesis of malaria caused by plasmodium falciparum (pf) independently or through complex interactions. in a case-control study ...201526066465
structure-activity relationship of hybrids of cinchona alkaloids and bile acids with in vitro antiplasmodial and antitrypanosomal activities.in this work, a series of hybrid compounds were tested as antiparasitic substances. these hybrids were prepared from bile acids and a series of antiparasitic cinchona alkaloids by the formation of a covalent c-c bond via a decarboxylative barton-zard reaction between the two entities. the bile acids showed only weak antiparasitic properties, but all the hybrids exhibited high in vitro activities (ic50: 0.48-5.39 μm) against trypanosoma brucei. these hybrids were more active than their respective ...201526063305
role and regulation of glutathione metabolism in plasmodium falciparum.malaria in humans is caused by one of five species of obligate intracellular protozoan parasites of the genus plasmodium. p. falciparum causes the most severe disease and is responsible for 600,000 deaths annually, primarily in sub-saharan africa. it has long been suggested that during their development, malaria parasites are exposed to environmental and metabolic stresses. one strategy to drug discovery was to increase these stresses by interfering with the parasites' antioxidant and redox syst ...201526060916
two crystal structures of the fk506-binding domain of plasmodium falciparum fkbp35 in complex with rapamycin at high resolution.antimalarial chemotherapy continues to be challenging in view of the emergence of drug resistance, especially artemisinin resistance in southeast asia. it is critical that novel antimalarial drugs are identified that inhibit new targets with unexplored mechanisms of action. it has been demonstrated that the immunosuppressive drug rapamycin, which is currently in clinical use to prevent organ-transplant rejection, has antimalarial effects. the plasmodium falciparum target protein is pffkbp35, a u ...201526057671
entonalactams a-c: isoindolinone derivatives from an australian rainforest fungus belonging to the genus entonaema.bioassay-guided fractionation of an antimalarial dcm/meoh extract derived from the australian rainforest fungus entonaema sp. resulted in the isolation of three new isoindolinone derivatives, entonalactams a-c (1-3), along with the known natural products 3-methoxy-5-methylbenzene-1,2-diol (4), daldinal b (5), and ergosta-4,6,8(14),22-tetraen-3-one (6). the chemical structures of the new secondary metabolites were determined following extensive 1d/2d nmr and ms data analysis. a single crystal x-r ...201526057224
ferrocene-pyrimidine conjugates: synthesis, electrochemistry, physicochemical properties and antiplasmodial activities.the promise of hybrid antimalarial agents and the precedence set by the antimalarial drug ferroquine prompted us to design ferrocene-pyrimidine conjugates. herein, we report the synthesis, electrochemistry and anti-plasmodial evaluation of ferrocenyl-pyrimidine conjugates against chloroquine susceptible nf54 strain of the malaria parasite plasmodium falciparum. also their physicochemical properties have been studied.201526057222
antimalarial isocyano and isothiocyanato sesquiterpenes with tri- and bicyclic skeletons from the nudibranch phyllidia ocellata.five new isocyano/isothiocyanato sesquiterpenes (1-5) with tri- or bicyclic carbon skeletons have been characterized from australian specimens of the nudibranch phyllidia ocellata. spectroscopic analyses at 900 mhz were informed by dft calculations. the 1s, 5s, 8r configuration of 2-isocyanoclovene (1) was determined by x-ray crystallographic analysis of formamide 6. a biosynthetic pathway to clovanes 1 and 2 from epicaryolane precursors is proposed. isocyanides 1, 2, and 4 showed activity again ...201526056748
topoisomerase ii from human malaria parasites: expression, purification, and selective inhibition.historically, type ii topoisomerases have yielded clinically useful drugs for the treatment of bacterial infections and cancer, but the corresponding enzymes from malaria parasites remain understudied. this is due to the general challenges of producing malaria proteins in functional forms in heterologous expression systems. here, we express full-length plasmodium falciparum topoisomerase ii (pftopoii) in a wheat germ cell-free transcription-translation system. functional activity of soluble pfto ...201526055707
molecular markers and in vitro susceptibility to doxycycline in plasmodium falciparum isolates from thailand.determinations of doxycycline 50% inhibitory concentrations (ic50) for 620 isolates from northwest thailand were performed via the isotopic method, and the data were analyzed by the bayesian method and distributed into two populations (mean ic50s of 13.15 μm and 31.60 μm). there was no significant difference between the group with low ic50s versus the group with high ic50s with regard to copy numbers of the plasmodium falciparum tetq (pftetq) gene (p = 0.11) or pfmdt gene (p = 0.87) or the numbe ...201526055380
tpub05, a homologue of the immunodominant plasmodium falciparum protein ub05, is a marker of protective immune responses in cattle experimentally vaccinated against east coast fever.east coast fever, a devastating disease of cattle, can be controlled partially by vaccination with live t. parva sporozoites. the antigens responsible for conferring immunity are not fully characterized. recently it was shown that the p. falciparum immunodominant protein ub05 is highly conserved in t. parva, the causative agent of east coast fever. the aim of the present investigation was to determine the role of the homologue tpub05 in protective immunity to east coast fever.201526053064
