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EY Lukianova-Hleb et al. Hemozoin-generated vapor nanobubbles for transdermal reagent- and needle-free detection of malaria. Proc Natl Acad Sci U S A

High Impact Journal from Malaria Portal - 31 December 2014 - 12:00am
Successful diagnosis, screening, and elimination of malaria critically depend on rapid and sensitive detection of this dangerous infection, preferably transdermally and without sophisticated reagents or blood drawing. . . .
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KJ Vogel et al. Phylogenetic investigation of Peptide hormone and growth factor receptors in five dipteran genomes. Front Endocrinol (Lausanne)

High Impact Journal from Malaria Portal - 31 December 2014 - 12:00am
Peptide hormones and growth factors bind to membrane receptors and regulate a myriad of processes in insects and other metazoans. . . .
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J Rydzak et al. Human erythrocyte glycophorin C as the receptor for EBA-140 Plasmodium falciparum merozoite ligand. Postepy Hig Med Dosw (Online)

High Impact Journal from Malaria Portal - 31 December 2014 - 12:00am
Erythrocyte invasion by the blood-stage Plasmodium falciparum parasites is a multistep process involving specific interactions between parasites and red blood cells. . . .
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R Sundararajan et al. Barriers to Malaria Control among Marginalized Tribal Communities: A Qualitative Study. PLoS One

High Impact Journal from Malaria Portal - 30 December 2014 - 12:00am
Malaria infection accounts for over one million deaths worldwide annually. . . .
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DV Canyon et al. Insights in public health: systems thinking: basic constructs, application challenges, misuse in health, and how public health leaders can pave the way forward. Hawaii J Med Public Health

High Impact Journal from Malaria Portal - 30 December 2014 - 12:00am
The strengthening of health systems is fundamental to improving health outcomes, crisis preparedness, and our capacity to meet global challenges, such as accelerating progress towards the Millennium Development Goals, reducing maternal and child mortality, combating HIV, malaria and other diseases, limiting the effects of a new influenza pandemic, and responding appropriately to climate change. . . .
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Biochemical and functional characterization of Plasmodium falciparum GTP cyclohydrolase I

Malaria Journal - 19 April 2014 - 12:00am
Background: Antifolates are currently in clinical use for malaria preventive therapy and treatment. The drugs kill the parasites by targeting the enzymes in the de novo folate pathway. The use of antifolates has now been limited by the spread of drug-resistant mutations. GTP cyclohydrolase I (GCH1) is the first and the rate-limiting enzyme in the folate pathway. The amplification of the gch1 gene found in certain Plasmodium falciparum isolates can cause antifolate resistance and influence the course of antifolate resistance evolution. These findings showed the importance of P. falciparum GCH1 in drug resistance intervention. However, little is known about P. falciparum GCH1 in terms of kinetic parameters and functional assays, precluding the opportunity to obtain the key information on its catalytic reaction and to eventually develop this enzyme as a drug target. Methods: Plasmodium falciparum GCH1 was cloned and expressed in bacteria. Enzymatic activity was determined by the measurement of fluorescent converted neopterin with assay validation by using mutant and GTP analogue. The genetic complementation study was performed in [increment]folE bacteria to functionally identify the residues and domains of P. falciparum GCH1 required for its enzymatic activity. Plasmodial GCH1 sequences were aligned and structurally modeled to reveal conserved catalytic residues. Results: Kinetic parameters and optimal conditions for enzymatic reactions were determined by the fluorescence-based assay. The inhibitor test against P. falciparum GCH1 is now possible as indicated by the inhibitory effect by 8-oxo-GTP. Genetic complementation was proven to be a convenient method to study the function of P. falciparum GCH1. A series of domain truncations revealed that the conserved core domain of GCH1 is responsible for its enzymatic activity. Homology modelling fits P. falciparum GCH1 into the classic Tunnelling-fold structure with well-conserved catalytic residues at the active site. Conclusions: Functional assays for P. falciparum GCH1 based on enzymatic activity and genetic complementation were successfully developed. The assays in combination with a homology model characterized the enzymatic activity of P. falciparum GCH1 and the importance of its key amino acid residues. The potential to use the assay for inhibitor screening was validated by 8-oxo-GTP, a known GTP analogue inhibitor.
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Changes in Malaria Parasite Drug Resistance in an Endemic Population Over a 25-Year Period With Resulting Genomic Evidence of Selection

