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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
plasmodium falciparum complicated malaria: modulation and connectivity between exportome and variant surface antigen gene families.in temperate and sub-tropical regions of asia and latin america, complicated malaria manifested as hepatic dysfunction or renal dysfunction is seen in all age groups. there has been a concerted focus on understanding the patho-physiological and molecular basis of complicated malaria in children, much less is known about it in adults. we report here, the analysis of data from a custom, cross strain microarray (agilent platform) using material from adult patient samples, showing hepatic dysfunctio ...201526022315
glycosyl hydroperoxides: a new class of potential antimalarial agents.motivated by the antimalarial properties observed in organic peroxides, an extensive series of glycosyl hydroperoxides was prepared with the aim of identifying new bioactive molecules. selected compounds were tested against a plasmodium falciparum culture (chloroquine-susceptible strain d10 and chloroquine-resistant strain w2). screening results indicated that the factors critical for antimalarial activity were the presence of a hydroperoxide moiety and solubility in water at ph 5.0. moreover, t ...201526022082
serum apolipoprotein-a1 and cholesterol levels in nigerian children with plasmodium falciparum infection.this study was carried out to determine whether or not plasmodium falciparum malaria infection significantly affected apolipoprotein-a1 and cholesterol levels and if apolipoprotein-a1 correlated with the malaria severity in children younger than 5 years old.201526021459
quality of artemisinin-based combination formulations for malaria treatment: prevalence and risk factors for poor quality medicines in public facilities and private sector drug outlets in enugu, nigeria.artemisinin-based combination therapies are recommended by the world health organisation (who) as first-line treatment for plasmodium falciparum malaria, yet medication must be of good quality for efficacious treatment. a recent meta-analysis reported 35% (796/2,296) of antimalarial drug samples from 21 sub-saharan african countries, purchased from outlets predominantly using convenience sampling, failed chemical content analysis. we used three sampling strategies to purchase artemisinin-contain ...201526018221
rational design of antimalarial drugs using molecular modeling and statistical analysis.artemisinin is an antimalarial compound isolated from artemisia annua l. that is effective against plasmodium falciparum. this paper proposes the development of new antimalarial derivatives of artemisinin from a sar study and statistical analysis by multiple linear regression (mlr). the hf/6-31g** method was used to determine the molecular properties of artemisinin and 10 derivatives with antimalarial action. mep maps and molecular docking were used to study the interface between ligand and rece ...201526017698
intervals to plasmodium falciparum recurrence after anti-malarial treatment in pregnancy: a longitudinal prospective cohort.plasmodium falciparum infections adversely affect pregnancy. anti-malarial treatment failure is common. the objective of this study was to examine the duration of persistent parasite carriage following anti-malarial treatment in pregnancy.201526017553
cost-effectiveness of malaria diagnosis using rapid diagnostic tests compared to microscopy or clinical symptoms alone in afghanistan.improving access to parasitological diagnosis of malaria is a central strategy for control and elimination of the disease. malaria rapid diagnostic tests (rdts) are relatively easy to perform and could be used in primary level clinics to increase coverage of diagnostics and improve treatment of malaria.201526016871
igg antibodies to endothelial protein c receptor-binding cysteine-rich interdomain region domains of plasmodium falciparum erythrocyte membrane protein 1 are acquired early in life in individuals exposed to malaria.severe malaria syndromes are precipitated by plasmodium falciparum parasites binding to endothelial receptors on the vascular lining. this binding is mediated by members of the highly variant p. falciparum erythrocyte membrane protein 1 (pfemp1) family. we have previously identified a subset of pfemp1 proteins associated with severe malaria and found that the receptor for these pfemp1 variants is endothelial protein c receptor (epcr). the binding is mediated through the amino-terminal cysteine-r ...201526015475
tailoring a pediatric formulation of artemether-lumefantrine for treatment of plasmodium falciparum malaria.specially created pediatric formulations have the potential to improve the acceptability, effectiveness, and accuracy of dosing of artemisinin-based combination therapy (act) in young children, a patient group that is inherently vulnerable to malaria. artemether-lumefantrine (al) dispersible is a pediatric formulation of al that is specifically tailored for the treatment of children with uncomplicated plasmodium falciparum malaria, offering benefits relating to efficacy, convenience and acceptan ...201526014953