presence of plasmodium falciparum dna in plasma does not predict clinical malaria in an hiv-1 infected population.hiv-1 and plasmodium falciparum malaria cause substantial morbidity in sub-saharan africa, especially as co-infecting pathogens. we examined the relationship between presence of p. falciparum dna in plasma samples and clinical malaria as well as the impact of atazanavir, an hiv-1 protease inhibitor (pi), on p. falciparum pcr positivity.201526053030
co-evolutionary analysis implies auxiliary functions of hsp110 in plasmodium falciparum.plasmodium falciparum encounters frequent environmental challenges during its life cycle which makes productive protein folding immensely challenging for its metastable proteome. to identify the important components of protein folding machinery involved in maintaining p. falciparum proteome, we performed a proteome-wide phylogenetic profiling across various species. we found that except hsp110, the parasite lost all other cytosolic nucleotide exchange factors essential for regulating hsp70 which ...201526052682
developing vaccines to prevent malaria in pregnant women.placental malaria (pm) is a major public health problem that constitutes a significant health concern for the mother, and especially for the developing fetus and offspring. current means of prevention have limitations, including a restricted window of intervention that excludes the first trimester of pregnancy, and the fact that very few drugs can be used for this purpose. the identification of the var2csa antigen, specific to pm parasites, offers an excellent opportunity to develop a vaccine ag ...201526051589
the evolutionary origins of southeast asian ovalocytosis.southeast asian ovalocytosis (sao) is a common red blood cell disorder that is maintained as a balanced polymorphism in human populations. in individuals heterozygous for the sao-causing mutation there are minimal detrimental effects and well-documented protection from severe malaria caused by plasmodium vivax and plasmodium falciparum; however, the sao-causing mutation is fully lethal in utero when homozygous. the present-day high frequency of sao in island southeast asia indicates the trait is ...201526047685
assessment of therapeutic efficacy and safety of artemether-lumefantrine (coartem®) in the treatment of uncomplicated plasmodium falciparum malaria patients in bahir dar district, northwest ethiopia: an observational cohort study.malaria is a complex disease, which varies in its epidemiology and clinical manifestation. although artemether-lumefantrine has been used as first-line drug for uncomplicated plasmodium falciparum malaria in bahir dar district since 2004, its efficacy has not yet been assessed. the main objective of this study was to quantify the proportion of patients with uncomplicated falciparum malaria who were prescribed artemether-lumefantrine and who failed treatment after a 28-day follow-up.201526045199
genome-wide collation of the plasmodium falciparum wdr protein superfamily reveals malarial parasite-specific features.despite a significant drop in malaria deaths during the past decade, malaria continues to be one of the biggest health problems around the globe. wd40 repeats (wdrs) containing proteins comprise one of the largest and functionally diverse protein superfamily in eukaryotes, acting as scaffolds for assembling large protein complexes. in the present study, we report an extensive in silico analysis of the wdr gene family in human malaria parasite plasmodium falciparum. our genome-wide identification ...201526043001
use of plasmodium falciparum culture-adapted field isolates for in vitro exflagellation-blocking assay.a major requirement for malaria elimination is the development of transmission-blocking interventions. in vitro transmission-blocking bioassays currently mostly rely on the use of very few plasmodium falciparum reference laboratory strains isolated decades ago. to fill a piece of the gap between laboratory experimental models and natural systems, the purpose of this work was to determine if culture-adapted field isolates of p. falciparum are suitable for in vitro transmission-blocking bioassays ...201526040313
development of a genetic tool for functional screening of anti-malarial bioactive extracts in metagenomic libraries.the chemical treatment of plasmodium falciparum for human infections is losing efficacy each year due to the rise of resistance. one possible strategy to find novel anti-malarial drugs is to access the largest reservoir of genomic biodiversity source on earth present in metagenomes of environmental microbial communities.201526040274
design and evaluation of antimalarial peptides derived from prediction of short linear motifs in proteins related to erythrocyte invasion.the purpose of this study was to investigate the blood stage of the malaria causing parasite, plasmodium falciparum, to predict potential protein interactions between the parasite merozoite and the host erythrocyte and design peptides that could interrupt these predicted interactions. we screened the p. falciparum and human proteomes for computationally predicted short linear motifs (slims) in cytoplasmic portions of transmembrane proteins that could play roles in the invasion of the erythrocyte ...201526039561
past five-year trend, current prevalence and household knowledge, attitude and practice of malaria in abeshge, south-central ethiopia.in ethiopia malaria remains a leading cause of outpatient consultation despite massive control efforts. this study was aimed at analysing 5-year retrospective trend and current prevalence of malaria as well as community knowledge, attitude and practice (kap) in walga health centre (whc) catchment area in abeshge district, south-central ethiopia.201526037129
