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Sample records for plasmodium permits generation

  1. Carbon tax or carbon permits: The impact on generators' risks

    SciTech Connect

    Green, R.

    2008-07-01

    Volatile fuel prices affect both the cost and price of electricity in a liberalized market. Generators with the price-setting technology will face less risk to their profit margins than those with costs that are not correlated with price, even if those costs are not volatile. Emissions permit prices may respond to relative fuel prices, further increasing volatility. This paper simulates the impact of this on generators' profits, comparing an emissions trading scheme and a carbon tax against predictions for the UK in 2020. The carbon tax reduces the volatility faced by nuclear generators, but raises that faced by fossil fuel stations. Optimal portfolios would contain a higher proportion of nuclear plant if a carbon tax was adopted.

  2. Generation of Antigenic Diversity in Plasmodium falciparum by Structured Rearrangement of Var Genes During Mitosis

    PubMed Central

    Kekre, Mihir; Otto, Thomas D.; Faizullabhoy, Adnan; Rayner, Julian C.; Kwiatkowski, Dominic

    2014-01-01

    The most polymorphic gene family in P. falciparum is the ∼60 var genes distributed across parasite chromosomes, both in the subtelomeres and in internal regions. They encode hypervariable surface proteins known as P. falciparum erythrocyte membrane protein 1 (PfEMP1) that are critical for pathogenesis and immune evasion in Plasmodium falciparum. How var gene sequence diversity is generated is not currently completely understood. To address this, we constructed large clone trees and performed whole genome sequence analysis to study the generation of novel var gene sequences in asexually replicating parasites. While single nucleotide polymorphisms (SNPs) were scattered across the genome, structural variants (deletions, duplications, translocations) were focused in and around var genes, with considerable variation in frequency between strains. Analysis of more than 100 recombination events involving var exon 1 revealed that the average nucleotide sequence identity of two recombining exons was only 63% (range: 52.7–72.4%) yet the crossovers were error-free and occurred in such a way that the resulting sequence was in frame and domain architecture was preserved. Var exon 1, which encodes the immunologically exposed part of the protein, recombined in up to 0.2% of infected erythrocytes in vitro per life cycle. The high rate of var exon 1 recombination indicates that millions of new antigenic structures could potentially be generated each day in a single infected individual. We propose a model whereby var gene sequence polymorphism is mainly generated during the asexual part of the life cycle. PMID:25521112

  3. De Novo Generated Human Red Blood Cells in Humanized Mice Support Plasmodium falciparum Infection.

    PubMed

    Amaladoss, Anburaj; Chen, Qingfeng; Liu, Min; Dummler, Sara K; Dao, Ming; Suresh, Subra; Chen, Jianzhu; Preiser, Peter R

    2015-01-01

    Immunodeficient mouse-human chimeras provide a powerful approach to study host specific pathogens like Plasmodium (P.) falciparum that causes human malaria. Existing mouse models of P. falciparum infection require repeated injections of human red blood cells (RBCs). In addition, clodronate lipsomes and anti-neutrophil antibodies are injected to suppress the clearance of human RBCs by the residual immune system of the immunodeficient mice. Engraftment of NOD-scid Il2rg-/- mice with human hematopoietic stem cells leads to reconstitution of human immune cells. Although human B cell reconstitution is robust and T cell reconstitution is reasonable in the recipient mice, human RBC reconstitution is generally poor or undetectable. The poor reconstitution is mainly the result of a deficiency of appropriate human cytokines that are necessary for the development and maintenance of these cell lineages. Delivery of plasmid DNA encoding human erythropoietin and interleukin-3 into humanized mice by hydrodynamic tail-vein injection resulted in significantly enhanced reconstitution of erythrocytes. With this improved humanized mouse, here we show that P. falciparum infects de novo generated human RBCs, develops into schizonts and causes successive reinvasion. We also show that different parasite strains exhibit variation in their ability to infect these humanized mice. Parasites could be detected by nested PCR in the blood samples of humanized mice infected with P. falciparum K1 and HB3 strains for 3 cycles, whereas in other strains such as 3D7, DD2, 7G8, FCR3 and W2mef parasites could only be detected for 1 cycle. In vivo adaptation of K1 strain further improves the infection efficiency and parasites can be detected by microscopy for 3 cycles. The parasitemia ranges between 0.13 and 0.25% at the first cycle of infection, falls between 0.08 and 0.15% at the second cycle, and drops to barely detectable levels at the third cycle of infection. Compared to existing mouse models, our

  4. Acyclic Immucillin Phosphonates. Second-Generation Inhibitors of Plasmodium falciparum Hypoxanthine- Guanine-Xanthine Phosphoribosyltransferase

    SciTech Connect

    Hazelton, Keith Z.; Ho, Meng-Chaio; Cassera, Maria B.; Clinch, Keith; Crump, Douglas R.; Rosario Jr., Irving; Merino, Emilio F.; Almo, Steve C.; Tyler, Peter C.; Schramm, Vern L.

    2012-06-22

    We found that Plasmodium falciparum is the primary cause of deaths from malaria. It is a purine auxotroph and relies on hypoxanthine salvage from the host purine pool. Purine starvation as an antimalarial target has been validated by inhibition of purine nucleoside phosphorylase. Hypoxanthine depletion kills Plasmodium falciparum in cell culture and in Aotus monkey infections. Hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT) from P. falciparum is required for hypoxanthine salvage by forming inosine 5'-monophosphate, a branchpoint for all purine nucleotide synthesis in the parasite. We present a class of HGXPRT inhibitors, the acyclic immucillin phosphonates (AIPs), and cell permeable AIP prodrugs. The AIPs are simple, potent, selective, and biologically stable inhibitors. The AIP prodrugs block proliferation of cultured parasites by inhibiting the incorporation of hypoxanthine into the parasite nucleotide pool and validates HGXPRT as a target in malaria.

  5. High-Quality Genome Assembly and Annotation for Plasmodium coatneyi, Generated Using Single-Molecule Real-Time PacBio Technology.

    PubMed

    Chien, Jung-Ting; Pakala, Suman B; Geraldo, Juliana A; Lapp, Stacey A; Humphrey, Jay C; Barnwell, John W; Kissinger, Jessica C; Galinski, Mary R

    2016-01-01

    Plasmodium coatneyi is a protozoan parasite species that causes simian malaria and is an excellent model for studying disease caused by the human malaria parasite, P. falciparum Here we report the complete (nontelomeric) genome sequence of P. coatneyi Hackeri generated by the application of only Pacific Biosciences RS II (PacBio RS II) single-molecule real-time (SMRT) high-resolution sequence technology and assembly using the Hierarchical Genome Assembly Process (HGAP). This is the first Plasmodium genome sequence reported to use only PacBio technology. This approach has proven to be superior to short-read only approaches for this species. PMID:27587810

  6. High-Quality Genome Assembly and Annotation for Plasmodium coatneyi, Generated Using Single-Molecule Real-Time PacBio Technology

    PubMed Central

    Chien, Jung-Ting; Pakala, Suman B.; Geraldo, Juliana A.; Lapp, Stacey A.; Humphrey, Jay C.; Barnwell, John W.; Kissinger, Jessica C.

    2016-01-01

    Plasmodium coatneyi is a protozoan parasite species that causes simian malaria and is an excellent model for studying disease caused by the human malaria parasite, P. falciparum. Here we report the complete (nontelomeric) genome sequence of P. coatneyi Hackeri generated by the application of only Pacific Biosciences RS II (PacBio RS II) single-molecule real-time (SMRT) high-resolution sequence technology and assembly using the Hierarchical Genome Assembly Process (HGAP). This is the first Plasmodium genome sequence reported to use only PacBio technology. This approach has proven to be superior to short-read only approaches for this species. PMID:27587810

  7. 78 FR 25081 - Reissuance of Final NPDES General Permits for Facilities/Operations That Generate, Treat, and/or...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-04-29

    ... AGENCY Reissuance of Final NPDES General Permits for Facilities/ Operations That Generate, Treat, and/or... Discharge Elimination System (NPDES) general permits for facilities or operations that generate, treat, and... EPA Region 8 Web page at http://www.epa.gov/region08/water/biosolids/documents.html . Please allow...

  8. Assessing the impact of next-generation rapid diagnostic tests on Plasmodium falciparum malaria elimination strategies.

    PubMed

    Slater, Hannah C; Ross, Amanda; Ouédraogo, André Lin; White, Lisa J; Nguon, Chea; Walker, Patrick G T; Ngor, Pengby; Aguas, Ricardo; Silal, Sheetal P; Dondorp, Arjen M; La Barre, Paul; Burton, Robert; Sauerwein, Robert W; Drakeley, Chris; Smith, Thomas A; Bousema, Teun; Ghani, Azra C

    2015-12-01

    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 from Burkina Faso. We find that a diagnostic with a lower detection limit of 200 parasites per microlitre would detect 55% of the infectious reservoir (the combined infectivity to mosquitoes of the whole population weighted by how often each individual is bitten) whereas a test with a limit of 20 parasites per microlitre would detect 83% and 2 parasites per microlitre would detect 95% of the infectious reservoir. Using mathematical models, we show that increasing the diagnostic sensitivity from 200 parasites per microlitre (equivalent to microscopy or current rapid diagnostic tests) to 2 parasites per microlitre would increase the number of regions where transmission could be interrupted with a mass-screen-and-treat programme from an entomological inoculation rate below 1 to one of up to 4. The higher sensitivity diagnostic could reduce the number of treatment rounds required to interrupt transmission in areas of lower prevalence. We predict that mass-screen-and-treat with a highly sensitive diagnostic is less effective than mass drug administration owing to the prophylactic protection provided to uninfected individuals by the latter approach. In low-transmission settings such as those in Southeast Asia, we find that a diagnostic tool with a sensitivity of 20 parasites per microlitre may be sufficient for targeted mass drug administration because this diagnostic is predicted to identify a similar village population prevalence compared with that currently detected using

  9. Next-generation sequencing reveals cryptic mtDNA diversity of Plasmodium relictum in the Hawaiian Islands

    USGS Publications Warehouse

    Jarvi, S.I.; Farias, M.E.; Lapointe, D.A.; Belcaid, M.; Atkinson, C.T.

    2013-01-01

    Next-generation 454 sequencing techniques were used to re-examine diversity of mitochondrial cytochrome b lineages of avian malaria (Plasmodium relictum) in Hawaii. We document a minimum of 23 variant lineages of the parasite based on single nucleotide transitional changes, in addition to the previously reported single lineage (GRW4). A new, publicly available portal (Integroomer) was developed for initial parsing of 454 datasets. Mean variant prevalence and frequency was higher in low elevation Hawaii Amakihi (Hemignathus virens) with Avipoxvirus-like lesions (P = 0·001), suggesting that the variants may be biologically distinct. By contrast, variant prevalence and frequency did not differ significantly among mid-elevation Apapane (Himatione sanguinea) with or without lesions (P = 0·691). The low frequency and the lack of detection of variants independent of GRW4 suggest that multiple independent introductions of P. relictum to Hawaii are unlikely. Multiple variants may have been introduced in heteroplasmy with GRW4 or exist within the tandem repeat structure of the mitochondrial genome. The discovery of multiple mitochondrial lineages of P. relictum in Hawaii provides a measure of genetic diversity within a geographically isolated population of this parasite and suggests the origins and evolution of parasite diversity may be more complicated than previously recognized.

  10. Adjuvant poly(N-isopropylacrylamide) generates more efficient monoclonal antibodies against truncated recombinant histidine-rich protein2 of Plasmodium falciparum for malaria diagnosis.

    PubMed

    Verma, Reena; Ravichandran, Ramakrishnan; Jayaprakash, Naatamai S; Kumar, Ashok; Vijayalakshmi, Mookambeswaran A; Venkataraman, Krishnan

    2015-05-01

    Adjuvants play an important role in eliciting immune responses and subsequent generation of antibodies with high specificity. Recently, poly(N-isopropylacrylamide) (PNiPAAm), also known as a "smart" polymer, has been proposed as a potential adjuvant for making antibodies and vaccines. This material exhibits efficient delivery, protection against degradation, and preservation of antigen epitopes. In this work, we used both CFA and smart polymer to develop a highly specific murine monoclonal antibody (mAb) against recombinant truncated histidine rich protein2 (HRP2) of Plasmodium falciparum. Our results indicate that the mAbs developed using these adjuvants were able to recognize recombinant HRP2 and native PfHRP2 protein from spent medium. The mAbs generated against recombinant truncated HRP2 showed better sensitivity to the antigen and importantly mAbs generated using PNiPAAm adjuvant were in the range of 10(8)-10(9) M(-1). The mAbs generated using PNiPAAm are very efficient and sensitive in detecting HRP2. To the best of our knowledge, this is the first report of such comparison having been made between these two adjuvants and we propose that the smart polymer has huge potential as an alternative to CFA. Additionally, we discuss the utility of the mAbs generated through PNiPAAm for specific diagnosis of malaria caused by P. falciparum. PMID:25641957

  11. 76 FR 61735 - Incidental Take Permit; Auwahi Wind Energy Generation Facility, Maui, HI; Draft Habitat...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-10-05

    ... endangered Hawaiian bird species, one bat species, and one moth species. The permit application includes a... cinereus semotus), and the endangered Blackburn's sphinx moth (Manduca blackburni) (collectively these four... turbine development, and that the species may roost on the project site. The adult Blackburn's sphinx...

  12. New efficient artemisinin derived agents against human leukemia cells, human cytomegalovirus and Plasmodium falciparum: 2nd generation 1,2,4-trioxane-ferrocene hybrids.

    PubMed

    Reiter, Christoph; Fröhlich, Tony; Zeino, Maen; Marschall, Manfred; Bahsi, Hanife; Leidenberger, Maria; Friedrich, Oliver; Kappes, Barbara; Hampel, Frank; Efferth, Thomas; Tsogoeva, Svetlana B

    2015-06-01

    In our ongoing search for highly active hybrid molecules exceeding their parent compounds in anticancer, antimalaria as well as antiviral activity and being an alternative to the standard drugs, we present the synthesis and biological investigations of 2nd generation 1,2,4-trioxane-ferrocene hybrids. In vitro tests against the CCRF-CEM leukemia cell line revealed di-1,2,4-trioxane-ferrocene hybrid 7 as the most active compound (IC50 of 0.01 μM). Regarding the activity against the multidrug resistant subline CEM/ADR5000, 1,2,4-trioxane-ferrocene hybrid 5 showed a remarkable activity (IC50 of 0.53 μM). Contrary to the antimalaria activity of hybrids 4-8 against Plasmodium falciparum 3D7 strain with slightly higher IC50 values (between 7.2 and 30.2 nM) than that of their parent compound DHA, hybrids 5-7 possessed very promising activity (IC50 values lower than 0.5 μM) against human cytomegalovirus (HCMV). The application of 1,2,4-trioxane-ferrocene hybrids against HCMV is unprecedented and demonstrated here for the first time.