evidence of plasmodium falciparum malaria multidrug resistance to artemisinin and piperaquine in western cambodia: dihydroartemisinin-piperaquine open-label multicenter clinical assessment.western cambodia is recognized as the epicenter of plasmodium falciparum multidrug resistance. recent reports of the efficacy of dihydroartemisinin (dha)-piperaquine (pp), the latest of the artemisinin-based combination therapies (acts) recommended by the who, have prompted further investigations. the clinical efficacy of dihydroartemisinin-piperaquine in uncomplicated falciparum malaria was assessed in western and eastern cambodia over 42 days. day 7 plasma piperaquine concentrations were measu ...201526014949
ex vivo drug susceptibility testing and molecular profiling of clinical plasmodium falciparum isolates from cambodia from 2008 to 2013 suggest emerging piperaquine resistance.cambodia's first-line artemisinin combination therapy, dihydroartemisinin-piperaquine (dha-ppq), is no longer sufficiently curative against multidrug-resistant plasmodium falciparum malaria at some thai-cambodian border regions. we report recent (2008 to 2013) drug resistance trends in 753 isolates from northern, western, and southern cambodia by surveying for ex vivo drug susceptibility and molecular drug resistance markers to guide the selection of an effective alternative to dha-ppq. over the ...201526014942
chloroquine-containing compounds: a patent review (2010 - 2014).chloroquine (cq) has been well known for its antimalarial effects since world war ii. however, it is gradually being phased out from clinical use against malaria due to emergence of cq-resistant plasmodium falciparum strains. besides low cost and tolerability, ongoing research has revealed interesting biochemical properties of cq that have inspired its repurposing/repositioning in the management of various infectious/noninfectious diseases. consequently, several novel compounds and compositions ...201526013494
review of mass drug administration for malaria and its operational challenges.mass drug administration (mda) was a component of many malaria programs during the eradication era, but later was seldomly deployed due to concerns regarding efficacy and feasibility and fear of accelerating drug resistance. recently, however, there has been renewed interest in the role of mda as an elimination tool. following a 2013 cochrane review that focused on the quantitative effects of malaria mda, we have conducted a systematic, qualitative review of published, unpublished, and gray lite ...201526013371
matrix metalloproteinase-9 polymorphism 1562 c > t (rs3918242) associated with protection against placental malaria.phagocytosis of malaria pigment (hemozoin) induces increased activity of matrix metalloproteinase (mmp)-9, an endopeptidase involved in cytokine regulation. in this study, we examined whether a common functional mmp-9 promoter polymorphism (rs3918242) affects plasmodium falciparum infection in pregnancy. eighteen percent of ghanaian primiparae carried the minor t allele. it was associated with reduced odds of placental hemozoin and of placental as well as peripheral blood parasitemia. the result ...201526013370
genetic diversity in the msp-1 and msp-2 alleles among plasmodium falciparum field isolates from jazan, saudi arabia.the genetic diversity of plasmodium falciparum infections in human is associated with the pathogenesis of malaria. it is commonly determined through amplification of the polymorphic regions of the merozoite surface proteins -1 (msp-1) and -2 (msp-2) genes. this study aimed to (1) determine the prevalence of the msp-1 and msp-2 allelic familiesand (2) identify the multiplicity of infection (moi) in p. falciparum field isolates from the jazan region in the kingdom of saudi arabia (ksa). blood samp ...201526012235
the effects of cell asynchrony on gene expression levels: analysis and application to plasmodium falciparum.to investigate the intraerythrocytic developmental cycle of plasmodium falciparum, time-series gene expression data is commonly measured of infected red blood cells. however, the observed data are usually blurred due to cell asynchrony during experiments. in this paper, the effect of cell asynchrony is investigated by conducting numerical experiments. the simulation results suggest that cell asynchrony has varying effects on different intrinsic expression patterns. specifically, the intrinsic pa ...201526011871
the stapled akap disruptor peptide stad-2 displays antimalarial activity through a pka-independent mechanism.drug resistance poses a significant threat to ongoing malaria control efforts. coupled with lack of a malaria vaccine, there is an urgent need for the development of new antimalarials with novel mechanisms of action and low susceptibility to parasite drug resistance. protein kinase a (pka) has been implicated as a critical regulator of pathogenesis in malaria. therefore, we sought to investigate the effects of disrupted pka signaling as a possible strategy for inhibition of parasite replication. ...201526010880