CiteULike malaria tags - 17 April 2014 - 10:54am
Journal of Infectious Diseases, Vol. 209, No. 7. (1 April 2014), pp. 1126-1135, doi:10.1093/infdis/jit618

Background. Analysis of genome-wide polymorphism in many organisms has potential to identify genes under recent selection. However, data on historical allele frequency changes are rarely available for direct confirmation.Methods. We genotyped single nucleotide polymorphisms (SNPs) in 4 Plasmodium falciparum drug resistance genes in 668 archived parasite-positive blood samples of a Gambian population between 1984 and 2008. This covered a period before antimalarial resistance was detected locally, through subsequent failure of multiple drugs until introduction of artemisinin combination therapy. We separately performed genome-wide sequence analysis of 52 clinical isolates from 2008 to prospect for loci under recent directional selection.Results. Resistance alleles increased from very low frequencies, peaking in 2000 for chloroquine resistance-associated crt and mdr1 genes and at the end of the survey period for dhfr and dhps genes respectively associated with pyrimethamine and sulfadoxine resistance. Temporal changes fit a model incorporating likely selection coefficients over the period. Three of the drug resistance loci were in the top 4 regions under strong selection implicated by the genome-wide analysis.Conclusions. Genome-wide polymorphism analysis of an endemic population sample robustly identifies loci with detailed documentation of recent selection, demonstrating power to prospectively detect emerging drug resistance genes.
Davis Nwakanma, Craig Duffy, Alfred Amambua-Ngwa, Eniyou Oriero, Kalifa Bojang, Margaret Pinder, Chris Drakeley, Colin Sutherland, Paul Milligan, Bronwyn MacInnis, Dominic Kwiatkowski, Taane Clark, Brian Greenwood, David Conway
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Epistasis between the haptoglobin common variant and α+thalassemia influences risk of severe malaria in Kenyan children

CiteULike malaria tags - 17 April 2014 - 9:54am
Blood, Vol. 123, No. 13. (27 March 2014), pp. 2008-2016, doi:10.1182/blood-2013-10-533489

Haptoglobin (Hp) scavenges free hemoglobin following malaria-induced hemolysis. Few studies have investigated the relationship between the common Hp variants and the risk of severe malaria, and their results are inconclusive. We conducted a case-control study of 996 children with severe Plasmodium falciparum malaria and 1220 community controls and genotyped for Hp, hemoglobin (Hb) S heterozygotes, and α+thalassemia. Hb S heterozygotes and α+thalassemia homozygotes were protected from severe malaria (odds ratio [OR], 0.12; 95% confidence interval [CI], 0.07-0.18 and OR, 0.69; 95% CI, 0.53-0.91, respectively). The risk of severe malaria also varied by Hp genotype: Hp2-1 was associated with the greatest protection against severe malaria and Hp2-2 with the greatest risk. Meta-analysis of the current and published studies suggests that Hp2-2 is associated with increased risk of severe malaria compared with Hp2-1. We found a significant interaction between Hp genotype and α+thalassemia in predicting risk of severe malaria: Hp2-1 in combination with heterozygous or homozygous α+thalassemia was associated with protection from severe malaria (OR, 0.73; 95% CI, 0.54-0.99 and OR, 0.48; 95% CI, 0.32-0.73, respectively), but α+thalassemia in combination with Hp2-2 was not protective. This epistatic interaction together with varying frequencies of α+thalassemia across Africa may explain the inconsistent relationship between Hp genotype and malaria reported in previous studies.
Sarah Atkinson, Sophie Uyoga, Emily Nyatichi, Alex Macharia, Gideon Nyutu, Carolyne Ndila, Dominic Kwiatkowski, Kirk Rockett, Thomas Williams
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A Jones et al. Transformation of HIV from pandemic to low-endemic levels: a public health approach to combination prevention. Lancet