  13. Overexpression of Plasmodium berghei ATG8 by Liver Forms Leads to Cumulative Defects in Organelle Dynamics and to Generation of Noninfectious Merozoites

    PubMed Central

    Voss, Christiane; Ehrenman, Karen; Mlambo, Godfree; Mishra, Satish; Kumar, Kota Arun; Sacci, John B.; Sinnis, Photini

    2016-01-01

    ABSTRACT Plasmodium parasites undergo continuous cellular renovation to adapt to various environments in the vertebrate host and insect vector. In hepatocytes, Plasmodium berghei discards unneeded organelles for replication, such as micronemes involved in invasion. Concomitantly, intrahepatic parasites expand organelles such as the apicoplast that produce essential metabolites. We previously showed that the ATG8 conjugation system is upregulated in P. berghei liver forms and that P. berghei ATG8 (PbATG8) localizes to the membranes of the apicoplast and cytoplasmic vesicles. Here, we focus on the contribution of PbATG8 to the organellar changes that occur in intrahepatic parasites. We illustrated that micronemes colocalize with PbATG8-containing structures before expulsion from the parasite. Interference with PbATG8 function by overexpression results in poor development into late liver stages and production of small merosomes that contain immature merozoites unable to initiate a blood infection. At the cellular level, PbATG8-overexpressing P. berghei exhibits a delay in microneme compartmentalization into PbATG8-containing autophagosomes and elimination compared to parasites from the parental strain. The apicoplast, identifiable by immunostaining of the acyl carrier protein (ACP), undergoes an abnormally fast proliferation in mutant parasites. Over time, the ACP staining becomes diffuse in merosomes, indicating a collapse of the apicoplast. PbATG8 is not incorporated into the progeny of mutant parasites, in contrast to parental merozoites in which PbATG8 and ACP localize to the apicoplast. These observations reveal that Plasmodium ATG8 is a key effector in the development of merozoites by controlling microneme clearance and apicoplast proliferation and that dysregulation in ATG8 levels is detrimental for malaria infectivity. PMID:27353755

  14. Plasmodium cynomolgi genome sequences provide insight into Plasmodium vivax and the monkey malaria clade

    PubMed Central

    Tachibana, Shin-Ichiro; Sullivan, Steven A.; Kawai, Satoru; Nakamura, Shota; Kim, Hyunjae R.; Goto, Naohisa; Arisue, Nobuko; Palacpac, Nirianne M. Q.; Honma, Hajime; Yagi, Masanori; Tougan, Takahiro; Katakai, Yuko; Kaneko, Osamu; Mita, Toshihiro; Kita, Kiyoshi; Yasutomi, Yasuhiro; Sutton, Patrick L.; Shakhbatyan, Rimma; Horii, Toshihiro; Yasunaga, Teruo; Barnwell, John W.; Escalante, Ananias A.; Carlton, Jane M.; Tanabe, Kazuyuki

    2013-01-01

    Plasmodium cynomolgi, a malaria parasite of Asian Old World monkeys, is the sister taxon of Plasmodium vivax, the most prevalent human malaria species outside Africa. Since P. cynomolgi shares many phenotypic, biologic and genetic characteristics of P. vivax, we generated draft genome sequences of three P. cynomolgi strains and performed comparative genomic analysis between them and P. vivax, as well as a third previously sequenced simian parasite, Plasmodium knowlesi. Here we show that genomes of the monkey malaria clade can be characterized by CNVs in multigene families involved in evasion of the human immune system and invasion of host erythrocytes. We identify genome-wide SNPs, microsatellites, and CNVs in the P. cynomolgi genome, providing a map of genetic variation for mapping parasite traits and studying parasite populations. The P. cynomolgi genome is a critical step in developing a model system for P. vivax research, and to counteract the neglect of P. vivax. PMID:22863735

  15. Antigenic Variation in Plasmodium falciparum.

    PubMed

    Petter, Michaela; Duffy, Michael F

    2015-01-01

    Plasmodium falciparum is the protozoan parasite that causes most malaria-associated morbidity and mortality in humans with over 500,000 deaths annually. The disease symptoms are associated with repeated cycles of invasion and asexual multiplication inside red blood cells of the parasite. Partial, non-sterile immunity to P. falciparum malaria develops only after repeated infections and continuous exposure. The successful evasion of the human immune system relies on the large repertoire of antigenically diverse parasite proteins displayed on the red blood cell surface and on the merozoite membrane where they are exposed to the human immune system. Expression switching of these polymorphic proteins between asexual parasite generations provides an efficient mechanism to adapt to the changing environment in the host and to maintain chronic infection. This chapter discusses antigenic diversity and variation in the malaria parasite and our current understanding of the molecular mechanisms that direct the expression of these proteins. PMID:26537377

  16. Plasmodium knowlesi infection: a diagnostic challenge

    PubMed Central

    Fan, Lijia; Lee, Shir Ying; Koay, Evelyn; Harkensee, Christian

    2013-01-01

    Plasmodium knowlesi malaria is an uncommon, but highly prevalent parasitic infection in parts of Malaysia. This is the case of a 14-year-old Singaporean boy presenting to our emergency department with an 11-day history of fever following a school trip to Malaysia. Hepatosplenomegaly was the only clinical finding; laboratory tests showed thrombocytopaenia, lymphopaenia, mild anaemia and liver transaminitis. Specific malaria antigen tests were negative, but the peripheral blood film showed plasmodia with atypical features, with a parasite load of 0.5%. PCR confirmed the diagnosis of P knowlesi. The patient was successfully treated with chloroquine. The clinical course of P knowlesi malaria is indistinguishable from that of Plasmodium falciparum. This case highlights the importance of taking detailed travel history, careful examination of malaria blood films and judicious use of molecular techniques. Antigen tests alone may have missed a malaria diagnosis altogether, while blood film examination may wrongly identify the species as Plasmodium malariae or P falciparum. Third-generation PCR assays can be used to reliably identify P knowlesi. PMID:23608876

  17. Branched tricarboxylic acid metabolism in Plasmodium falciparum.

    PubMed

    Olszewski, Kellen L; Mather, Michael W; Morrisey, Joanne M; Garcia, Benjamin A; Vaidya, Akhil B; Rabinowitz, Joshua D; Llinás, Manuel

    2010-08-01

    A central hub of carbon metabolism is the tricarboxylic acid cycle, which serves to connect the processes of glycolysis, gluconeogenesis, respiration, amino acid synthesis and other biosynthetic pathways. The protozoan intracellular malaria parasites (Plasmodium spp.), however, have long been suspected of possessing a significantly streamlined carbon metabolic network in which tricarboxylic acid metabolism plays a minor role. Blood-stage Plasmodium parasites rely almost entirely on glucose fermentation for energy and consume minimal amounts of oxygen, yet the parasite genome encodes all of the enzymes necessary for a complete tricarboxylic acid cycle. Here, by tracing (13)C-labelled compounds using mass spectrometry we show that tricarboxylic acid metabolism in the human malaria parasite Plasmodium falciparum is largely disconnected from glycolysis and is organized along a fundamentally different architecture from the canonical textbook pathway. We find that this pathway is not cyclic, but rather is a branched structure in which the major carbon sources are the amino acids glutamate and glutamine. As a consequence of this branched architecture, several reactions must run in the reverse of the standard direction, thereby generating two-carbon units in the form of acetyl-coenzyme A. We further show that glutamine-derived acetyl-coenzyme A is used for histone acetylation, whereas glucose-derived acetyl-coenzyme A is used to acetylate amino sugars. Thus, the parasite has evolved two independent production mechanisms for acetyl-coenzyme A with different biological functions. These results significantly clarify our understanding of the Plasmodium metabolic network and highlight the ability of altered variants of central carbon metabolism to arise in response to unique environments. PMID:20686576

  18. Deleting the Redundant TSH Receptor C-Peptide Region Permits Generation of the Conformationally Intact Extracellular Domain by Insect Cells

    PubMed Central

    Chen, Chun-Rong; Salazar, Larry M.; McLachlan, Sandra M.

    2015-01-01

    The TSH receptor (TSHR) extracellular domain (ECD) comprises a N-terminal leucine-rich repeat domain and an hinge region (HR), the latter contributing to ligand binding and critical for receptor activation. The crystal structure of the leucine-rich repeat domain component has been solved, but previous attempts to generate conformationally intact complete ECD or the isolated HR component for structural analysis have failed. The TSHR HR contains a C-peptide segment that is removed during spontaneous TSHR intramolecular cleavage into disulfide linked A- and B-subunits. We hypothesized that deletion of the redundant C-peptide would overcome the obstacle to generating conformationally intact TSHR ECD protein. Indeed, lacking the C-peptide region, the TSHR ECD (termed ECD-D1) and the isolated HR (termed HR-D1) were secreted into medium of insect cells infected with baculoviruses coding for these modified proteins. The identities of TSHR ECD-D1 and HR-D1 were confirmed by ELISA and immunoblotting using TSHR-specific monoclonal antibodies. The TSHR-ECD-D1 in conditioned medium was folded correctly, as demonstrated by its ability to inhibit radiolabeled TSH binding to the TSH holoreceptor. The TSHR ECD-D1 purification was accomplished in a single step using a TSHR monoclonal antibody affinity column, whereas the HR-D1 required a multistep protocol with a low yield. In conclusion, we report a novel approach to generate the TSHR ECD, as well as the isolated HR in insect cells, the former in sufficient amounts for structural studies. However, such studies will require previous complexing of the ECD with a ligand such as TSH or a thyroid-stimulating antibody. PMID:25860033

  19. Wolbachia increases susceptibility to Plasmodium infection in a natural system

    PubMed Central

    Zélé, F.; Nicot, A.; Berthomieu, A.; Weill, M.; Duron, O.; Rivero, A.

    2014-01-01

    Current views about the impact of Wolbachia on Plasmodium infections are almost entirely based on data regarding artificially transfected mosquitoes. This work has shown that Wolbachia reduces the intensity of Plasmodium infections in mosquitoes, raising the exciting possibility of using Wolbachia to control or limit the spread of malaria. Whether natural Wolbachia infections have the same parasite-inhibiting properties is not yet clear. Wolbachia–mosquito combinations with a long evolutionary history are, however, key for understanding what may happen with Wolbachia-transfected mosquitoes after several generations of coevolution. We investigate this issue using an entirely natural mosquito–Wolbachia–Plasmodium combination. In contrast to most previous studies, which have been centred on the quantification of the midgut stages of Plasmodium, we obtain a measurement of parasitaemia that relates directly to transmission by following infections to the salivary gland stages. We show that Wolbachia increases the susceptibility of Culex pipiens mosquitoes to Plasmodium relictum, significantly increasing the prevalence of salivary gland stage infections. This effect is independent of the density of Wolbachia in the mosquito. These results suggest that naturally Wolbachia-infected mosquitoes may, in fact, be better vectors of malaria than Wolbachia-free ones. PMID:24500167

  20. Analysis of expressed sequence tags from Plasmodium falciparum.

    PubMed

    Chakrabarti, D; Reddy, G R; Dame, J B; Almira, E C; Laipis, P J; Ferl, R J; Yang, T P; Rowe, T C; Schuster, S M

    1994-07-01

    An initiative was undertaken to sequence all genes of the human malaria parasite Plasmodium falciparum in an effort to gain a better understanding at the molecular level of the parasite that inflicts much suffering in the developing world. 550 random complimentary DNA clones were partially sequenced from the intraerythrocytic form of the parasite as one of the approaches to analyze the transcribed sequences of its genome. The sequences, after editing, generated 389 expressed sequence tag sites and over 105 kb of DNA sequences. About 32% of these clones showed significant homology with other genes in the database. These clones represent 340 new Plasmodium falciparum expressed sequence tags.

  1. [From malaria parasite point of view--Plasmodium falciparum evolution].

    PubMed

    Zerka, Agata; Kaczmarek, Radosław; Jaśkiewicz, Ewa

    2015-12-31

    Malaria is caused by infection with protozoan parasites belonging to the genus Plasmodium, which have arguably exerted the greatest selection pressure on humans in the history of our species. Besides humans, different Plasmodium parasites infect a wide range of animal hosts, from marine invertebrates to primates. On the other hand, individual Plasmodium species show high host specificity. The extraordinary evolution of Plasmodium probably began when a free-living red algae turned parasitic, and culminated with its ability to thrive inside a human red blood cell. Studies on the African apes generated new data on the evolution of malaria parasites in general and the deadliest human-specific species, Plasmodium falciparum, in particular. Initially, it was hypothesized that P. falciparum descended from the chimpanzee malaria parasite P. reichenowi, after the human and the chimp lineage diverged about 6 million years ago. However, a recently identified new species infecting gorillas, unexpectedly showed similarity to P. falciparum and was therefore named P. praefalciparum. That finding spurred an alternative hypothesis, which proposes that P. falciparum descended from its gorilla rather than chimp counterpart. In addition, the gorilla-to-human host shift may have occurred more recently (about 10 thousand years ago) than the theoretical P. falciparum-P. reichenowi split. One of the key aims of the studies on Plasmodium evolution is to elucidate the mechanisms that allow the incessant host shifting and retaining the host specificity, especially in the case of human-specific species. Thorough understanding of these phenomena will be necessary to design effective malaria treatment and prevention strategies.

  2. A Panel of Artificial APCs Expressing Prevalent HLA Alleles Permits Generation of Cytotoxic T Cells Specific for Both Dominant and Subdominant Viral Epitopes for Adoptive Therapy1

    PubMed Central

    Hasan, Aisha N.; Kollen, Wouter J.; Trivedi, Deepa; Selvakumar, Annamalai; Dupont, Bo; Sadelain, Michel; O'Reilly, Richard J.

    2009-01-01

    Adoptive transfer of virus-specific T cells can treat infections complicating allogeneic hematopoietic cell transplants. However, autologous antigen-presenting cells (APCs) are often limited in supply. Here, we describe a panel of artificial APCs (AAPCs) consisting of murine 3T3 cells transduced to express human B7.1, ICAM-1 and LFA-3 that each stably express one of a series of 6 common HLA class I alleles. In comparative analyses, T cells sensitized with AAPCs expressing a shared HLA allele or autologous APCs loaded with a pool of 15-mers spanning the sequence of CMVpp65 produced similar yields of HLA-restricted CMVpp65 specific T cells; significantly higher yields could be achieved by sensitization with AAPCs transduced to express the CMVpp65 protein. T cells generated were CD8+, IFNγ+ and exhibited HLA-restricted CMVpp65 specific cytotoxicity. T cells sensitized with either peptide-loaded or transduced AAPCs recognized epitopes presented by each HLA allele known to be immunogenic in man. Sensitization with AAPCs also permitted expansion of IFNγ+ cytotoxic effector cells against subdominant epitopes that were either absent or in low frequencies in T cells sensitized with autologous APCs. This replenishable panel of AAPCs can be used for immediate sensitization and expansion of virus-specific T cells of desired HLA restriction for adoptive immunotherapy. It may be of particular value for recipients of transplants from HLA disparate donors. PMID:19635907

  3. Branched Tricarboxylic Acid Metabolism in Plasmodium falciparum

    PubMed Central

    Olszewski, Kellen L.; Mather, Michael W.; Morrisey, Joanne M.; Garcia, Benjamin A.; Vaidya, Akhil B.; Rabinowitz, Joshua D.; Llinás, Manuel

    2010-01-01

    A central hub of carbon metabolism is the tricarboxylic acid (TCA) cycle1, which serves to connect the processes of glycolysis, gluconeogenesis, respiration, amino acid synthesis and other biosynthetic pathways. The protozoan intracellular malaria parasites (Plasmodium spp.), however, have long been suspected of possessing a significantly streamlined carbon metabolic network in which TCA metabolism plays a minor role2. Blood-stage Plasmodium parasites rely almost entirely on glucose fermentation for energy and consume minimal amounts of oxygen3, yet the parasite genome encodes all of the enzymes necessary for a complete TCA cycle4. By tracing 13C-labeled compounds using mass spectrometry5 we show that TCA metabolism in the human malaria parasite P. falciparum is largely disconnected from glycolysis and is organized along a fundamentally different architecture than the canonical textbook pathway. We find that this pathway is not cyclic but rather a branched structure in which the major carbon sources are the amino acids glutamate and glutamine. As a consequence of this branched architecture, several reactions must run in the reverse of the standard direction thereby generating two-carbon units in the form of acetyl-coenzyme A (acetyl-CoA). We further show that glutamine-derived acetyl-CoA is used for histone acetylation while glucose-derived acetyl-CoA is used to acetylate aminosugars. Thus the parasite has evolved two independent acetyl-CoA-production mechanisms with different biological functions. These results significantly clarify our understanding of the Plasmodium metabolic network and highlight the ability of altered variants of central carbon metabolism to arise in response to unique environments. PMID:20686576