immunoliposome-mediated drug delivery to plasmodium-infected and non-infected red blood cells as a dual therapeutic/prophylactic antimalarial strategy.one of the most important factors behind resistance evolution in malaria is the failure to deliver sufficiently high amounts of drugs to early stages of plasmodium-infected red blood cells (prbcs). despite having been considered for decades as a promising approach, the delivery of antimalarials encapsulated in immunoliposomes targeted to prbcs has not progressed towards clinical applications, whereas in vitro assays rarely reach drug efficacy improvements above 10-fold. here we show that encapsu ...201526008752
molecular docking and qsar analyses for understanding the antimalarial activity of some 7-substituted-4-aminoquinoline derivatives.the quinoline moiety is one of the widely studied scaffolds for generating derivatives with various pharmacophoric groups due to its potential antimalarial activities. in the present study, a series of 7-substituted-4-aminoquinoline derivatives were selected to understand their antimalarial properties computationally by molecular modeling techniques including 2d qsar, comparative molecular field analysis (comfa), comparative molecular similarity indices analysis (comsia) and molecular docking. t ...201526006759
antiplasmodial potential of traditional antimalarial phytotherapy remedies used by the kwale community of the kenyan coast.in kenya, 22 million people are at risk of malaria, 70% of them are in rural areas and most of these people use traditional plant based medicines to treat malaria. the aim of the study was to escalate documentation, from an earlier study of medicinal plants, traditionally used to treat malaria by the digo community of kwale county, taking cognizance of their pharmacological information by evaluating their antiplasmodial efficacies.201526002768
survey of chloroquine-resistant mutations in the plasmodium falciparum pfcrt and pfmdr-1 genes in hadhramout, yemen.malaria is still a major public health problem in yemen. more than 95% of the malaria cases are due to plasmodium ‎falciparum‎. recently in yemen, the antimalarial treatment policy was changed from chloroquine (cq) to artemisinin combination therapy (acts). however, cq is still available and prescribed in the yemeni market. the persistence of cq resistance will be prolonged if the shift to act and the simultaneous withdrawal of cq are not rigorously implemented. the aim of the current survey is ...201526001972
how do antimalarial drugs reach their intracellular targets?drugs represent the primary treatment available for human malaria, as caused by plasmodium spp. currently approved drugs and antimalarial drug leads generally work against parasite enzymes or activities within infected erythrocytes. to reach their specific targets, these chemicals must cross at least three membranes beginning with the host cell membrane. uptake at each membrane may involve partitioning and diffusion through the lipid bilayer or facilitated transport through channels or carriers. ...201525999857
malaria vaccines: moving forward after encouraging first steps.an effective malaria vaccine that reduces morbidity and mortality and contributes to malaria elimination is a much-needed tool, particularly in endemic areas where health-care delivery and vector control efforts are difficult to sustain. rts,s/as01 is likely to be the first licensed malaria vaccine and represents an important step toward malaria control and elimination. however, a partially effective vaccine such as rts,s/as01 poses challenges for evaluating the efficacy of second-generation mal ...201525995985
hemiparesis post cerebral malaria.cerebral malaria is one of the most serious complications in the plasmodium falciparum infection. in endemic areas, the cerebral malaria interested mainly children. the occurrence in adults is very rare and most interested adult traveling in tropical zones. this case report describes a motor deficit post cerebral malaria in a young adult traveling in malaria endemic area. this complication has been reported especially in children and seems very rare in adults.201525995798
nowhere to hide: interrogating different metabolic parameters of plasmodium falciparum gametocytes in a transmission blocking drug discovery pipeline towards malaria elimination.the discovery of malaria transmission-blocking compounds is seen as key to malaria elimination strategies and gametocyte-screening platforms are critical filters to identify active molecules. however, unlike asexual parasite assays measuring parasite proliferation, greater variability in end-point readout exists between different gametocytocidal assays. this is compounded by difficulties in routinely producing viable, functional and stage-specific gametocyte populations. here, a parallel evaluat ...201525994518