inhibiting the mammalian target of rapamycin blocks the development of experimental cerebral malaria.malaria is an infectious disease caused by parasites of several plasmodium spp. cerebral malaria (cm) is a common form of severe malaria resulting in nearly 700,000 deaths each year in africa alone. at present, there is no adjunctive therapy for cm. although the mechanisms underlying the pathogenesis of cm are incompletely understood, it is likely that both intrinsic features of the parasite and the human host's immune response contribute to disease. the kinase mammalian target of rapamycin (mto ...201526037126
preserved dendritic cell hla-dr expression and reduced regulatory t cell activation in asymptomatic plasmodium falciparum and p. vivax infection.clinical illness with plasmodium falciparum or plasmodium vivax compromises the function of dendritic cells (dc) and expands regulatory t (treg) cells. individuals with asymptomatic parasitemia have clinical immunity, restricting parasite expansion and preventing clinical disease. the role of dc and treg cells during asymptomatic plasmodium infection is unclear. during a cross-sectional household survey in papua, indonesia, we examined the number and activation of blood plasmacytoid dc (pdc), cd ...201526034211
lack of artemisinin resistance in plasmodium falciparum in uganda based on parasitological and molecular assays.we evaluated markers of artemisinin resistance in plasmodium falciparum isolated in kampala in 2014. by standard in vitro assays, all isolates were highly sensitive to dihydroartemisinin (dha). by the ring-stage survival assay, after a 6-h dha pulse, parasitemia was undetectable in 40 of 43 cultures at 72 h. two of 53 isolates had nonsynonymous k13-propeller gene polymorphisms but did not have the mutations associated with resistance in asia. thus, we did not see evidence for artemisinin resista ...201526033725
antimalarial effect of 3-methoxy-1,2-dioxetanes on the erythrocytic cycle of plasmodium falciparum.the antimalarial activity of peroxides most likely originates from their interaction with iron(ii) species located inside the malaria parasite, which forms destructive radical species through a fenton-like mechanism. this article reports the first evaluation of the in vitro antimalarial activity of three peroxides of the class 1,2-dioxetanes against plasmodium falciparum; the results reveal that the studied 3-methoxy-1,2-dioxetanes display significant antimalarial activity, at a similar level as ...201526032859
a cautionary note on fecal sampling and molecular epidemiology in predatory wild great apes.fecal samples are an important source of information on parasites (viruses, prokaryotes, or eukaryotes) infecting wild great apes. molecular analysis of fecal samples has already been used for deciphering the origins of major human pathogens such as hiv-1 or plasmodium falciparum. however, for apes that hunt (chimpanzees and bonobos), detection of parasite nucleic acids may reflect either true infection of the host of interest or ingestion of an infected prey, for example, another non-human prim ...201526031302
enlightening the malaria parasite life cycle: bioluminescent plasmodium in fundamental and applied research.the unicellular protozoan parasites of the genus plasmodium impose on human health worldwide the enormous burden of malaria. the possibility to genetically modify several species of malaria parasites represented a major advance in the possibility to elucidate their biology and is now turning laboratory lines of transgenic plasmodium into precious weapons to fight malaria. amongst the various genetically modified plasmodia, transgenic parasite lines expressing bioluminescent reporters have been e ...201526029172
the value of local malaria strains for serological studies: local strains versus palo alto reference strain.the standardization of the type of crude plasmodium falciparum extracts for assays to evaluate the overall anti-blood-stage immune response in humans may be beneficial to malaria pre-elimination programmes. however, there is no consensus on which strain is appropriate for routine analyses. this study aimed to compare the responses of malaria igg antibodies in serum collections from dielmo and ndiop to crude extracts of merozoites and schizonts of local and reference strains of p. falciparum.201526026312
resistance to antimalarial drugs: an endless world war against plasmodium that we risk losing.the objective of this review was to describe the 'state of the art' of plasmodium falciparum resistance to the main antimalarial drugs. a brief note on plasmodium vivax is also included. resistance of p. falciparum to the various antimalarials has a long history of hits and misses. during the last 60 years, the pace at which this parasite has developed resistance to antimalarial drugs has exceeded the pace at which new drugs have been developed. in the last decade, the introduction of artemisini ...201527873670
an ab initio method for designing multi-target specific pharmacophores using complementary interaction field of aspartic proteases.for past few decades, key objectives of rational drug discovery have been the designing of specific and selective ligands for target proteins. infectious diseases like malaria are continuously becoming resistant to traditional medicines, which inculcates need for new approaches to design inhibitors for antimalarial targets. a novel method for ab initio designing of multi target specific pharmacophores using the interaction field maps of active sites of multiple proteins has been developed to des ...201527490384
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