  4. Detectability of Plasmodium falciparum clones

    PubMed Central

    2010-01-01

    Background In areas of high transmission people often harbour multiple clones of Plasmodium falciparum, but even PCR-based diagnostic methods can only detect a fraction (the detectability, q) of all clones present in a host. Accurate measurements of detectability are desirable since it affects estimates of multiplicity of infection, prevalence, and frequency of breakthrough infections in clinical drug trials. Detectability can be estimated by typing repeated samples from the same host but it has been unclear what should be the time interval between the samples and how the data should be analysed. Methods A longitudinal molecular study was conducted in the Kassena-Nankana district in northern Ghana. From each of the 80 participants, four finger prick samples were collected over a period of 8 days, and tested for presence of different Merozoite Surface Protein (msp) 2 genotypes. Implications for estimating q were derived from these data by comparing the fit of statistical models of serial dependence and over-dispersion. Results The distribution of the frequencies of detection for msp2 genotypes was close to binomial if the time span between consecutive blood samples was at least 7 days. For shorter intervals the probabilities of detection were positively correlated, i.e. the shorter the interval between two blood collections, the more likely the diagnostic results matched for a particular genotype. Estimates of q were rather insensitive to the statistical model fitted. Conclusions A simple algorithm based on analysing blood samples collected 7 days apart is justified for generating robust estimates of detectability. The finding of positive correlation of detection probabilities for short time intervals argues against imperfect detection being directly linked to the 48-hour periodicity of P. falciparum. The results suggest that the detectability of a given parasite clone changes over time, at an unknown rate, but fast enough to regard blood samples taken one week

  5. Plasmodium Falciparum Malaria

    PubMed Central

    Schmidt, John A.; Udeinya, Iroka J.; Leech, James H.; Hay, Robert J.; Aikawa, Masamichi; Barnwell, John; Green, Ira; Miller, Louis H.

    1982-01-01

    Erythrocytes infected with Plasmodium falciparum trophozoites and schizonts are not seen in the peripheral circulation because they attach to venular endothelium via knoblike structures on the infected erythrocyte membrane. We have recently shown that erythrocytes containing P. falciparum trophozoites and schizonts likewise attach to cultured human venous endothelial cells via knobs. In search of a more practical target cell for large scale binding studies designed to characterize and isolate the knob ligand, we tested various normal cells and continuous cell lines for their ability to bind P. falciparum-infected erythrocytes. Of the 18 cell types tested, binding of infected erythrocytes was observed to a human amelanotic melanoma cell line and amnion epithelial cells as well as to human aortic and umbilical vein endothelial cells. 96-100% of amelanotic melanoma cells bound 17±4 (±1 SEM) infected erythrocytes per positive cell, whereas fewer endothelial cells (4-59%) and amnion epithelial cells (8-19%) were capable of binding 12±5 and 4±1 infected erythrocytes per positive cell, respectively. Further studies designed to compare the mechanism of binding to the amelanotic melanoma cell line and endothelial cells showed the following results. First, that adhesion of infected erythrocytes to these two cell types was parasite stage-specific in that only erythrocytes containing late ring forms, trophozoites, and schizonts bound. Erythrocytes containing early ring forms, which do not attach to venular endothelium in vivo, did not bind to either cell type. Second, erythrocytes infected with trophozoites and schizonts of P. vivax or a knobless strain of P. falciparum, both of which continue to circulate in vivo, did not bind to either target cell type. Third, transmission electron microscopy showed that infected erythrocytes attached to the amelanotic melanoma cells via knobs. We conclude that cultured human endothelial cells and an amelanotic melanoma cell line share

  6. CRISPR-mediated genome editing of Plasmodium falciparum malaria parasites.

    PubMed

    Lee, Marcus Cs; Fidock, David A

    2014-01-01

    The development of the CRISPR-Cas system is revolutionizing genome editing in a variety of organisms. The system has now been used to manipulate the genome of Plasmodium falciparum, the most lethal malaria-causing species. The ability to generate gene deletions or nucleotide substitutions rapidly and economically promises to accelerate the analysis of novel drug targets and to help elucidate the function of specific genes or gene families, while complementing genome-wide association studies.

  7. Regulatory and Permitting Issues

    SciTech Connect

    Larry Myer

    2005-12-01

    As part of the West Coast Regional Carbon Sequestration Partnership (WESTCARB), Terralog Technologies USA, Inc., reviewed current state and federal regulations related to carbon dioxide capture and storage within geologic formations and enhanced carbon uptake in terrestrial ecosystems. We have evaluated and summarized the current and possible future permitting requirements for the six states that comprise the West Coast Regional Partnership. Four options exist for CO{sub 2} injection into appropriate geologic formations, including storage in: (1) oil and gas reservoirs, (2) saline formations, (3) unmineable coal beds, and (4) salt caverns. Terrestrial CO{sub 2} sequestration involves improved carbon conservation management (e.g. reduction of deforestation), carbon substitution (e.g., substitution for fossil fuel-based products, energy conservation through urban forestry, biomass for energy generation), and improved carbon storage management (e.g., expanding the storage of carbon in forest ecosystems). The primary terrestrial options for the West Coast Region include: (1) reforestation of under-producing lands (including streamside forest restoration), (2) improved forest management, (3) forest protection and conservation, and (4) fuel treatments for the reduction of risk of uncharacteristically severe fires (potentially with associated biomass energy generation). The permits and/or contracts required for any land-use changes/disturbances and biomass energy generation that may occur as part of WESTCARB's activities have been summarized for each state.

  8. Detection of Plasmodium sp. in capybara.

    PubMed

    dos Santos, Leonilda Correia; Curotto, Sandra Mara Rotter; de Moraes, Wanderlei; Cubas, Zalmir Silvino; Costa-Nascimento, Maria de Jesus; de Barros Filho, Ivan Roque; Biondo, Alexander Welker; Kirchgatter, Karin

    2009-07-01

    In the present study, we have microscopically and molecularly surveyed blood samples from 11 captive capybaras (Hydrochaeris hydrochaeris) from the Sanctuary Zoo for Plasmodium sp. infection. One animal presented positive on blood smear by light microscopy. Polymerase chain reaction was carried out accordingly using a nested genus-specific protocol, which uses oligonucleotides from conserved sequences flanking a variable sequence region in the small subunit ribosomal RNA (ssrRNA) of all Plasmodium organisms. This revealed three positive animals. Products from two samples were purified and sequenced. The results showed less than 1% divergence between the two capybara sequences. When compared with GenBank sequences, a 55% similarity was obtained to Toxoplasma gondii and a higher similarity (73-77.2%) was found to ssrRNAs from Plasmodium species that infect reptile, avian, rodents, and human beings. The most similar Plasmodium sequence was from Plasmodium mexicanum that infects lizards of North America, where around 78% identity was found. This work is the first report of Plasmodium in capybaras, and due to the low similarity with other Plasmodium species, we suggest it is a new species, which, in the future could be denominated "Plasmodium hydrochaeri".

  9. Control of Plasmodium knowlesi malaria

    NASA Astrophysics Data System (ADS)

    Abdullahi, Mohammed Baba; Hasan, Yahya Abu; Abdullah, Farah Aini

    2015-10-01

    The most significant and efficient measures against Plasmodium knowlesi outbreaks are efficient anti malaria drug, biological control in form of predatory mosquitoes and culling control strategies. In this paper optimal control theory is applied to a system of ordinary differential equation. It describes the disease transmission and Pontryagin's Maximum Principle is applied for analysis of the control. To this end, three control strategies representing biological control, culling and treatment were incorporated into the disease transmission model. The simulation results show that the implementation of the combination strategy during the epidemic is the most cost-effective strategy for disease transmission.

  10. In silico identification of genetically attenuated vaccine candidate genes for Plasmodium liver stage.

    PubMed

    Kumar, Hirdesh; Frischknecht, Friedrich; Mair, Gunnar R; Gomes, James

    2015-12-01

    Genetically attenuated parasites (GAPs) that lack genes essential for the liver stage of the malaria parasite, and therefore cause developmental arrest, have been developed as live vaccines in rodent malaria models and recently been tested in humans. The genes targeted for deletion were often identified by trial and error. Here we present a systematic gene - protein and transcript - expression analyses of several Plasmodium species with the aim to identify candidate genes for the generation of novel GAPs. With a lack of liver stage expression data for human malaria parasites, we used data available for liver stage development of Plasmodium yoelii, a rodent malaria model, to identify proteins expressed in the liver stage but absent from blood stage parasites. An orthology-based search was then employed to identify orthologous proteins in the human malaria parasite Plasmodium falciparum resulting in a total of 310 genes expressed in the liver stage but lacking evidence of protein expression in blood stage parasites. Among these 310 possible GAP candidates, we further studied Plasmodium liver stage proteins by phyletic distribution and functional domain analyses and shortlisted twenty GAP-candidates; these are: fabB/F, fabI, arp, 3 genes encoding subunits of the PDH complex, dnaJ, urm1, rS5, ancp, mcp, arh, gk, lisp2, valS, palm, and four conserved Plasmodium proteins of unknown function. Parasites lacking one or several of these genes might yield new attenuated malaria parasites for experimental vaccination studies.

  11. Spatial association with PTEX complexes defines regions for effector export into Plasmodium falciparum-infected erythrocytes

    PubMed Central

    Riglar, David T.; Rogers, Kelly L.; Hanssen, Eric; Turnbull, Lynne; Bullen, Hayley E.; Charnaud, Sarah C.; Przyborski, Jude; Gilson, Paul R.; Whitchurch, Cynthia B.; Crabb, Brendan S.; Baum, Jake; Cowman, Alan F.

    2013-01-01

    Export of proteins into the infected erythrocyte is critical for malaria parasite survival. The majority of effector proteins are thought to export via a proteinaceous translocon, resident in the parasitophorous vacuole membrane surrounding the parasite. Identification of the Plasmodium translocon of exported proteins and its biochemical association with exported proteins suggests it performs this role. Direct evidence for this, however, is lacking. Here using viable purified Plasmodium falciparum merozoites and three-dimensional structured illumination microscopy, we investigate remodelling events immediately following parasite invasion. We show that multiple complexes of the Plasmodium translocon of exported proteins localize together in foci that dynamically change in clustering behaviour. Furthermore, we provide conclusive evidence of spatial association between exported proteins and exported protein 2, a core component of the Plasmodium translocon of exported proteins, during native conditions and upon generation of translocation intermediates. These data provide the most direct cellular evidence to date that protein export occurs at regions of the parasitophorous vacuole membrane housing the Plasmodium translocon of exported proteins complex. PMID:23361006

  12. Parasite-induced ER stress response in hepatocytes facilitates Plasmodium liver stage infection.

    PubMed

    Inácio, Patricia; Zuzarte-Luís, Vanessa; Ruivo, Margarida T G; Falkard, Brie; Nagaraj, Nagarjuna; Rooijers, Koos; Mann, Matthias; Mair, Gunnar; Fidock, David A; Mota, Maria M

    2015-08-01

    Upon infection of a mammalian host, Plasmodium parasites first replicate inside hepatocytes, generating thousands of new parasites. Although Plasmodium intra-hepatic development represents a substantial metabolic challenge to the host hepatocyte, how infected cells respond to and integrate this stress remains poorly understood. Here, we present proteomic and transcriptomic analyses, revealing that the endoplasmic reticulum (ER)-resident unfolded protein response (UPR) is activated in host hepatocytes upon Plasmodium berghei infection. The expression of XBP1s--the active form of the UPR mediator XBP1--and the liver-specific UPR mediator CREBH is induced by P. berghei infection in vivo. Furthermore, this UPR induction increases parasite liver burden. Altogether, our data suggest that ER stress is a central feature of P. berghei intra-hepatic development, contributing to the success of infection. PMID:26113366

  13. Parasite-induced ER stress response in hepatocytes facilitates Plasmodium liver stage infection

    PubMed Central

    Inácio, Patricia; Zuzarte-Luís, Vanessa; Ruivo, Margarida TG; Falkard, Brie; Nagaraj, Nagarjuna; Rooijers, Koos; Mann, Matthias; Mair, Gunnar; Fidock, David A; Mota, Maria M

    2015-01-01

    Upon infection of a mammalian host, Plasmodium parasites first replicate inside hepatocytes, generating thousands of new parasites. Although Plasmodium intra-hepatic development represents a substantial metabolic challenge to the host hepatocyte, how infected cells respond to and integrate this stress remains poorly understood. Here, we present proteomic and transcriptomic analyses, revealing that the endoplasmic reticulum (ER)-resident unfolded protein response (UPR) is activated in host hepatocytes upon Plasmodium berghei infection. The expression of XBP1s—the active form of the UPR mediator XBP1—and the liver-specific UPR mediator CREBH is induced by P. berghei infection in vivo. Furthermore, this UPR induction increases parasite liver burden. Altogether, our data suggest that ER stress is a central feature of P. berghei intra-hepatic development, contributing to the success of infection. PMID:26113366

  14. Parasite-induced ER stress response in hepatocytes facilitates Plasmodium liver stage infection.

    PubMed

    Inácio, Patricia; Zuzarte-Luís, Vanessa; Ruivo, Margarida T G; Falkard, Brie; Nagaraj, Nagarjuna; Rooijers, Koos; Mann, Matthias; Mair, Gunnar; Fidock, David A; Mota, Maria M

    2015-08-01

    Upon infection of a mammalian host, Plasmodium parasites first replicate inside hepatocytes, generating thousands of new parasites. Although Plasmodium intra-hepatic development represents a substantial metabolic challenge to the host hepatocyte, how infected cells respond to and integrate this stress remains poorly understood. Here, we present proteomic and transcriptomic analyses, revealing that the endoplasmic reticulum (ER)-resident unfolded protein response (UPR) is activated in host hepatocytes upon Plasmodium berghei infection. The expression of XBP1s--the active form of the UPR mediator XBP1--and the liver-specific UPR mediator CREBH is induced by P. berghei infection in vivo. Furthermore, this UPR induction increases parasite liver burden. Altogether, our data suggest that ER stress is a central feature of P. berghei intra-hepatic development, contributing to the success of infection.

  15. Phenotypic and genotypic characterisation of drug-resistant Plasmodium vivax.

    PubMed

    Price, Ric N; Auburn, Sarah; Marfurt, Jutta; Cheng, Qin

    2012-11-01

    In this review we present recent developments in the analysis of Plasmodium vivax clinical trials and ex vivo drug-susceptibility assays, as well approaches currently being used to identify molecular markers of drug resistance. Clinical trials incorporating the measurement of in vivo drug concentrations and parasite clearance times are needed to detect early signs of resistance. Analysis of P. vivax growth dynamics ex vivo have defined the criteria for acceptable assay thresholds for drug susceptibility testing, and their subsequent interpretation. Genotyping and next-generation sequencing studies in P. vivax field isolates are set to transform our understanding of the molecular mechanisms of drug resistance.