bioeconomic analysis of child-targeted subsidies for artemisinin combination therapies: a cost-effectiveness analysis.the affordable medicines facility for malaria (amfm) was conceived as a global market-based mechanism to increase access to effective malaria treatment and prolong effectiveness of artemisinin. although results from a pilot implementation suggested that the subsidy was effective in increasing access to high-quality artemisinin combination therapies (acts), the global fund has converted amfm into a country-driven mechanism whereby individual countries could choose to fund the subsidy from within ...201525994293
a unique virulence gene occupies a principal position in immune evasion by the malaria parasite plasmodium falciparum.mutually exclusive gene expression, whereby only one member of a multi-gene family is selected for activation, is used by the malaria parasite plasmodium falciparum to escape the human immune system and perpetuate long-term, chronic infections. a family of genes called var encodes the chief antigenic and virulence determinant of p. falciparum malaria. var genes are transcribed in a mutually exclusive manner, with switching between active genes resulting in antigenic variation. while recent work ...201525993442
fcrl5 delineates functionally impaired memory b cells associated with plasmodium falciparum exposure.exposure to plasmodium falciparum is associated with circulating "atypical" memory b cells (atmbcs), which appear similar to dysfunctional b cells found in hiv-infected individuals. functional analysis of atmbcs has been limited, with one report suggesting these cells are not dysfunctional but produce protective antibodies. to better understand the function of malaria-associated atmbcs, we performed global transcriptome analysis of these cells, obtained from individuals living in an area of high ...201525993340
gametocyte clearance kinetics determined by quantitative magnetic fractionation in melanesian children with uncomplicated malaria treated with artemisinin combination therapy.quantitative magnetic fractionation and a published mathematical model were used to characterize between-treatment differences in gametocyte density and prevalence in 70 papua new guinean children with uncomplicated plasmodium falciparum and/or plasmodium vivax malaria randomized to one of two artemisinin combination therapies (artemether-lumefantrine or artemisinin-naphthoquine) in an intervention trial. there was an initial rise in peripheral p. falciparum gametocyte density with both treatmen ...201525987625
immunophilins: structures, mechanisms and ligands.immunophilins consist of a family of highly conserved proteins which possess binding abilities to immunosuppressive drugs. cyclophilins (cyps) and fk506-binding proteins (fkbp) are family proteins collectively referred as immunophilins. most cyps and fkbp family members catalyse peptidyl-prolyl cis/trans isomerase (ppiase) mediated reactions and form binary complexes with their ligands cyclosporine a and fk506. immunophilins are also involved in key biochemical processes including protein foldin ...201525986569
molecular markers of anti-malarial drug resistance in southwest ethiopia over time: regional surveillance from 2006 to 2013.drug resistance is one of the main reasons of anti-malarial treatment failures and impedes malaria containment strategies. as single nucleotide polymorphisms (snps) have been found to correlate with anti-malarial drug resistance, the surveillance strategy includes continuous monitoring of known molecular markers and detection of new mutation patterns. with the introduction of artemisinin-based combination therapy, selection of specific patterns has been observed worldwide.201525986047
assessing the infectious reservoir of falciparum malaria: past and future.renewed interest in malaria eradication has placed greater emphasis on the development of tools to interrupt plasmodium transmission, such as transmission-blocking vaccines. however, effective deployment of such tools is likely to depend on improving our understanding of which individuals transmit infections to mosquitoes. to date, only a handful of studies have directly determined the infectiousness of individuals in endemic populations. here we review these studies and their relative merits. w ...201525985898
proteomic analysis of plasmodium falciparum induced alterations in humans from different endemic regions of india to decipher malaria pathogenesis and identify surrogate markers of severity.india significantly contributes to the global malaria burden and has the largest population in the world at risk of malaria. this study aims to analyze alterations in the human serum proteome as a consequence of non-severe and severe infections by the malaria parasite plasmodium falciparum to identify markers related to disease severity and to obtain mechanistic insights about disease pathogenesis and host immune responses. in discovery phase of the study, a comprehensive quantitative proteomic ...201525982387