High Impact Journal from Malaria Portal - 17 April 2014 - 12:00am
Large declines in HIV incidence have been reported since 2001, and scientific advances in HIV prevention provide strong hope to reduce incidence further. . . .
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SP Parwe et al. Synthesis of ciprofloxacin-conjugated poly (L-lactic acid) polymer for nanofiber fabrication and antibacterial evaluation. Int J Nanomedicine

High Impact Journal from Malaria Portal - 17 April 2014 - 12:00am
Ciprofloxacin was conjugated with polylactide (PLA) via the secondary amine group of the piperazine ring using PLA and 7-(4-(2-Chloroacetyl) piperazin-1-yl)-1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid. . . .
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AK Onyebuchi et al. Adherence to intermittent preventive treatment for malaria with sulphadoxine-pyrimethamine and outcome of pregnancy among parturients in South East Nigeria. Patient Prefer Adherence

High Impact Journal from Malaria Portal - 17 April 2014 - 12:00am
Intermittent preventive treatment of malaria for pregnant women (IPTp) is a very important strategy for the control of malaria in pregnancy in malaria-endemic tropical countries, where mosquito bites easily occur during evening outdoor activities. . . .
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Molecular characterization of Plasmodium falciparum uracil-DNA glycosylase and its potential as a new anti-malarial drug target

Malaria Journal - 17 April 2014 - 12:00am
Background: Based on resistance of currently used anti-malarials, a new anti-malarial drug target against Plasmodium falciparum is urgently needed. Damaged DNA cannot be transcribed without prior DNA repair; therefore, uracil-DNA glycosylase, playing an important role in base excision repair, may act as a candidate for a new anti-malarial drug target. Methods: Initially, the native PfUDG from parasite crude extract was partially purified using two columns, and the glycosylase activity was monitored. The existence of malarial UDG activity prompted the recombinant expression of PfUDG for further characterization. The PfUDG from chloroquine and pyrimethamine resistant P. falciparum strain K1 was amplified, cloned into the expression vector, and expressed in Escherichia coli. The recombinant PfUDG was analysed by SDS-PAGE and identified by LC-MS/MS. The three dimensional structure was modelled. Biochemical properties were characterized. Inhibitory effects of 12 uracil-derivatives on PfUDG activity were investigated. Inhibition of parasite growth was determined in vitro using SYBR Green I and compared with results from human cytotoxicity tests. Results: The native PfUDG was partially purified with a specific activity of 1,811.7 units/mg (113.2 fold purification). After cloning of 966-bp PCR product, the 40-kDa hexa-histidine tagged PfUDG was expressed and identified. The amino acid sequence of PfUDG showed only 24.8% similarity compared with the human enzyme. The biochemical characteristics of PfUDGs were quite similar. They were inhibited by uracil glycosylase inhibitor protein as found in other organisms. Interestingly, recombinant PfUDG was inhibited by two uracil-derived compounds; 1-methoxyethyl-6-(p-n-octylanilino)uracil (IC50 of 16.75 muM) and 6-(phenylhydrazino)uracil (IC50 of 77.5 muM). Both compounds also inhibited parasite growth with IC50s of 15.6 and 12.8 muM, respectively. Moreover, 1-methoxyethyl-6-(p-n-octylanilino)uracil was not toxic to HepG2 cells, with IC50 of > 160 muM while 6-(phenylhydrazino)uracil exhibited cytoxicity, with IC50 of 27.5 muM. Conclusions: The recombinant PfUDG was expressed, characterized and compared to partially purified native PfUDG. Their characteristics were not significantly different. PfUDG differs from human enzyme in its size and predicted amino acid sequence. Two uracil derivatives inhibited PfUDG and parasite growth; however, only one non-cytotoxic compound was found. Therefore, this selective compound can act as a lead compound for anti-malarial development in the future.
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The prevalence of glucose-6-phosphate dehydrogenase deficiency in Gambian school children