  16. Plasmodium vivax Transmission in Africa

    PubMed Central

    Howes, Rosalind E.; Reiner Jr., Robert C.; Battle, Katherine E.; Longbottom, Joshua; Mappin, Bonnie; Ordanovich, Dariya; Tatem, Andrew J.; Drakeley, Chris; Gething, Peter W.; Zimmerman, Peter A.; Smith, David L.; Hay, Simon I.

    2015-01-01

    Malaria in sub-Saharan Africa has historically been almost exclusively attributed to Plasmodium falciparum (Pf). Current diagnostic and surveillance systems in much of sub-Saharan Africa are not designed to identify or report non-Pf human malaria infections accurately, resulting in a dearth of routine epidemiological data about their significance. The high prevalence of Duffy negativity provided a rationale for excluding the possibility of Plasmodium vivax (Pv) transmission. However, review of varied evidence sources including traveller infections, community prevalence surveys, local clinical case reports, entomological and serological studies contradicts this viewpoint. Here, these data reports are weighted in a unified framework to reflect the strength of evidence of indigenous Pv transmission in terms of diagnostic specificity, size of individual reports and corroboration between evidence sources. Direct evidence was reported from 21 of the 47 malaria-endemic countries studied, while 42 countries were attributed with infections of visiting travellers. Overall, moderate to conclusive evidence of transmission was available from 18 countries, distributed across all parts of the continent. Approximately 86.6 million Duffy positive hosts were at risk of infection in Africa in 2015. Analysis of the mechanisms sustaining Pv transmission across this continent of low frequency of susceptible hosts found that reports of Pv prevalence were consistent with transmission being potentially limited to Duffy positive populations. Finally, reports of apparent Duffy-independent transmission are discussed. While Pv is evidently not a major malaria parasite across most of sub-Saharan Africa, the evidence presented here highlights its widespread low-level endemicity. An increased awareness of Pv as a potential malaria parasite, coupled with policy shifts towards species-specific diagnostics and reporting, will allow a robust assessment of the public health significance of Pv, as well

  17. Plasmodium vivax Transmission in Africa.

    PubMed

    Howes, Rosalind E; Reiner, Robert C; Battle, Katherine E; Longbottom, Joshua; Mappin, Bonnie; Ordanovich, Dariya; Tatem, Andrew J; Drakeley, Chris; Gething, Peter W; Zimmerman, Peter A; Smith, David L; Hay, Simon I

    2015-11-01

    Malaria in sub-Saharan Africa has historically been almost exclusively attributed to Plasmodium falciparum (Pf). Current diagnostic and surveillance systems in much of sub-Saharan Africa are not designed to identify or report non-Pf human malaria infections accurately, resulting in a dearth of routine epidemiological data about their significance. The high prevalence of Duffy negativity provided a rationale for excluding the possibility of Plasmodium vivax (Pv) transmission. However, review of varied evidence sources including traveller infections, community prevalence surveys, local clinical case reports, entomological and serological studies contradicts this viewpoint. Here, these data reports are weighted in a unified framework to reflect the strength of evidence of indigenous Pv transmission in terms of diagnostic specificity, size of individual reports and corroboration between evidence sources. Direct evidence was reported from 21 of the 47 malaria-endemic countries studied, while 42 countries were attributed with infections of visiting travellers. Overall, moderate to conclusive evidence of transmission was available from 18 countries, distributed across all parts of the continent. Approximately 86.6 million Duffy positive hosts were at risk of infection in Africa in 2015. Analysis of the mechanisms sustaining Pv transmission across this continent of low frequency of susceptible hosts found that reports of Pv prevalence were consistent with transmission being potentially limited to Duffy positive populations. Finally, reports of apparent Duffy-independent transmission are discussed. While Pv is evidently not a major malaria parasite across most of sub-Saharan Africa, the evidence presented here highlights its widespread low-level endemicity. An increased awareness of Pv as a potential malaria parasite, coupled with policy shifts towards species-specific diagnostics and reporting, will allow a robust assessment of the public health significance of Pv, as well

  18. [Emerging and spread of the fifth Plasmodium spp. pathogenic for human malaria: Plasmodium knowlesi].

    PubMed

    Sabbatani, Sergio; Fiorino, Sirio; Manfredi, Roberto

    2010-02-01

    The beginning of the third millennium has been characterized by the emerging and progressive characterization of a novel malaria Plasmodium pathogen of simian origin (Plasmodium knowlesi), which now represents the fifth human malaria parasite. Evolutionary, environmental, and diagnostic-clinical features are briefly outlined on the ground of the most recent literature evidences.

  19. 77 FR 5009 - Clean Air Act Operating Permit Program; Petition for Objection to State Operating Permit for Duke...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-02-01

    ... object to a Clean Air Act (Act) Title V operating permit for Duke Energy Indiana--Edwardsport Generating... AGENCY Clean Air Act Operating Permit Program; Petition for Objection to State Operating Permit for Duke Energy Indiana--Edwardsport Generating Station AGENCY: Environmental Protection Agency (EPA)....

  20. Federal Environmental Permitting Handbook

    SciTech Connect

    Not Available

    1991-05-01

    The handbook consists of eight chapters addressing permitting and licensing requirements under the Resource Conservation and Recovery Act (RCRA), the Comprehensive Environmental Response, Compensation, and Liability Act of 1980, as amended by the Superfund Amendments and Reauthorization Act of 1986 (CERCLA/SARA), the Atomic Energy Act (AEA), the Clean Air Act (CAA), the Clean Water Act (CWA), the Federal Insectide, Fungicide, and Rodenticide Act (FIFRA), the Safe Drinking Water Act (SDWA), and the Toxic Substances Control Act (TSCA). Each chapter consists of: (1) an introduction to the statute and permitting requirements; (2) a diagram illustrating the relationship between permitting requirements under the statute being discussed and permitting requirements from other environmental statutes which may have to be addressed when applying for a particular permit (e.g., when applying for a RCRA permit, permits and permit applications under the CWA, CAA, SDWA, etc. would have to be listed in the RCRA permit application); and, (3) a compilation of the permitting requirements for the regulatory program resulting from the statute. In addition, the Handbook contains a permitting keyword index and a listing of hotline telephone numbers for each of the statutes.

  1. Evolutionary relationships between 15 Plasmodium species from new and old world primates (including humans): an 18S rDNA cladistic analysis.

    PubMed

    Leclerc, M C; Hugot, J P; Durand, P; Renaud, F

    2004-12-01

    We present a new phylogenetic analysis of 15 primate Plasmodium species based on 18S rDNA sequences including new sequences of Plasmodium coatneyi, P. fieldi, P. gonderi, P. hylobati and P. simium. The results are discussed in the context of the parasite host species and their geographical distribution. Contrary to other phylogenies constructed with this 18S rDNA molecule, we observed that the topology of phylogenetic trees was not affected either by the quality of the nucleotide matrices, or by the species present in the outgroup. This analysis showed the following. (1) The polyphyly of human Plasmodium is confirmed. (2) The monophyly of Plasmodium from Old World monkeys is confirmed by the new added sequences and P. gonderi, an African species, possibly could be at the root of this group. (3) The most parsimonious biogeographical hypothesis is that P. vivax originated in Asia; thus, its related species P. simium appears to be derived through a transfer from the human P. vivax to New World monkey species in South America. (4) Sampling efforts of non-human primate Plasmodium could permit improvement of the knowledge of primate Plasmodium phylogeny and also consideration of the risks of malaria emergence from monkey reservoirs.

  2. Inference of the oxidative stress network in Anopheles stephensi upon Plasmodium infection.

    PubMed

    Shrinet, Jatin; Nandal, Umesh Kumar; Adak, Tridibes; Bhatnagar, Raj K; Sunil, Sujatha

    2014-01-01

    Ookinete invasion of Anopheles midgut is a critical step for malaria transmission; the parasite numbers drop drastically and practically reach a minimum during the parasite's whole life cycle. At this stage, the parasite as well as the vector undergoes immense oxidative stress. Thereafter, the vector undergoes oxidative stress at different time points as the parasite invades its tissues during the parasite development. The present study was undertaken to reconstruct the network of differentially expressed genes involved in oxidative stress in Anopheles stephensi during Plasmodium development and maturation in the midgut. Using high throughput next generation sequencing methods, we generated the transcriptome of the An. stephensi midgut during Plasmodium vinckei petteri oocyst invasion of the midgut epithelium. Further, we utilized large datasets available on public domain on Anopheles during Plasmodium ookinete invasion and Drosophila datasets and arrived upon clusters of genes that may play a role in oxidative stress. Finally, we used support vector machines for the functional prediction of the un-annotated genes of An. stephensi. Integrating the results from all the different data analyses, we identified a total of 516 genes that were involved in oxidative stress in An. stephensi during Plasmodium development. The significantly regulated genes were further extracted from this gene cluster and used to infer an oxidative stress network of An. stephensi. Using system biology approaches, we have been able to ascertain the role of several putative genes in An. stephensi with respect to oxidative stress. Further experimental validations of these genes are underway.

  3. Helminth Parasites Alter Protection against Plasmodium Infection

    PubMed Central

    Salazar-Castañon, Víctor H.; Legorreta-Herrera, Martha

    2014-01-01

    More than one-third of the world's population is infected with one or more helminthic parasites. Helminth infections are prevalent throughout tropical and subtropical regions where malaria pathogens are transmitted. Malaria is the most widespread and deadliest parasitic disease. The severity of the disease is strongly related to parasite density and the host's immune responses. Furthermore, coinfections between both parasites occur frequently. However, little is known regarding how concomitant infection with helminths and Plasmodium affects the host's immune response. Helminthic infections are frequently massive, chronic, and strong inductors of a Th2-type response. This implies that infection by such parasites could alter the host's susceptibility to subsequent infections by Plasmodium. There are a number of reports on the interactions between helminths and Plasmodium; in some, the burden of Plasmodium parasites increased, but others reported a reduction in the parasite. This review focuses on explaining many of these discrepancies regarding helminth-Plasmodium coinfections in terms of the effects that helminths have on the immune system. In particular, it focuses on helminth-induced immunosuppression and the effects of cytokines controlling polarization toward the Th1 or Th2 arms of the immune response. PMID:25276830

  4. Helminth parasites alter protection against Plasmodium infection.

    PubMed

    Salazar-Castañon, Víctor H; Legorreta-Herrera, Martha; Rodriguez-Sosa, Miriam

    2014-01-01

    More than one-third of the world's population is infected with one or more helminthic parasites. Helminth infections are prevalent throughout tropical and subtropical regions where malaria pathogens are transmitted. Malaria is the most widespread and deadliest parasitic disease. The severity of the disease is strongly related to parasite density and the host's immune responses. Furthermore, coinfections between both parasites occur frequently. However, little is known regarding how concomitant infection with helminths and Plasmodium affects the host's immune response. Helminthic infections are frequently massive, chronic, and strong inductors of a Th2-type response. This implies that infection by such parasites could alter the host's susceptibility to subsequent infections by Plasmodium. There are a number of reports on the interactions between helminths and Plasmodium; in some, the burden of Plasmodium parasites increased, but others reported a reduction in the parasite. This review focuses on explaining many of these discrepancies regarding helminth-Plasmodium coinfections in terms of the effects that helminths have on the immune system. In particular, it focuses on helminth-induced immunosuppression and the effects of cytokines controlling polarization toward the Th1 or Th2 arms of the immune response.

  5. Genome editing in the human malaria parasite Plasmodium falciparum using the CRISPR-Cas9 system.

    PubMed

    Ghorbal, Mehdi; Gorman, Molly; Macpherson, Cameron Ross; Martins, Rafael Miyazawa; Scherf, Artur; Lopez-Rubio, Jose-Juan

    2014-08-01

    Genome manipulation in the malaria parasite Plasmodium falciparum remains largely intractable and improved genomic tools are needed to further understand pathogenesis and drug resistance. We demonstrated the CRISPR-Cas9 system for use in P. falciparum by disrupting chromosomal loci and generating marker-free, single-nucleotide substitutions with high efficiency. Additionally, an artemisinin-resistant strain was generated by introducing a previously implicated polymorphism, thus illustrating the value of efficient genome editing in malaria research.

  6. CCS Project Permit Acquisition Protocols

    SciTech Connect

    Lee, Si-Yong; Zaluski, Wade; Matthews, Vince; McPherson, Brian

    2013-06-30

    Geologic carbon storage projects require a vast range of permits prior to deployment. These include land-access permits, drilling permits, seismic survey permits, underground injection control permits, and any number of local and state permits, depending on the location of the project. For the “Characterization of Most Promising Sequestration Formations in the Rocky Mountain Region” (RMCCS) project in particular, critical permits included site access permits, seismic survey permits, and drilling permits for the characterization well. Permits for these and other activities were acquired either prior to or during the project.

  7. Occurrence of Plasmodium in Anatidae

    USGS Publications Warehouse

    Herman, C.M.; Kocan, R.M.

    1970-01-01

    Until a little over a decade ago reports of Plasrnodium in geese, ducks, and swans were the result of examination of single blood smears from wild birds. One would gather from the earlier studies that Anatidae are infrequently infected. During the past decade we have conducted studies on prevalence of Plasmodium by an isodiagnosis technique, inoculating blood from wild birds into captive young geese, ducks, and other species of birds and determining the status of infection in the donors by examination of repetitive blood smears from the recipients. Examination by this technique of a series of adult Canada geese from the Seney National Wildlife Refuge in northern Michigan uncovered a prevalence of 60% during five successive years. Domestic geese were the primary recipients but we found that several other species of geese, ducks, and gulls were also susceptible. Similar studies on Canada geese from other areas (Maryland, New Jersey, New York, and southern Michigan) uncovered infection rates from zero to 27%. Following isolation of Plasmodlum in a single canvasback duck (Aythya valisineria) in southern Michigan by inoculation into a domestic duck, a series of 88 canvasbacks from Chesapeake Bay in Maryland this winter uncovered an infection rate of 27%. The most common parasite observed in both the geese and was as P. circumflexum.

  8. Major Histocompatibility Complex and Malaria: Focus on Plasmodium vivax Infection

    PubMed Central

    Lima-Junior, Josué da Costa; Pratt-Riccio, Lilian Rose

    2016-01-01

    The importance of host and parasite genetic factors in malaria resistance or susceptibility has been investigated since the middle of the last century. Nowadays, of all diseases that affect man, malaria still plays one of the highest levels of selective pressure on human genome. Susceptibility to malaria depends on exposure profile, epidemiological characteristics, and several components of the innate and adaptive immune system that influences the quality of the immune response generated during the Plasmodium lifecycle in the vertebrate host. But it is well known that the parasite’s enormous capacity of genetic variation in conjunction with the host genetics polymorphism is also associated with a wide spectrum of susceptibility degrees to complicated or severe forms of the disease. In this scenario, variations in genes of the major histocompatibility complex (MHC) associated with host resistance or susceptibility to malaria have been identified and used as markers in host–pathogen interaction studies, mainly those evaluating the impact on the immune response, acquisition of resistance, or increased susceptibility to infection or vulnerability to disease. However, due to the intense selective pressure, number of cases, and mortality rates, the majority of the reported associations reported concerned Plasmodium falciparum malaria. Studies on the MHC polymorphism and its association with Plasmodium vivax, which is the most widespread Plasmodium and the most prevalent species outside the African continent, are less frequent but equally important. Despite punctual contributions, there are accumulated evidences of human genetic control in P. vivax infection and disease. Herein, we review the current knowledge in the field of MHC and derived molecules (HLA Class I, Class II, TNF-α, LTA, BAT1, and CTL4) regarding P. vivax malaria. We discuss particularly the results of P. vivax studies on HLA class I and II polymorphisms in relation to host susceptibility, naturally

  9. Artemisinin-resistant Plasmodium falciparum malaria

    PubMed Central

    Fairhurst, Rick M.; Dondorp, Arjen M.