field deployment of loop-mediated isothermal amplification for centralized mass-screening of asymptomatic malaria in zanzibar: a pre-elimination setting.molecular tools for detection of low-density asymptomatic plasmodium infections are needed in malaria elimination efforts. this study reports results from the hitherto largest implementation of loop-mediated isothermal amplification (lamp) for centralized mass screening of asymptomatic malaria in zanzibar.201525982190
complement activation correlates with disease severity and contributes to cytokine responses in plasmodium falciparum malaria.the impact of complement activation and its possible relation to cytokine responses during malaria pathology was investigated in plasma samples from patients with confirmed plasmodium falciparum malaria and in human whole-blood specimens stimulated with malaria-relevant agents ex vivo. complement was significantly activated in the malaria cohort, compared with healthy controls, and was positively correlated with disease severity and with certain cytokines, in particular interleukin 8 (il-8)/cxcl ...201525980034
antiprotozoal assessment and phenolic acid profiling of five fumaria (fumitory) species.to explore some fumaria species which were recorded to be traditionally used against malaria and other protozoal diseases.201525975499
an assessment of the supply, programmatic use, and regulatory issues of single low-dose primaquine as a plasmodium falciparum gametocytocide for sub-saharan africa.global ambitions to eliminate malaria are intensifying, underscoring a critical need for transmission blocking tools. in 2012, the who recommended the use of 0.25 mg/kg of single low-dose (sld) primaquine to stop plasmodium falciparum transmission. to ensure the availability of sld primaquine to countries in need of this tool, more information on the supply, programmatic, and regulatory barriers to the rollout of sld primaquine is required.201525971688
development of two novel high-throughput assays to quantify ubiquitylated proteins in cell lysates: application to screening of new anti-malarials.the ubiquitin proteasome system (ups) is one of the main proteolytical pathways in eukaryotic cells and plays an essential role in key cellular processes such as cell cycle, stress response, signal transduction, and transcriptional regulation. many components of this pathway have been implicated in diverse pathologies including cancer, neurodegeneration and infectious diseases, such as malaria. the success of proteasome inhibitors in clinical trials underlines the potential of the ups in drug di ...201525968882
multiple clinical episodes of plasmodium falciparum malaria in a low transmission intensity setting: exposure versus immunity.epidemiological studies indicate that some children experience many more episodes of clinical malaria than their age mates in a given location. whether this is as a result of the micro-heterogeneity of malaria transmission with some children effectively getting more exposure to infectious mosquitoes than others, or reflects a failure in the acquisition of immunity needs to be elucidated. here, we investigated the determinants of increased susceptibility to clinical malaria by comparing the inten ...201525967134
exploration of new drug-like inhibitors for serine/threonine protein phosphatase 5 of plasmodium falciparum: a docking and simulation study.protein phosphorylation is an important mechanism that implicates in physiology of any organism including parasitic protozoa. metallic protein ser/thr protein phosphatase 5 (pp5) controls various cellular signaling pathways of plasmodium falciparum. the structure and inhibitory mechanism of pp5 in p. falciparum is not known. in fact, no experimental structural data are available for p. falciparum ser/thr protein phosphatase 5 (pfpp5) till date. hence, we have proposed computer-generated model of ...201525967133
structural basis for epitope masking and strain specificity of a conserved epitope in an intrinsically disordered malaria vaccine candidate.merozoite surface protein 2 (msp2) is an intrinsically disordered, membrane-anchored antigen of the malaria parasite plasmodium falciparum. msp2 can elicit a protective, albeit strain-specific, antibody response in humans. antibodies are generated to the conserved n- and c-terminal regions but many of these react poorly with the native antigen on the parasite surface. here we demonstrate that recognition of a conserved n-terminal epitope by mab 6d8 is incompatible with the membrane-bound conform ...201525965408
capture and ligation probe-pcr (clip-pcr) for molecular screening, with application to active malaria surveillance for elimination.malaria control programs have achieved remarkable success during the past decade. nonetheless, sensitive and affordable methods for active screening of malaria parasites in low-transmission settings remain urgently needed.201525964304
population pharmacokinetics, tolerability, and safety of dihydroartemisinin-piperaquine and sulfadoxine-pyrimethamine-piperaquine in pregnant and nonpregnant papua new guinean women.the tolerability, safety, and disposition of dihydroartemisinin (dha) and piperaquine (pq) were assessed in 32 pregnant (second/third trimester) and 33 nonpregnant papua new guinean women randomized to adult treatment courses of dha-pq (three daily doses) or sulfadoxine-pyrimethamine (sp)-pq (three daily pq doses, single dose of sp). all dose adminstrations were observed, and subjects fasted for 2 h postdose. plasma pq was assayed by using high-performance liquid chromatography, and dha was asse ...201525963981