Malaria Journal - 17 April 2014 - 12:00am
Background: Primaquine, the only available drug effective against Plasmodium falciparum sexual stages, induces also a dose-dependent haemolysis, especially in glucose-6-phosphate dehydrogenase deficient (G6PDd) individuals. Therefore, it is important to determine the prevalence of this deficiency in areas that would potentially benefit from its use. The prevalence of G6PD deficiency by genotype and enzyme activity was determined in healthy school children in The Gambia. Methods: Blood samples from primary school children collected during a dry season malaria survey were screened for G6PDd and malaria infection. Genotypes for allele mutations reported in the country; 376, 202A-, 968A- and 542 were analysed while enzyme activity (phenotype) was assayed using a semi-quantitative commercial test kit. Enzyme activity values were fitted in a finite mixture model to determine the distribution and calculate a cut-off for deficiency. The association between genotype and phenotype for boys and girls as well as the association between mutant genotype and deficient phenotype was analysed. Results: Samples from 1,437 children; 51% boys were analysed. The prevalence of P. falciparum malaria infection was 14%. The prevalence of the 202A-, 968 and 542 mutations was 1.8%, 2.1% and 1.0%, respectively, and higher in boys than in girls. The prevalence of G6PDd phenotype was 6.4% (92/1,437), 7.8% (57/728) in boys and 4.9% (35/709) in girls with significantly higher odds in the former (OR 1.64, 95% CI 1.05, 2.53, p = 0.026). The deficient phenotype was associated with reduced odds of malaria infection (OR 0.77, 95% CI 0.36, 1.62, p = 0.49). Conclusions: There is a weak association between genotype and phenotype estimates of G6PDd prevalence. The phenotype expression of deficiency represents combinations of mutant alleles rather than specific mutations. Genotype studies in individuals with a deficient phenotype would help identify alleles responsible for haemolysis.
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Limitations of haemozoin-based diagnosis of Plasmodium falciparum using dark-field microscopy

Malaria Journal - 17 April 2014 - 12:00am
Background: The haemozoin crystal continues to be investigated extensively for its potential as a biomarker for malaria diagnostics. In order for haemozoin to be a valuable biomarker, it must be present in detectable quantities in the peripheral blood and distinguishable from false positives. Here, dark-field microscopy coupled with sophisticated image processing algorithms is used to characterize the abundance of detectable haemozoin within infected erythrocytes from field samples in order to determine the window of detection in peripheral blood. Methods: Thin smears from Plasmodium falciparum-infected and uninfected patients were imaged in both dark field (DF) unstained and bright field (BF) Giemsa-stained modes. The images were co-registered such that each parasite had thumbnails in both BF and DF modes, providing an accurate map between parasites and DF objects. This map was used to find the abundance of haemozoin as a function of parasite stage through careful parasite staging and correlation with DF objects. An automated image-processing and classification algorithm classified the bright spots in the DF images as either haemozoin or non-haemozoin objects. Results: The algorithm distinguishes haemozoin from non-haemozoin objects in DF images with an object-level sensitivity of 95% and specificity of 97%. Ring stages older than about 6 hours begin to show detectable haemozoin, and rings between 10-16 hours reliably contain detectable haemozoin. However, DF microscopy coupled with the image-processing algorithm detect no haemozoin in rings younger than six hours.DiscussionAlthough this method demonstrates the most sensitive detection of haemozoin in field samples reported to date, it does not detect haemozoin in ring-stage parasites younger than six hours. Thus, haemozoin is a poor biomarker for field samples primarily composed of young ring-stage parasites because the crystal is not present in detectable quantities by the methods described here. Based on these results, the implications for patient-level diagnosis and recommendations for future work are discussed.
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Multitarget TB drug could treat other diseases, evade resistance

News from Malaria Portal - 16 April 2014 - 12:00am
A drug under clinical trials to treat tuberculosis could be the basis for a class of broad-spectrum drugs that act against various bacteria, fungal infections and parasites, yet evade resistance, according to a study by University of Illinois chemists and
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Study sheds light on how the immune system protects children from malaria

News from Malaria Portal - 16 April 2014 - 12:00am
According to a study published today in PLOS Pathogens, children who live in regions of the world where malaria is common can mount an immune response to infection with malaria parasites that may enable them to avoid repeated bouts of high fever and illne
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The malaria pathogen's cellular skeleton under a super-microscope

News from Malaria Portal - 16 April 2014 - 12:00am
The tropical disease malaria is caused by the Plasmodium parasite. For its survival and propagation, Plasmodium requires a protein called actin. Scientists of the Helmholtz Centre for Infection Research used high-resolution structural biology methods to i
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