    2016-01-01

    For more than five decades, Southeast Asia (SEA) has been fertile ground for the emergence of drug-resistant Plasmodium falciparum malaria. After generating parasites resistant to chloroquine, sulfadoxine, pyrimethamine, quinine, and mefloquine, this region has now spawned parasites resistant to artemisinins – the world's most potent antimalarial drugs. In areas where artemisinin resistance is prevalent, artemisinin combination therapies (ACTs) – the first-line treatments for malaria – are failing fast. This worrisome development threatens to make malaria practically untreatable in SEA, and threatens to compromise global endeavors to eliminate this disease. A recent series of clinical, in-vitro, genomics, and transcriptomics studies in SEA have defined in-vivo and in-vitro phenotypes of artemisinin resistance; identified its causal genetic determinant; explored its molecular mechanism; and assessed its clinical impact. Specifically, these studies have established that artemisinin resistance manifests as slow parasite clearance in patients and increased survival of early ring-stage parasites in vitro; is caused by single nucleotide polymorphisms in the parasite's ‘K13’ gene; is associated with an upregulated “unfolded protein response” pathway that may antagonize the pro-oxidant activity of artemisinins; and selects for partner drug resistance that rapidly leads to ACT failures. In SEA, clinical studies are urgently needed to monitor ACT efficacy where K13 mutations are prevalent; test whether new combinations of currently-available drugs cure ACT failures; and advance new antimalarial compounds through preclinical pipelines and into clinical trials. Intensifying these efforts should help to forestall the spread of artemisinin and partner drug resistance from SEA to Sub-Saharan Africa, where the world's malaria transmission, morbidity, and mortality rates are highest. PMID:27337450

  10. Should Consumers Be Priced Out of Pollution-Permit Markets?

    ERIC Educational Resources Information Center

    Smith, Stefani C.; Yates, Andrew J.

    2003-01-01

    Presents a simple diagrammatic exposition of a pollution-permit market in which firms that generate pollution and consumers who are harmed by pollution are allowed to purchase permits at a single market price. Illustrates that the market equilibrium is efficient only if the endowment of permits is equal to the efficient level of pollution. (JEH)

  11. Characterization of the Plasmodium Interspersed Repeats (PIR) proteins of Plasmodium chabaudi indicates functional diversity

    PubMed Central

    Yam, Xue Yan; Brugat, Thibaut; Siau, Anthony; Lawton, Jennifer; Wong, Daniel S.; Farah, Abdirahman; Twang, Jing Shun; Gao, Xiaohong; Langhorne, Jean; Preiser, Peter R.

    2016-01-01

    Plasmodium multigene families play a central role in the pathogenesis of malaria. The Plasmodium interspersed repeat (pir) genes comprise the largest multigene family in many Plasmodium spp. However their function(s) remains unknown. Using the rodent model of malaria, Plasmodium chabaudi, we show that individual CIR proteins have differential localizations within infected red cell (iRBC), suggesting different functional roles in a blood-stage infection. Some CIRs appear to be located on the surface of iRBC and merozoites and are therefore well placed to interact with host molecules. In line with this hypothesis, we show for the first time that a subset of recombinant CIRs bind mouse RBCs suggesting a role for CIR in rosette formation and/or invasion. Together, our results unravel differences in subcellular localization and ability to bind mouse erythrocytes between the members of the cir family, which strongly suggest different functional roles in a blood-stage infection. PMID:26996203

  12. Characterization of the Plasmodium Interspersed Repeats (PIR) proteins of Plasmodium chabaudi indicates functional diversity.

    PubMed

    Yam, Xue Yan; Brugat, Thibaut; Siau, Anthony; Lawton, Jennifer; Wong, Daniel S; Farah, Abdirahman; Twang, Jing Shun; Gao, Xiaohong; Langhorne, Jean; Preiser, Peter R

    2016-01-01

    Plasmodium multigene families play a central role in the pathogenesis of malaria. The Plasmodium interspersed repeat (pir) genes comprise the largest multigene family in many Plasmodium spp. However their function(s) remains unknown. Using the rodent model of malaria, Plasmodium chabaudi, we show that individual CIR proteins have differential localizations within infected red cell (iRBC), suggesting different functional roles in a blood-stage infection. Some CIRs appear to be located on the surface of iRBC and merozoites and are therefore well placed to interact with host molecules. In line with this hypothesis, we show for the first time that a subset of recombinant CIRs bind mouse RBCs suggesting a role for CIR in rosette formation and/or invasion. Together, our results unravel differences in subcellular localization and ability to bind mouse erythrocytes between the members of the cir family, which strongly suggest different functional roles in a blood-stage infection. PMID:26996203

  13. Platform for Plasmodium vivax vaccine discovery and development.

    PubMed

    Valencia, Sócrates Herrera; Rodríguez, Diana Carolina; Acero, Diana Lucía; Ocampo, Vanessa; Arévalo-Herrera, Myriam

    2011-08-01

    Plasmodium vivax is the most prevalent malaria parasite on the American continent. It generates a global burden of 80-100 million cases annually and represents a tremendous public health problem, particularly in the American and Asian continents. A malaria vaccine would be considered the most cost-effective measure against this vector-borne disease and it would contribute to a reduction in malaria cases and to eventual eradication. Although significant progress has been achieved in the search for Plasmodium falciparum antigens that could be used in a vaccine, limited progress has been made in the search for P. vivax components that might be eligible for vaccine development. This is primarily due to the lack of in vitro cultures to serve as an antigen source and to inadequate funding. While the most advanced P. falciparum vaccine candidate is currently being tested in Phase III trials in Africa, the most advanced P. vivax candidates have only advanced to Phase I trials. Herein, we describe the overall strategy and progress in P. vivax vaccine research, from antigen discovery to preclinical and clinical development and we discuss the regional potential of Latin America to develop a comprehensive platform for vaccine development.

  14. Platform for Plasmodium vivax vaccine discovery and development

    PubMed Central

    Valencia/, Sócrates Herrera; Rodríguez, Diana Carolina; Acero, Diana Lucía; Ocampo, Vanessa; Arévalo-Herrera, Myriam

    2016-01-01

    Plasmodium vivax is the most prevalent malaria parasite on the American continent. It generates a global burden of 80–100 million cases annually and represents a tremendous public health problem, particularly in the American and Asian continents. A malaria vaccine would be considered the most cost-effective measure against this vector-borne disease and it would contribute to a reduction in malaria cases and to eventual eradication. Although significant progress has been achieved in the search for Plasmodium falciparum antigens that could be used in a vaccine, limited progress has been made in the search for P. vivax components that might be eligible for vaccine development. This is primarily due to the lack of in vitro cultures to serve as an antigen source and to inadequate funding. While the most advanced P. falciparum vaccine candidate is currently being tested in Phase III trials in Africa, the most advanced P. vivax candidates have only advanced to Phase I trials. Herein, we describe the overall strategy and progress in P. vivax vaccine research, from antigen discovery to preclinical and clinical development and we discuss the regional potential of Latin America to develop a comprehensive platform for vaccine development. PMID:21881773

  15. Lipophilic bisphosphonates are potent inhibitors of Plasmodium liver-stage growth.

    PubMed

    Singh, Agam Prasad; Zhang, Yonghui; No, Joo-Hwan; Docampo, Roberto; Nussenzweig, Victor; Oldfield, Eric

    2010-07-01

    Nitrogen-containing bisphosphonates, drugs used to treat bone resorption diseases, also have activity against a broad range of protists, including blood-stage Plasmodium spp. Here, we show that new-generation "lipophilic" bisphosphonates designed as anticancer agents that block protein prenylation also have potent activity against Plasmodium liver stages, with a high (>100) therapeutic index. Treatment of mice with the bisphosphonate BPH-715 and challenge with Plasmodium berghei sporozoites revealed complete protection (no blood-stage parasites after 28 days). There was also activity against blood-stage forms in vitro and a 4-day delay in the prepatent period in vivo. The lipophilic bisphosphonates have activity against a Plasmodium geranylgeranyl diphosphate synthase (GGPPS), as well as low nM activity against human farnesyl and geranylgeranyl diphosphate synthases. The most active inhibitor in vitro and in vivo had enzyme inhibitory activity similar to that of the other, less active compounds but was more lipophilic. Lipophilic bisphosphonates are thus promising leads for novel antimalarials that target liver-stage infection.

  16. 75 FR 55791 - Clean Air Act Operating Permit Program; Petition for Objection to State Operating Permit for...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-09-14

    ... AGENCY Clean Air Act Operating Permit Program; Petition for Objection to State Operating Permit for Alliant Energy--WPL Edgewater Generating Station AGENCY: Environmental Protection Agency (EPA). ACTION: Notice of final order on petition to object to Clean Air Act operating permit. SUMMARY: This...

  17. Plasmodium cynomolgi genome sequences provide insight into Plasmodium vivax and the monkey malaria clade.

    PubMed

    Tachibana, Shin-Ichiro; Sullivan, Steven A; Kawai, Satoru; Nakamura, Shota; Kim, Hyunjae R; Goto, Naohisa; Arisue, Nobuko; Palacpac, Nirianne M Q; Honma, Hajime; Yagi, Masanori; Tougan, Takahiro; Katakai, Yuko; Kaneko, Osamu; Mita, Toshihiro; Kita, Kiyoshi; Yasutomi, Yasuhiro; Sutton, Patrick L; Shakhbatyan, Rimma; Horii, Toshihiro; Yasunaga, Teruo; Barnwell, John W; Escalante, Ananias A; Carlton, Jane M; Tanabe, Kazuyuki

    2012-09-01

    P. cynomolgi, a malaria-causing parasite of Asian Old World monkeys, is the sister taxon of P. vivax, the most prevalent malaria-causing species in humans outside of Africa. Because P. cynomolgi shares many phenotypic, biological and genetic characteristics with P. vivax, we generated draft genome sequences for three P. cynomolgi strains and performed genomic analysis comparing them with the P. vivax genome, as well as with the genome of a third previously sequenced simian parasite, Plasmodium knowlesi. Here, we show that genomes of the monkey malaria clade can be characterized by copy-number variants (CNVs) in multigene families involved in evasion of the human immune system and invasion of host erythrocytes. We identify genome-wide SNPs, microsatellites and CNVs in the P. cynomolgi genome, providing a map of genetic variation that can be used to map parasite traits and study parasite populations. The sequencing of the P. cynomolgi genome is a critical step in developing a model system for P. vivax research and in counteracting the neglect of P. vivax. PMID:22863735

  18. Plasmodium cynomolgi genome sequences provide insight into Plasmodium vivax and the monkey malaria clade.

    PubMed

    Tachibana, Shin-Ichiro; Sullivan, Steven A; Kawai, Satoru; Nakamura, Shota; Kim, Hyunjae R; Goto, Naohisa; Arisue, Nobuko; Palacpac, Nirianne M Q; Honma, Hajime; Yagi, Masanori; Tougan, Takahiro; Katakai, Yuko; Kaneko, Osamu; Mita, Toshihiro; Kita, Kiyoshi; Yasutomi, Yasuhiro; Sutton, Patrick L; Shakhbatyan, Rimma; Horii, Toshihiro; Yasunaga, Teruo; Barnwell, John W; Escalante, Ananias A; Carlton, Jane M; Tanabe, Kazuyuki

    2012-09-01

    P. cynomolgi, a malaria-causing parasite of Asian Old World monkeys, is the sister taxon of P. vivax, the most prevalent malaria-causing species in humans outside of Africa. Because P. cynomolgi shares many phenotypic, biological and genetic characteristics with P. vivax, we generated draft genome sequences for three P. cynomolgi strains and performed genomic analysis comparing them with the P. vivax genome, as well as with the genome of a third previously sequenced simian parasite, Plasmodium knowlesi. Here, we show that genomes of the monkey malaria clade can be characterized by copy-number variants (CNVs) in multigene families involved in evasion of the human immune system and invasion of host erythrocytes. We identify genome-wide SNPs, microsatellites and CNVs in the P. cynomolgi genome, providing a map of genetic variation that can be used to map parasite traits and study parasite populations. The sequencing of the P. cynomolgi genome is a critical step in developing a model system for P. vivax research and in counteracting the neglect of P. vivax.

  19. Generations.

    PubMed

    Chambers, David W

    2005-01-01

    Groups naturally promote their strengths and prefer values and rules that give them an identity and an advantage. This shows up as generational tensions across cohorts who share common experiences, including common elders. Dramatic cultural events in America since 1925 can help create an understanding of the differing value structures of the Silents, the Boomers, Gen Xers, and the Millennials. Differences in how these generations see motivation and values, fundamental reality, relations with others, and work are presented, as are some applications of these differences to the dental profession. PMID:16623137

  20. Spatial Epidemiology of Plasmodium vivax, Afghanistan

    PubMed Central

    Leslie, Toby; Kolaczinski, Kate; Mohsen, Engineer; Mehboob, Najeebullah; Saleheen, Sarah; Khudonazarov, Juma; Freeman, Tim; Clements, Archie; Rowland, Mark; Kolaczinski, Jan

    2006-01-01

    Plasmodium vivax is endemic to many areas of Afghanistan. Geographic analysis helped highlight areas of malaria risk and clarified ecologic risk factors for transmission. Remote sensing enabled development of a risk map, thereby providing a valuable tool to help guide malaria control strategies. PMID:17176583

  1. Infection of laboratory-colonized Anopheles darlingi mosquitoes by Plasmodium vivax.

    PubMed

    Moreno, Marta; Tong, Carlos; Guzmán, Mitchel; Chuquiyauri, Raul; Llanos-Cuentas, Alejandro; Rodriguez, Hugo; Gamboa, Dionicia; Meister, Stephan; Winzeler, Elizabeth A; Maguina, Paula; Conn, Jan E; Vinetz, Joseph M

    2014-04-01

    Anopheles darlingi Root is the most important malaria vector in the Amazonia region of South America. However, continuous propagation of An. darlingi in the laboratory has been elusive, limiting entomological, genetic/genomic, and vector-pathogen interaction studies of this mosquito species. Here, we report the establishment of an An. darlingi colony derived from wild-caught mosquitoes obtained in the northeastern Peruvian Amazon region of Iquitos in the Loreto Department. We show that the numbers of eggs, larvae, pupae, and adults continue to rise at least to the F6 generation. Comparison of feeding Plasmodium vivax ex vivo of F4 and F5 to F1 generation mosquitoes showed the comparable presence of oocysts and sporozoites, with numbers that corresponded to blood-stage asexual parasitemia and gametocytemia, confirming P. vivax vectorial capacity in the colonized mosquitoes. These results provide new avenues for research on An. darlingi biology and study of An. darlingi-Plasmodium interactions.

  2. Infection of Laboratory-Colonized Anopheles darlingi Mosquitoes by Plasmodium vivax

    PubMed Central

    Moreno, Marta; Tong, Carlos; Guzmán, Mitchel; Chuquiyauri, Raul; Llanos-Cuentas, Alejandro; Rodriguez, Hugo; Gamboa, Dionicia; Meister, Stephan; Winzeler, Elizabeth A.; Maguina, Paula; Conn, Jan E.; Vinetz, Joseph M.