anti-malarials are anti-cancers and vice versa - one arrow two sparrows.repurposing is the novel means of drug discovery in modern science due to its affordability, safety and availability. here, we systematically discussed the efficacy and mode of action of multiple bioactive, synthetic compounds and their potential derivatives which are used to treat/prevent malaria and cancer. we have also discussed the detailed molecular pathway involved in anti-cancer potentiality of an anti-malarial drug and vice versa. although the causative agents, pathophysiology and manife ...201525963804
detection of mixed-species infections of plasmodium falciparum and plasmodium vivax by nested pcr and rapid diagnostic tests in southeastern iran.coexistence of two species of plasmodium in a single host has disrupted the diagnosis and treatment of malaria. this study was designed to evaluate the ability of rapid diagnostic test (rdt) kits for the diagnosis of mixed-species malaria infections in southeastern iran. a total of 100 malaria patients were included in the study out of 164 randomly suspected symptomatic malaria patients from may to november 2012. nested polymerase chain reaction (pcr) was also used to judge the ability of micros ...201525962771
geostatistical modeling of malaria endemicity using serological indicators of exposure collected through school surveys.ethiopia has a diverse ecology and geography resulting in spatial and temporal variation in malaria transmission. evidence-based strategies are thus needed to monitor transmission intensity and target interventions. a purposive selection of dried blood spots collected during cross-sectional school-based surveys in oromia regional state, ethiopia, were tested for presence of antibodies against plasmodium falciparum and p. vivax antigens. spatially explicit binomial models of seroprevalence were c ...201525962770
primaquine dosing errors: the human cost of a pharmaceutical anachronism.confusion between salt/base forms of primaquine may result in malaria prophylaxis failure. during 1995-2011, there were 14 malaria cases in israel despite primaquine primary prophylaxis. in 6/14 cases, primaquine was underdosed because of confusion between salt and base forms, including two plasmodium falciparum cases. primaquine labeling clarification may be lifesaving.201525962769
microgeography and molecular epidemiology of malaria at the thailand-myanmar border in the malaria pre-elimination phase.endemic malaria in thailand continues to only exist along international borders. this pattern is frequently attributed to importation of malaria from surrounding nations. a microgeographical approach was used to investigate malaria cases in a study village along the thailand-myanmar border.201525962514
in vivo efficacy of sulphadoxine-pyrimethamine for the treatment of asymptomatic parasitaemia in pregnant women in machinga district, malawi.the effectiveness of sulphadoxine-pyrimethamine (sp) intermittent preventive treatment of malaria in pregnancy (iptp) might be compromised by high prevalence of resistance-associated plasmodium falciparum dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) mutations. as a proxy for iptp-sp effectiveness, the in vivo efficacy of sp to clear parasitaemia and prevent reinfection in asymptomatic parasitaemic pregnant women in an area with high sp resistance prevalence was assessed.201525962439
acquisition of functional antibodies that block the binding of erythrocyte-binding antigen 175 and protection against plasmodium falciparum malaria in children.the targets and mechanisms of human immunity to malaria are poorly understood, which poses a major barrier to malaria vaccine development. antibodies play a key role in human immunity and may act by inhibiting receptor-binding functions of key merozoite invasion ligands. antibodies to the major invasion ligand and vaccine candidate, erythrocyte-binding antigen 175 (eba-175), have been linked with protection, but how these antibodies function has not been established.201526136391
disruption of cellular homeostasis induces organelle stress and triggers apoptosis like cell-death pathways in malaria parasite.a regulated protein turnover machinery in the cell is essential for effective cellular homeostasis; any interference with this system induces cellular stress and alters the normal functioning of proteins important for cell survival. in this study, we show that persistent cellular stress and organelle dysfunction because of disruption of cellular homeostasis in human malaria parasite plasmodium falciparum, leads to apoptosis-like cell death. quantitative global proteomic analysis of the stressed ...201526136076