    2014-01-01

    Anopheles darlingi Root is the most important malaria vector in the Amazonia region of South America. However, continuous propagation of An. darlingi in the laboratory has been elusive, limiting entomological, genetic/genomic, and vector–pathogen interaction studies of this mosquito species. Here, we report the establishment of an An. darlingi colony derived from wild-caught mosquitoes obtained in the northeastern Peruvian Amazon region of Iquitos in the Loreto Department. We show that the numbers of eggs, larvae, pupae, and adults continue to rise at least to the F6 generation. Comparison of feeding Plasmodium vivax ex vivo of F4 and F5 to F1 generation mosquitoes showed the comparable presence of oocysts and sporozoites, with numbers that corresponded to blood-stage asexual parasitemia and gametocytemia, confirming P. vivax vectorial capacity in the colonized mosquitoes. These results provide new avenues for research on An. darlingi biology and study of An. darlingi–Plasmodium interactions. PMID:24534811

  3. Louisiana Title V General Permits

    SciTech Connect

    Boyer, B.E.; Neal, T.L.

    1995-12-31

    Title V of the Federal Clean Air Act Amendments of 1990 requires federal operating permits for all major sources of air pollution. In 1992, Title 40, Part 70 of the Code of Federal Regulations (40 CFR Part 70) codified the law s requirements. These federal regulations, entitled Operating Permit Program, define the minimum requirements for state administered operating permit programs. The intent of Title V is to put into one document all requirements of an operating permit. General Permits for oil and gas facilities may be preferred if the facility can comply with all permit requirements. If greater flexibility than allowed by the General Permit is required, then the facility should apply for an individual Title V permit. General Permits are designed to streamline the permitting process, shorten the time it takes to obtain approval for initial and modified permits. The advantages of the General Permit include reduced paperwork and greater consistency because the permits are standardized. There should be less uncertainty because permit requirements will be known at the time of application. Approval times for Initial and modified General Permits should be reduced. Lengthy public notice procedures (and possible hearings) will be required for only the initial approval of the General Permit and not for each applicant to the permit. A disadvantage of General Permits is reduced flexibility since the facility must comply with the requirements of a standardized permit.

  4. Killing of Plasmodium yoelii by enzyme-induced products of the oxidative burst.

    PubMed Central

    Dockrell, H M; Playfair, J H

    1984-01-01

    The murine malaria parasite Plasmodium yoelii was killed in vitro when incubated with glucose and glucose oxidase, a system generating hydrogen peroxide, or with xanthine and xanthine oxidase, a system which produces the superoxide anion and subsequently other products of the oxidative burst. Catalase blocked the killing in both cases; superoxide dismutase and scavengers of hydroxyl radicals or singlet oxygen were ineffective in the xanthine oxidase system. Thus, hydrogen peroxide appears to be the main reactive oxygen species killing P. yoelii. PMID:6546375

  5. Hanford Facility RCRA permit handbook

    SciTech Connect

    1996-03-01

    Purpose of this Hanford Facility (HF) RCRA Permit Handbook is to provide, in one document, information to be used for clarification of permit conditions and guidance for implementing the HF RCRA Permit.

  6. Geographical variation in Plasmodium vivax relapse

    PubMed Central

    2014-01-01

    Background Plasmodium vivax has the widest geographic distribution of the human malaria parasites and nearly 2.5 billion people live at risk of infection. The control of P. vivax in individuals and populations is complicated by its ability to relapse weeks to months after initial infection. Strains of P. vivax from different geographical areas are thought to exhibit varied relapse timings. In tropical regions strains relapse quickly (three to six weeks), whereas those in temperate regions do so more slowly (six to twelve months), but no comprehensive assessment of evidence has been conducted. Here observed patterns of relapse periodicity are used to generate predictions of relapse incidence within geographic regions representative of varying parasite transmission. Methods A global review of reports of P. vivax relapse in patients not treated with a radical cure was conducted. Records of time to first P. vivax relapse were positioned by geographic origin relative to expert opinion regions of relapse behaviour and epidemiological zones. Mixed-effects meta-analysis was conducted to determine which geographic classification best described the data, such that a description of the pattern of relapse periodicity within each region could be described. Model outputs of incidence and mean time to relapse were mapped to illustrate the global variation in relapse. Results Differences in relapse periodicity were best described by a historical geographic classification system used to describe malaria transmission zones based on areas sharing zoological and ecological features. Maps of incidence and time to relapse showed high relapse frequency to be predominant in tropical regions and prolonged relapse in temperate areas. Conclusions The results indicate that relapse periodicity varies systematically by geographic region and are categorized by nine global regions characterized by similar malaria transmission dynamics. This indicates that relapse may be an adaptation evolved to

  7. 50 CFR 622.50 - Permits, permit moratorium, and endorsements.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ..., AND SOUTH ATLANTIC Shrimp Fishery of the Gulf of Mexico § 622.50 Permits, permit moratorium, and endorsements. (a) Gulf shrimp permit. For a person aboard a vessel to fish for shrimp in the Gulf EEZ or possess shrimp in or from the Gulf EEZ, a commercial vessel permit for Gulf shrimp must have been...

  8. 50 CFR 622.50 - Permits, permit moratorium, and endorsements.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ..., AND SOUTH ATLANTIC Shrimp Fishery of the Gulf of Mexico § 622.50 Permits, permit moratorium, and endorsements. (a) Gulf shrimp permit. For a person aboard a vessel to fish for shrimp in the Gulf EEZ or possess shrimp in or from the Gulf EEZ, a commercial vessel permit for Gulf shrimp must have been...

  9. Plasmodium vivax Malaria Endemicity in Indonesia in 2010

    PubMed Central

    Elyazar, Iqbal R. F.; Gething, Peter W.; Patil, Anand P.; Rogayah, Hanifah; Sariwati, Elvieda; Palupi, Niken W.; Tarmizi, Siti N.; Kusriastuti, Rita; Baird, J. Kevin; Hay, Simon I.

    2012-01-01

    Background Plasmodium vivax imposes substantial morbidity and mortality burdens in endemic zones. Detailed understanding of the contemporary spatial distribution of this parasite is needed to combat it. We used model based geostatistics (MBG) techniques to generate a contemporary map of risk of Plasmodium vivax malaria in Indonesia in 2010. Methods Plasmodium vivax Annual Parasite Incidence data (2006–2008) and temperature masks were used to map P. vivax transmission limits. A total of 4,658 community surveys of P. vivax parasite rate (PvPR) were identified (1985–2010) for mapping quantitative estimates of contemporary endemicity within those limits. After error-checking a total of 4,457 points were included into a national database of age-standardized 1–99 year old PvPR data. A Bayesian MBG procedure created a predicted PvPR1–99 endemicity surface with uncertainty estimates. Population at risk estimates were derived with reference to a 2010 human population surface. Results We estimated 129.6 million people in Indonesia lived at risk of P. vivax transmission in 2010. Among these, 79.3% inhabited unstable transmission areas and 20.7% resided in stable transmission areas. In western Indonesia, the predicted P. vivax prevalence was uniformly low. Over 70% of the population at risk in this region lived on Java and Bali islands, where little malaria transmission occurs. High predicted prevalence areas were observed in the Lesser Sundas, Maluku and Papua. In general, prediction uncertainty was relatively low in the west and high in the east. Conclusion Most Indonesians living with endemic P. vivax experience relatively low risk of infection. However, blood surveys for this parasite are likely relatively insensitive and certainly do not detect the dormant liver stage reservoir of infection. The prospects for P. vivax elimination would be improved with deeper understanding of glucose-6-phosphate dehydrogenase deficiency (G6PDd) distribution, anti-relapse therapy

  10. Energy metabolism affects susceptibility of A. gambiae mosquitoes to Plasmodium infection

    PubMed Central

    Oliveira, Jose Henrique M.; Gonçalves, Renata L.S.; Oliveira, Giselle A.; Oliveira, Pedro L.; Oliveira, Marcus F.; Barillas-Mury, Carolina

    2011-01-01

    Previous studies showed that A. gambiae L35 females, which are refractory (R) to Plasmodium infection, express higher levels of genes involved in redox-metabolism and mitochondrial respiration than susceptible (S) G3 females. Our studies revealed that R females have reduced longevity, faster utilization of lipid reserves, impaired mitochondrial State-3 respiration, increased rate of mitochondrial electron leak and higher expression levels of several glycolytic enzyme genes. Furthermore, when State-3 respiration was reduced in S females by silencing expression of the adenine nucleotide translocator (ANT), hydrogen peroxide generation was higher and the mRNA levels of lactate dehydrogenase increased in the midgut, while the prevalence and intensity of P. berghei infection were significantly reduced. We conclude that there are broad metabolic differences between R and S An. gambiae mosquitoes that influence their susceptibility to Plasmodium infection. PMID:21320598

  11. PERMITTING HAZARDOUS WASTE INCINERATORS

    EPA Science Inventory

    This publication is a compilation of information presented at a seminar series designed to address the issues that affect the issuance of hazardous waste incineration permits and to improve the overall understanding of trial burn testing. pecifically, the document provides guidan...

  12. Permit application modifications

    SciTech Connect

    1995-11-01

    This document contains the Permit Application Modifications for the Y-12 Industrial Landfill V site on the Oak Ridge Reservation. These modifications include the assessment of stability of the proposed Landfill V under static and loading conditions. Analyses performed include the general slope stability, veneer stability of the bottom liner and cover system, and a liquefaction potential assessment of the foundation soils.

  13. Anopheline species and their Plasmodium infection status in Aligarh, India.

    PubMed

    Saifi, Muheet Alam; Alyousif, Mohamed Saleh; Amoudi, Mikky A

    2016-09-01

    Malaria is a global issue and India contributes substantially to global malaria incidence. Information related to malaria vectors is very limited in Aligarh. The environmental and climatological situations permit the continual breeding of vectors in permanent breeding sites. This study was designed with the aim to screen all the anophelines species and possible malaria vectors in three different localities of Aligarh. Anopheles mosquitoes were collected from three different localities (Fort, Jalali and Tappal) during peak malaria transmission season (July to November) by using mouth aspirator and CDC light traps. Enzyme-linked immunosorbent assay (ELISA) was done to detect Plasmodium falciparum, Plasmodium vivax-210 and P. vivax-247 circumsporozoite proteins (CSP) from the collected female species. A total of 794 female anopheline mosquitoes belonging to 7 species were collected by different methods. Circumsporozoite protein-enzyme-linked immunosorbent assay was performed with 780 anopheline mosquitoes out of which 13 mosquitoes were positive in CSP-ELISA. Thus, the overall infection rate was 1.66% (13/780). Four (0.51%) mosquitoes belonging to three species were positive for P. falciparum, 7 (0.89%) mosquitoes belonging to three species were positive for VK 210 and 2 (0.25%) mosquitoes belonging to Anopheles culicifacies and Anopheles stephensi species were positive for VK 247. No mixed infection was found in this study. According to species, the highest infection rate was observed in An. culicifacies (7/288, 2.43%) followed by An. stephensi (2.40%) and Anopheles annularis (1.98%). An. culicifacies and An. stephensi were previously incriminated as malaria vectors in Aligarh. There was, however, no previous report in favor of infections in An. annularis in Aligarh. The on-going Malaria Control Program in India needs up to date information on malaria vectors. A major challenge is the lack of knowledge about vectors and their role in malaria transmission. Findings of

  14. Antimalarial Benzoxaboroles Target Plasmodium falciparum Leucyl-tRNA Synthetase.

    PubMed

    Sonoiki, Ebere; Palencia, Andres; Guo, Denghui; Ahyong, Vida; Dong, Chen; Li, Xianfeng; Hernandez, Vincent S; Zhang, Yong-Kang; Choi, Wai; Gut, Jiri; Legac, Jennifer; Cooper, Roland; Alley, M R K; Freund, Yvonne R; DeRisi, Joseph; Cusack, Stephen; Rosenthal, Philip J

    2016-08-01

    There is a need for new antimalarials, ideally with novel mechanisms of action. Benzoxaboroles have been shown to be active against bacteria, fungi, and trypanosomes. Therefore, we investigated the antimalarial activity and mechanism of action of 3-aminomethyl benzoxaboroles against Plasmodium falciparum Two 3-aminomethyl compounds, AN6426 and AN8432, demonstrated good potency against cultured multidrug-resistant (W2 strain) P. falciparum (50% inhibitory concentration [IC50] of 310 nM and 490 nM, respectively) and efficacy against murine Plasmodium berghei infection when administered orally once daily for 4 days (90% effective dose [ED90], 7.4 and 16.2 mg/kg of body weight, respectively). To characterize mechanisms of action, we selected parasites with decreased drug sensitivity by culturing with stepwise increases in concentration of AN6426. Resistant clones were characterized by whole-genome sequencing. Three generations of resistant parasites had polymorphisms in the predicted editing domain of the gene encoding a P. falciparum leucyl-tRNA synthetase (LeuRS; PF3D7_0622800) and in another gene (PF3D7_1218100), which encodes a protein of unknown function. Solution of the structure of the P. falciparum LeuRS editing domain suggested key roles for mutated residues in LeuRS editing. Short incubations with AN6426 and AN8432, unlike artemisinin, caused dose-dependent inhibition of [(14)C]leucine incorporation by cultured wild-type, but not resistant, parasites. The growth of resistant, but not wild-type, parasites was impaired in the presence of the unnatural amino acid norvaline, consistent with a loss of LeuRS editing activity in resistant parasites. In summary, the benzoxaboroles AN6426 and AN8432 offer effective antimalarial activity and act, at least in part, against a novel target, the editing domain of P. falciparum LeuRS.

  15. Plasmodium falciparum: characterization of defined antigens by monoclonal antibodies.

    PubMed Central

    Perrin, L H; Ramirez, E; Er-Hsiang, L; Lambert, P H

    1980-01-01

    Monoclonal antibodies directed against Plasmodium falciparum detect stage-specific, species-specific and common antigenic determinants of Plasmodia. These antibodies provide new tools for purification and characterization of Plasmodium falciparum antigens in relation to future procedures for immunoprophylaxis. Images Fig. 2 PMID:6160002

  16. Mosquito transmission of wild turkey malaria, Plasmodium hermani.

    PubMed

    Young, M D; Nayar, J K; Forrester, D J

    1977-04-01

    Culex nigripalpus experimentally transmitted Plasmodium hermani, a plasmodium of wild turkeys (Meleagris gallopavo) in Florida. The mosquitoes were infected by feeding upon blood induced parasitemias in domestic turkey poults. The resulting sporozoites, transmitted by either mosquito bites or injection, produced malaria infections in domestic poults.

  17. Construction of living cellular automata using the Physarum plasmodium

    NASA Astrophysics Data System (ADS)

    Shirakawa, Tomohiro; Sato, Hiroshi; Ishiguro, Shinji

    2015-04-01

    The plasmodium of Physarum polycephalum is a unicellular and multinuclear giant amoeba that has an amorphous cell body. To clearly observe how the plasmodium makes decisions in its motile and exploratory behaviours, we developed a new experimental system to pseudo-discretize the motility of the organism. In our experimental space that has agar surfaces arranged in a two-dimensional lattice, the continuous and omnidirectional movement of the plasmodium was limited to the stepwise one, and the direction of the locomotion was also limited to four neighbours. In such an experimental system, a cellular automata-like system was constructed using the living cell. We further analysed the exploratory behaviours of the plasmodium by duplicating the experimental results in the simulation models of cellular automata. As a result, it was revealed that the behaviours of the plasmodium are not reproduced by only local state transition rules; and for the reproduction, a kind of historical rule setting is needed.

  18. Simple Molecular Methods for Early Detection of Chloroquine Drug Resistance in Plasmodium vivax and Plasmodium falciparum

    PubMed Central

    Singh, Raksha; Urhehar, Anant Dattatraya

    2016-01-01

    Introduction Malaria is a human disease of which causes high morbidity and mortality. In Plasmodium falciparum malaria, the resistance to antimalarial drugs, especially chloroquine (CQ) is one of the paramount factors contributing to the global increase in morbidity and mortality, due to malaria. Hence, there is a need for detection of chloroquine drug resistance genes i.e., pfcrt-o (Plasmodium falciparum chloroquine resistance transporter-o) and pfmdr-1 (Plasmodium falciparum multidrug resistance-1) of P. falciparum and pvcrt-o (Plasmodium vivax chloroquine resistance transporter-o) and pvmdr-1 (Plasmodium vivax multidrug resistance-1) of P. vivax by using molecular methods to prevent mortality in malarial cases. Aim To standardize chloroquine drug sensitivity testing by molecular method so as to provide reports of chloroquine within 6-8 hours to physicians for better treatment. Materials and Methods This study was conducted over a period of one year from January to December 2014. A Total of 300 blood samples were collected from malaria suspected patient attending MGM Hospital, Kamothe, Navi Mumbai, India. Out of 300 blood samples, 44 were malaria positive as assessed by Thick and Thin blood smear stained, by Leishman’s method and examination with light microscope. Chloroquine drug sensitivity testing was performed using WHO III plate method (micro test). Nested PCR was done for detection of pfcrt-o and pfmdr-1 for P. falciparum and pvcrt-o, pvmdr-1 genes for P. vivax. Results Total 44 samples were included in this study, out of which 22 samples confirmed for Plasmodium falciparum and 22 samples confirmed for Plasmodium vivax. Out of 22 P. falciparum 15 (68.18%) samples were chloroquine resistant. P. vivax showed chloroquine resistance to 5 samples (22.73%) by method similar to WHO III plate method (micro test) and nested PCR. Conclusion Drug resistance testing by molecular methods is useful for early detection of antimalarial drug resistance. pfmdr-1 along with

  19. Simple Molecular Methods for Early Detection of Chloroquine Drug Resistance in Plasmodium vivax and Plasmodium falciparum

    PubMed Central

    Singh, Raksha; Urhehar, Anant Dattatraya

    2016-01-01

    Introduction Malaria is a human disease of which causes high morbidity and mortality. In Plasmodium falciparum malaria, the resistance to antimalarial drugs, especially chloroquine (CQ) is one of the paramount factors contributing to the global increase in morbidity and mortality, due to malaria. Hence, there is a need for detection of chloroquine drug resistance genes i.e., pfcrt-o (Plasmodium falciparum chloroquine resistance transporter-o) and pfmdr-1 (Plasmodium falciparum multidrug resistance-1) of P. falciparum and pvcrt-o (Plasmodium vivax chloroquine resistance transporter-o) and pvmdr-1 (Plasmodium vivax multidrug resistance-1) of P. vivax by using molecular methods to prevent mortality in malarial cases. Aim To standardize chloroquine drug sensitivity testing by molecular method so as to provide reports of chloroquine within 6-8 hours to physicians for better treatment. Materials and Methods This study was conducted over a period of one year from January to December 2014. A Total of 300 blood samples were collected from malaria suspected patient attending MGM Hospital, Kamothe, Navi Mumbai, India. Out of 300 blood samples, 44 were malaria positive as assessed by Thick and Thin blood smear stained, by Leishman’s method and examination with light microscope. Chloroquine drug sensitivity testing was performed using WHO III plate method (micro test). Nested PCR was done for detection of pfcrt-o and pfmdr-1 for P. falciparum and pvcrt-o, pvmdr-1 genes for P. vivax. Results Total 44 samples were included in this study, out of which 22 samples confirmed for Plasmodium falciparum and 22 samples confirmed for Plasmodium vivax. Out of 22 P. falciparum 15 (68.18%) samples were chloroquine resistant. P. vivax showed chloroquine resistance to 5 samples (22.73%) by method similar to WHO III plate method (micro test) and nested PCR. Conclusion Drug resistance testing by molecular methods is useful for early detection of antimalarial drug resistance. pfmdr-1 along with

  20. DNA repair mechanisms and their biological roles in the malaria parasite Plasmodium falciparum.

    PubMed

    Lee, Andrew H; Symington, Lorraine S; Fidock, David A

    2014-09-01

    Research into the complex genetic underpinnings of the malaria parasite Plasmodium falciparum is entering a new era with the arrival of site-specific genome engineering. Previously restricted only to model systems but now expanded to most laboratory organisms, and even to humans for experimental gene therapy studies, this technology allows researchers to rapidly generate previously unattainable genetic modifications. This technological advance is dependent on DNA double-strand break repair (DSBR), specifically homologous recombination in the case of Plasmodium. Our understanding of DSBR in malaria parasites, however, is based largely on assumptions and knowledge taken from other model systems, which do not always hold true in Plasmodium. Here we describe the causes of double-strand breaks, the mechanisms of DSBR, and the differences between model systems and P. falciparum. These mechanisms drive basic parasite functions, such as meiosis, antigen diversification, and copy number variation, and allow the parasite to continually evolve in the contexts of host immune pressure and drug selection. Finally, we discuss the new technologies that leverage DSBR mechanisms to accelerate genetic investigations into this global infectious pathogen.

  1. Plasmepsin 4-Deficient Plasmodium berghei Are Virulence Attenuated and Induce Protective Immunity against Experimental Malaria

    PubMed Central

    Spaccapelo, Roberta; Janse, Chris J.; Caterbi, Sara; Franke-Fayard, Blandine; Bonilla, J. Alfredo; Syphard, Luke M.; Di Cristina, Manlio; Dottorini, Tania; Savarino, Andrea; Cassone, Antonio; Bistoni, Francesco; Waters, Andrew P.; Dame, John B.; Crisanti, Andrea

    2010-01-01

    Plasmodium parasites lacking plasmepsin 4 (PM4), an aspartic protease that functions in the lysosomal compartment and contributes to hemoglobin digestion, have only a modest decrease in the asexual blood-stage growth rate; however, PM4 deficiency in the rodent malaria parasite Plasmodium berghei results in significantly less virulence than that for the parental parasite. P. berghei Δpm4 parasites failed to induce experimental cerebral malaria (ECM) in ECM-susceptible mice, and ECM-resistant mice were able to clear infections. Furthermore, after a single infection, all convalescent mice were protected against subsequent parasite challenge for at least 1 year. Real-time in vivo parasite imaging and splenectomy experiments demonstrated that protective immunity acted through antibody-mediated parasite clearance in the spleen. This work demonstrates, for the first time, that a single Plasmodium gene disruption can generate virulence-attenuated parasites that do not induce cerebral complications and, moreover, are able to stimulate strong protective immunity against subsequent challenge with wild-type parasites. Parasite blood-stage attenuation should help identify protective immune responses against malaria, unravel parasite-derived factors involved in malarial pathologies, such as cerebral malaria, and potentially pave the way for blood-stage whole organism vaccines. PMID:20019192

  2. The Glutathione Biosynthetic Pathway of Plasmodium Is Essential for Mosquito Transmission

    PubMed Central

    Vega-Rodríguez, Joel; Janse, Chris J.; Pastrana-Mena, Rebecca; Waters, Andrew P.; Coppens, Isabelle; Rodríguez-Orengo, José F.; Jacobs-Lorena, Marcelo; Serrano, Adelfa E.

    2009-01-01

    Infection of red blood cells (RBC) subjects the malaria parasite to oxidative stress. Therefore, efficient antioxidant and redox systems are required to prevent damage by reactive oxygen species. Plasmodium spp. have thioredoxin and glutathione (GSH) systems that are thought to play a major role as antioxidants during blood stage infection. In this report, we analyzed a critical component of the GSH biosynthesis pathway using reverse genetics. Plasmodium berghei parasites lacking expression of gamma-glutamylcysteine synthetase (γ-GCS), the rate limiting enzyme in de novo synthesis of GSH, were generated through targeted gene disruption thus demonstrating, quite unexpectedly, that γ-GCS is not essential for blood stage development. Despite a significant reduction in GSH levels, blood stage forms of pbggcs− parasites showed only a defect in growth as compared to wild type. In contrast, a dramatic effect on development of the parasites in the mosquito was observed. Infection of mosquitoes with pbggcs− parasites resulted in reduced numbers of stunted oocysts that did not produce sporozoites. These results have important implications for the design of drugs aiming at interfering with the GSH redox-system in blood stages and demonstrate that de novo synthesis of GSH is pivotal for development of Plasmodium in the mosquito. PMID:19229315

  3. Selective killing of the human malaria parasite Plasmodium falciparum by a benzylthiazolium dye.

    PubMed

    Kelly, Jane X; Winter, Rolf W; Braun, Theodore P; Osei-Agyemang, Myralyn; Hinrichs, David J; Riscoe, Michael K

    2007-06-01

    Malaria is an infectious disease caused by protozoan parasites of the genus Plasmodium. The most virulent form of the disease is caused by Plasmodium falciparum which infects hundreds of millions of people and is responsible for the deaths of 1-2 million individuals each year. An essential part of the parasitic process is the remodeling of the red blood cell membrane and its protein constituents to permit a higher flux of nutrients and waste products into or away from the intracellular parasite. Much of this increased permeability is due to a single type of broad specificity channel variously called the new permeation pathway (NPP), the nutrient channel, and the Plasmodial surface anion channel (PSAC). This channel is permeable to a range of low molecular weight solutes both charged and uncharged, with a strong preference for anions. Drugs such as furosemide that are known to block anion-selective channels inhibit PSAC. In this study, we have investigated a dye known as benzothiocarboxypurine, BCP, which had been studied as a possible diagnostic aid given its selective uptake by P. falciparum infected red cells. We found that the dye enters parasitized red cells via the furosemide-inhibitable PSAC, forms a brightly fluorescent complex with parasite nucleic acids, and is selectively toxic to infected cells. Our study describes an antimalarial agent that exploits the altered permeability of Plasmodium-infected red cells as a means to killing the parasite and highlights a chemical reagent that may prove useful in high throughput screening of compounds for inhibitors of the channel.

  4. Somatically Hypermutated Plasmodium-Specific IgM(+) Memory B Cells Are Rapid, Plastic, Early Responders upon Malaria Rechallenge.

    PubMed

    Krishnamurty, Akshay T; Thouvenel, Christopher D; Portugal, Silvia; Keitany, Gladys J; Kim, Karen S; Holder, Anthony; Crompton, Peter D; Rawlings, David J; Pepper, Marion

    2016-08-16

    Humoral immunity consists of pre-existing antibodies expressed by long-lived plasma cells and rapidly reactive memory B cells (MBC). Recent studies of MBC development and function after protein immunization have uncovered significant MBC heterogeneity. To clarify functional roles for distinct MBC subsets during malaria infection, we generated tetramers that identify Plasmodium-specific MBCs in both humans and mice. Long-lived murine Plasmodium-specific MBCs consisted of three populations: somatically hypermutated immunoglobulin M(+) (IgM(+)) and IgG(+) MBC subsets and an unmutated IgD(+) MBC population. Rechallenge experiments revealed that high affinity, somatically hypermutated Plasmodium-specific IgM(+) MBCs proliferated and gave rise to antibody-secreting cells that dominated the early secondary response to parasite rechallenge. IgM(+) MBCs also gave rise to T cell-dependent IgM(+) and IgG(+)B220(+)CD138(+) plasmablasts or T cell-independent B220(-)CD138(+) IgM(+) plasma cells. Thus, even in competition with IgG(+) MBCs, IgM(+) MBCs are rapid, plastic, early responders to a secondary Plasmodium rechallenge and should be targeted by vaccine strategies. PMID:27473412

  5. No evidence for ape Plasmodium infections in humans in Gabon.

    PubMed

    Délicat-Loembet, Lucresse; Rougeron, Virginie; Ollomo, Benjamin; Arnathau, Céline; Roche, Benjamin; Elguero, Eric; Moukodoum, Nancy Diamella; Okougha, Alain-Prince; Mve Ondo, Bertrand; Boundenga, Larson; Houzé, Sandrine; Galan, Maxime; Nkoghé, Dieudonné; Leroy, Eric M; Durand, Patrick; Paupy, Christophe; Renaud, François; Prugnolle, Franck

    2015-01-01

    African great apes are naturally infected by a multitude of Plasmodium species most of them recently discovered, among which several are closely related to human malaria agents. However, it is still unknown whether these animals can serve as source of infections for humans living in their vicinity. To evaluate this possibility, we analysed the nature of Plasmodium infections from a bank of 4281 human blood samples collected in 210 villages of Gabon, Central Africa. Among them, 2255 were detected positive to Plasmodium using molecular methods (Plasmodium Cytochrome b amplification). A high throughput sequencing technology (454 GS-FLX Titanium technology, Roche) was then used to identify the Plasmodium species present within each positive sample. Overall, we identified with confidence only three species infecting humans in Gabon: P. falciparum, P. malariae and P. ovale. None of the species known to infect non-human primates in Central Africa was found. Our study shows that ape Plasmodium parasites of the subgenus Laverania do not constitute a frequent source of infection for humans. It also suggests that some strong host genetic barriers must exist to prevent the cross species transmission of ape Plasmodium in a context of ever increasing contacts between humans and wildlife.

  6. No Evidence for Ape Plasmodium Infections in Humans in Gabon

    PubMed Central

    Ollomo, Benjamin; Arnathau, Céline; Roche, Benjamin; Elguero, Eric; Moukodoum, Nancy Diamella; Okougha, Alain-Prince; Mve Ondo, Bertrand; Boundenga, Larson; Houzé, Sandrine; Galan, Maxime; Nkoghé, Dieudonné; Leroy, Eric M.; Durand, Patrick; Paupy, Christophe; Renaud, François; Prugnolle, Franck

    2015-01-01

    African great apes are naturally infected by a multitude of Plasmodium species most of them recently discovered, among which several are closely related to human malaria agents. However, it is still unknown whether these animals can serve as source of infections for humans living in their vicinity. To evaluate this possibility, we analysed the nature of Plasmodium infections from a bank of 4281 human blood samples collected in 210 villages of Gabon, Central Africa. Among them, 2255 were detected positive to Plasmodium using molecular methods (Plasmodium Cytochrome b amplification). A high throughput sequencing technology (454 GS-FLX Titanium technology, Roche) was then used to identify the Plasmodium species present within each positive sample. Overall, we identified with confidence only three species infecting humans in Gabon: P. falciparum, P. malariae and P. ovale. None of the species known to infect non-human primates in Central Africa was found. Our study shows that ape Plasmodium parasites of the subgenus Laverania do not constitute a frequent source of infection for humans. It also suggests that some strong host genetic barriers must exist to prevent the cross species transmission of ape Plasmodium in a context of ever increasing contacts between humans and wildlife. PMID:26039338

  7. Use of molecular beacon probes for real-time PCR detection of Plasmodium falciparum and other plasmodium species in peripheral blood specimens.

    PubMed

    Elsayed, Sameer; Plewes, Katherine; Church, Deirdre; Chow, Barbara; Zhang, Kunyan

    2006-02-01

    We describe the development and evaluation of a novel pair of real-time, fluorescence-based PCR assays using molecular beacon probes for rapid, sensitive, and specific detection and quantification of Plasmodium falciparum and other Plasmodium species organisms.