an assay to probe plasmodium falciparum growth, transmission stage formation and early gametocyte development.conversion from asexual proliferation to sexual differentiation initiates the production of the gametocyte, which is the malaria parasite stage required for human-to-mosquito transmission. this protocol describes an assay designed to probe the effect of drugs or other perturbations on asexual replication, sexual conversion and early gametocyte development in the major human malaria parasite plasmodium falciparum. synchronized asexually replicating parasites are induced for gametocyte production ...201526134953
α2-macroglobulin can crosslink multiple plasmodium falciparum erythrocyte membrane protein 1 (pfemp1) molecules and may facilitate adhesion of parasitized erythrocytes.rosetting, the adhesion of plasmodium falciparum-infected erythrocytes to uninfected erythrocytes, involves clonal variants of the parasite protein p. falciparum erythrocyte membrane protein 1 (pfemp1) and soluble serum factors. while rosetting is a well-known phenotypic marker of parasites associated with severe malaria, the reason for this association remains unclear, as do the molecular details of the interaction between the infected erythrocyte (ie) and the adhering erythrocytes. here, we id ...201526134405
identification of malaria parasite-infected red blood cell surface aptamers by inertial microfluidic selex (i-selex).plasmodium falciparum malaria parasites invade and remodel human red blood cells (rbcs) by trafficking parasite-synthesized proteins to the rbc surface. while these proteins mediate interactions with host cells that contribute to disease pathogenesis, the infected rbc surface proteome remains poorly characterized. here we use a novel strategy (i-selex) to discover high affinity aptamers that selectively recognize distinct epitopes uniquely present on parasite-infected rbcs. based on inertial foc ...201526126714
elq-300 prodrugs for enhanced delivery and single-dose cure of malaria.elq-300 is a preclinical candidate that targets the liver and blood stages of plasmodium falciparum, as well as the forms that are crucial to transmission of disease: gametocytes, zygotes, and ookinetes. a significant obstacle to the clinical development of elq-300 is related to its physicochemical properties. its relatively poor aqueous solubility and high crystallinity limit absorption to the degree that only low blood concentrations can be achieved following oral dosing. while these low blood ...201526124159
prevalence of plasmodium falciparum resistance markers to sulfadoxine-pyrimethamine among pregnant women receiving intermittent preventive treatment for malaria in uganda.the aim of this study was to assess the prevalence of mutations in plasmodium falciparum dihydrofolate reductase (pfdhfr) and dihydropteroate synthase (pfdhps) genes among pregnant women using sulfadoxine-pyrimethamine (sp) as an intermittent preventive treatment (iptp). a molecular epidemiological study of p. falciparum parasite resistance markers to sp was conducted from august 2010 to february 2012 in mukono district in central uganda. dna was extracted from 413 p. falciparum-positive samples ...201526124154
mosquitocidal and antiplasmodial activity of senna occidentalis (cassiae) and ocimum basilicum (lamiaceae) from maruthamalai hills against anopheles stephensi and plasmodium falciparum.each year, mosquito-borne diseases infect nearly 700 million people, resulting to more than 1 million deaths. in this study, we evaluated the larvicidal, pupicidal, and smoke toxicity of senna occidentalis and ocimum basilicum leaf extracts against the malaria vector anopheles stephensi. furthermore, the antiplasmodial activity of plant extracts was evaluated against chloroquine (cq)-resistant (cq-r) and cq-sensitive (cq-s) strains of plasmodium falciparum. in larvicidal and pupicidal experiment ...201526122992
molecular determination of antifolate resistance associated point mutations in plasmodium falciparum dihydrofolate reductase (dhfr) and dihydropteroate synthetase (dhps) genes among the field samples in arunachal pradesh.antimalarial resistance in p. falciparum malaria parasite creates a serious obstacle in malaria control programme. keeping this in mind, in the present study antifolate resistance associated point mutations in p. falciparum dihydrofolate reductase (pfdhfr) and dihydropteroate synthetase (pfdhps) genes among the field samples in arunachal pradesh were determined.201526119542
exploring protein solution structure: second moments of fluorescent spectra report heterogeneity of tryptophan rotamers.trp fluorescent spectra appear as a log-normal function but are usually analyzed with λmax, full width at half maximum, and the first moment of incomplete spectra. log-normal analyses have successfully separated fluorescence contributions from some multi-trp proteins but deviations were observed in single trp proteins. the possibility that disparate rotamer environments might account for these deviations was explored by moment spectral analysis of single trp mutants spanning the sequence of tear ...201526119357
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