  8. UDP-galactose and acetyl-CoA transporters as Plasmodium multidrug resistance genes.

    PubMed

    Lim, Michelle Yi-Xiu; LaMonte, Gregory; Lee, Marcus C S; Reimer, Christin; Tan, Bee Huat; Corey, Victoria; Tjahjadi, Bianca F; Chua, Adeline; Nachon, Marie; Wintjens, René; Gedeck, Peter; Malleret, Benoit; Renia, Laurent; Bonamy, Ghislain M C; Ho, Paul Chi-Lui; Yeung, Bryan K S; Chow, Eric D; Lim, Liting; Fidock, David A; Diagana, Thierry T; Winzeler, Elizabeth A; Bifani, Pablo

    2016-01-01

    A molecular understanding of drug resistance mechanisms enables surveillance of the effectiveness of new antimicrobial therapies during development and deployment in the field. We used conventional drug resistance selection as well as a regime of limiting dilution at early stages of drug treatment to probe two antimalarial imidazolopiperazines, KAF156 and GNF179. The latter approach permits the isolation of low-fitness mutants that might otherwise be out-competed during selection. Whole-genome sequencing of 24 independently derived resistant Plasmodium falciparum clones revealed four parasites with mutations in the known cyclic amine resistance locus (pfcarl) and a further 20 with mutations in two previously unreported P. falciparum drug resistance genes, an acetyl-CoA transporter (pfact) and a UDP-galactose transporter (pfugt). Mutations were validated both in vitro by CRISPR editing in P. falciparum and in vivo by evolution of resistant Plasmodium berghei mutants. Both PfACT and PfUGT were localized to the endoplasmic reticulum by fluorescence microscopy. As mutations in pfact and pfugt conveyed resistance against additional unrelated chemical scaffolds, these genes are probably involved in broad mechanisms of antimalarial drug resistance. PMID:27642791

  9. UDP-galactose and acetyl-CoA transporters as Plasmodium multidrug resistance genes.

    PubMed

    Lim, Michelle Yi-Xiu; LaMonte, Gregory; Lee, Marcus C S; Reimer, Christin; Tan, Bee Huat; Corey, Victoria; Tjahjadi, Bianca F; Chua, Adeline; Nachon, Marie; Wintjens, René; Gedeck, Peter; Malleret, Benoit; Renia, Laurent; Bonamy, Ghislain M C; Ho, Paul Chi-Lui; Yeung, Bryan K S; Chow, Eric D; Lim, Liting; Fidock, David A; Diagana, Thierry T; Winzeler, Elizabeth A; Bifani, Pablo

    2016-09-19

    A molecular understanding of drug resistance mechanisms enables surveillance of the effectiveness of new antimicrobial therapies during development and deployment in the field. We used conventional drug resistance selection as well as a regime of limiting dilution at early stages of drug treatment to probe two antimalarial imidazolopiperazines, KAF156 and GNF179. The latter approach permits the isolation of low-fitness mutants that might otherwise be out-competed during selection. Whole-genome sequencing of 24 independently derived resistant Plasmodium falciparum clones revealed four parasites with mutations in the known cyclic amine resistance locus (pfcarl) and a further 20 with mutations in two previously unreported P. falciparum drug resistance genes, an acetyl-CoA transporter (pfact) and a UDP-galactose transporter (pfugt). Mutations were validated both in vitro by CRISPR editing in P. falciparum and in vivo by evolution of resistant Plasmodium berghei mutants. Both PfACT and PfUGT were localized to the endoplasmic reticulum by fluorescence microscopy. As mutations in pfact and pfugt conveyed resistance against additional unrelated chemical scaffolds, these genes are probably involved in broad mechanisms of antimalarial drug resistance.

  10. Mining the Plasmodium genome database to define organellar function: what does the apicoplast do?

    PubMed Central

    Roos, David S; Crawford, Michael J; Donald, Robert G K; Fraunholz, Martin; Harb, Omar S; He, Cynthia Y; Kissinger, Jessica C; Shaw, Michael K; Striepen, Boris

    2002-01-01

    Apicomplexan species constitute a diverse group of parasitic protozoa, which are responsible for a wide range of diseases in many organisms. Despite differences in the diseases they cause, these parasites share an underlying biology, from the genetic controls used to differentiate through the complex parasite life cycle, to the basic biochemical pathways employed for intracellular survival, to the distinctive cell biology necessary for host cell attachment and invasion. Different parasites lend themselves to the study of different aspects of parasite biology: Eimeria for biochemical studies, Toxoplasma for molecular genetic and cell biological investigation, etc. The Plasmodium falciparum Genome Project contributes the first large-scale genomic sequence for an apicomplexan parasite. The Plasmodium Genome Database (http://PlasmoDB.org) has been designed to permit individual investigators to ask their own questions, even prior to formal release of the reference P. falciparum genome sequence. As a case in point, PlasmoDB has been exploited to identify metabolic pathways associated with the apicomplexan plastid, or 'apicoplast' - an essential organelle derived by secondary endosymbiosis of an alga, and retention of the algal plastid. PMID:11839180

  11. Plasmodium ovale curtisi and Plasmodium ovale wallikeri in North-West Ethiopia

    PubMed Central

    2013-01-01

    Background In Ethiopia Plasmodium falciparum and Plasmodium vivax are the dominant species accounting for roughly 60 and 40% of malaria cases, respectively. Recently a major shift from P. falciparum to P. vivax has been observed in various parts of the country but the epidemiology of the other human malaria species, Plasmodium ovale spp. and Plasmodium malariae remains poorly understood. The aim of this study was to assess P. ovale curtisi and wallikeri infection in north-west Ethiopia by using microscopy and nested PCR. Methods A health institution-based survey using non-probability sampling techniques was conducted at Maksegnet, Enfranze and Kola Diba health centres and Metema hospital in North Gondar. Three-hundred patients with signs and symptoms consistent with malaria were included in this study and capillary blood was collected for microscopic examination and molecular analysis of Plasmodium species. Samples were collected on Whatman 903 filter papers, stored in small plastic bags with desiccant and transported to Vienna (Austria) for molecular analysis. Data from study participants were entered and analysed by SPSS 20 software. Results Out of 300 study participants (167 males and 133 females), 184 samples were classified positive for malaria (133 P. falciparum and 51 P. vivax) by microscopy. By species-specific PCR 233 Plasmodium spp (95% CI: 72.6-82) were detected and the majority 155 (66.5%, 95% CI: 60.2-72.3) were P. falciparum followed by P. vivax 69 (29.6%, 95% CI; 24.1-35.8) and 9 (3.9%, 95% CI: 2-7.2) samples were positive for P. ovale. Seven of P. ovale parasites were confirmed as P. ovale wallikeri and two were confirmed as P. ovale curtisi. None of the samples tested positive for P. malariae. During microscopic examination there were high (16.3%) false negative reports and all mixed infections and P. ovale cases were missed or misclassified. Conclusion This study indicates that P. ovale malaria is under-reported in Ethiopia and provides the first

  12. Human Infections and Detection of Plasmodium knowlesi

    PubMed Central

    Daneshvar, Cyrus

    2013-01-01

    SUMMARY Plasmodium knowlesi is a malaria parasite that is found in nature in long-tailed and pig-tailed macaques. Naturally acquired human infections were thought to be extremely rare until a large focus of human infections was reported in 2004 in Sarawak, Malaysian Borneo. Human infections have since been described throughout Southeast Asia, and P. knowlesi is now recognized as the fifth species of Plasmodium causing malaria in humans. The molecular, entomological, and epidemiological data indicate that human infections with P. knowlesi are not newly emergent and that knowlesi malaria is primarily a zoonosis. Human infections were undiagnosed until molecular detection methods that could distinguish P. knowlesi from the morphologically similar human malaria parasite P. malariae became available. P. knowlesi infections cause a spectrum of disease and are potentially fatal, but if detected early enough, infections in humans are readily treatable. In this review on knowlesi malaria, we describe the early studies on P. knowlesi and focus on the epidemiology, diagnosis, clinical aspects, and treatment of knowlesi malaria. We also discuss the gaps in our knowledge and the challenges that lie ahead in studying the epidemiology and pathogenesis of knowlesi malaria and in the prevention and control of this zoonotic infection. PMID:23554413

  13. Plasmodium vivax malaria during pregnancy, Bolivia.

    PubMed

    Brutus, Laurent; Santalla, José; Schneider, Dominique; Avila, Juan Carlos; Deloron, Philippe

    2013-10-01

    Plasmodium vivax is a major cause of illness in areas with low transmission of malaria in Latin America, Asia, and the Horn of Africa. However, pregnancy-associated malaria remains poorly characterized in such areas. Using a hospital-based survey of women giving birth and an antenatal survey, we assessed the prevalence rates of Plasmodium spp. infections in pregnant women in Bolivia, and evaluated the consequences of malaria during pregnancy on the health of mothers and newborns. P. vivax infection was detected in 7.9% of pregnant women attending antenatal visits, and placental infection occurred in 2.8% of deliveries; these rates did not vary with parity. Forty-two percent of all P. vivax malaria episodes were symptomatic. P. vivax-infected pregnant women were frequently anemic (6.5%) and delivered babies of reduced birthweight. P. vivax infections during pregnancy are clearly associated with serious adverse outcomes and should be considered in prevention strategies of pregnancy-associated malaria.

  14. The sex ratio of Plasmodium gametocytes.

    PubMed

    Schall, J J

    1989-06-01

    Sex ratio theory usually predicts an equilibrium sex ratio and equal proportions of males and females in a population, including the progenitors of the reproductive cells of protozoans. This proposal was tested with three species of malarial parasites of lizards, Plasmodium mexicanum of the western fence lizard, and P. agamae and P. giganteum of the African rainbow lizard, using single samples from naturally infected lizards, repeated samples from free-ranging lizards (P. mexicanum only), and repeated samples from laboratory maintained animals. Macrogametocytes were usually more abundant than microgametocytes, and were slightly larger, revealing a typically greater investment of resources by the progenitors of female reproductive cells. However, the proportion of microgametocytes varied among the three species and among infections within each species of Plasmodium. The sex ratio of gametocytes often remained constant within infections followed over time even if the absolute number of gametocytes was changing. However, the equilibrium sex ratio of gametocytes varied among those infections that had an unchanging microgametocyte proportion. Thus, although an equilibrium sex ratio apparently occurs for most infections, there appears to be no characteristic proportion of microgametocytes for any of the species. Potential explanations for this conflict with theory are presented. PMID:2771445

  15. Management of relapsing Plasmodium vivax malaria

    PubMed Central

    Chu, Cindy S; White, Nicholas J

    2016-01-01

    ABSTRACT Introduction: Relapses are important contributors to illness and morbidity in Plasmodium vivax and P. ovale infections. Relapse prevention (radical cure) with primaquine is required for optimal management, control and ultimately elimination of Plasmodium vivax malaria. A review was conducted with publications in English, French, Portuguese and Spanish using the search terms ‘P. vivax’ and ‘relapse’. Areas covered: Hypnozoites causing relapses may be activated weeks or months after initial infection. Incidence and temporal patterns of relapse varies geographically. Relapses derive from parasites either genetically similar or different from the primary infection indicating that some derive from previous infections. Malaria illness itself may activate relapse. Primaquine is the only widely available treatment for radical cure. However, it is often not given because of uncertainty over the risks of primaquine induced haemolysis when G6PD deficiency testing is unavailable. Recommended dosing of primaquine for radical cure in East Asia and Oceania is 0.5 mg base/kg/day and elsewhere is 0.25 mg base/kg/day. Alternative treatments are under investigation. Expert commentary: Geographic heterogeneity in relapse patterns and chloroquine susceptibility of P. vivax, and G6PD deficiency epidemiology mean that radical treatment should be given much more than it is today. G6PD testing should be made widely available so primaquine can be given more safely. PMID:27530139

  16. Wildlife Researchers Running the Permit Maze

    PubMed Central

    Paul, Ellen; Sikes, Robert S.

    2013-01-01

    The study of wildlife, whether in the field or in the lab, may start with a hypothesis, a literature search, or a grant proposal, but in many cases, the work will never happen unless the researcher successfully navigates a maze of permit requirements. A single project can involve multiple permits at the national and state levels, and it can take months to obtain any one permit. Therefore, permits may not have been issued at the time of protocol review, but Public Health Service Policy makes accommodations for this situation. Once in hand, however, the permits convey critical information to the Institutional Animal Care and Use Committee (IACUC): one or more government agencies have determined that the activity will not be detrimental to the population or that any detriment is justified by the scientific knowledge that will be generated. This paper assumes that IACUCs are reviewing all wildlife protocols involving live vertebrates, regardless of the current, albeit temporary, distinction made by Animal and Plant Health Inspection Service Animal Care with regard to birds. PMID:23904528

  17. 76 FR 53452 - Clean Air Act Operating Permit Program; Response to Petition To Reopen the 2001 Title V Permit...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-08-26

    ... AGENCY Clean Air Act Operating Permit Program; Response to Petition To Reopen the 2001 Title V Permit for.... ] SUMMARY: Pursuant to the Clean Air Act (CAA), the Director of the EPA Region III Air Protection Division... Reliant Energy Mid-Atlantic Power Holdings, LLC, for its Portland Generating Station in Northampton...

  18. Chloroquine resistance of Plasmodium berghei: biochemical basis and countermeasures*

    PubMed Central

    Salganik, R. I.; Pankova, T. G.; Chekhonadskikh, T. V.; Igonina, T. M.

    1987-01-01

    Microsomal monooxygenases, enzymes that metabolize xenobiotics, may be responsible for the chloroquine resistance of malarial parasites. Plasmodium cells contain cytochrome P-450 and exhibit aryl hydrocarbon hydroxylase and aminopyrine N-dimethylase activity, two monooxygenases that inactivate chloroquine. The activities of these monooxygenases are considerably higher in chloroquine-resistant strains of Plasmodium berghei than in the chloroquine-sensitive strain of the parasite. Inhibitors of microsomal monooxygenases have the potential to overcome the chloroquine resistance of Plasmodium spp., and, of those inhibitors tested, the copper-lysine complex, copper(lysine)2, was the most effective. PMID:3117393

  19. Permitting (Title V. 1990 CAAA)

    SciTech Connect

    Schulze, R.A.

    1995-08-01

    The status of the Clean Air Act Operating Permits Program as of March 2, 1995 is outlined. By November 15, 1993, operating permits programs were to have been submitted by all states and territories consistent with the Federal Operating Permits Program regulations. Submittals were required from 56 states, including the District of Columbia and Territories. In many cases, local programs are responsible for developing and implementing the operating permits programs for their areas of jurisdiction. Steps in the approval process are listed. Under the Clean Air Act, EPA is to implement sanctions by May 15, 1995 in those situations where a complete operating permit program has not been submitted for EPA review.

  20. 50 CFR 665.662 - Permits.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... coral MUS in any PRIA precious coral permit area must have a permit issued under § 665.13. (b) Each permit will be valid for fishing only in the permit area specified on the permit. Precious Coral Permit... surrendering to the Regional Administrator any current permit for the precious coral fishery issued under §...

  1. 50 CFR 665.662 - Permits.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... coral MUS in any PRIA precious coral permit area must have a permit issued under § 665.13. (b) Each permit will be valid for fishing only in the permit area specified on the permit. Precious Coral Permit... surrendering to the Regional Administrator any current permit for the precious coral fishery issued under §...

  2. 50 CFR 665.662 - Permits.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... coral MUS in any PRIA precious coral permit area must have a permit issued under § 665.13. (b) Each permit will be valid for fishing only in the permit area specified on the permit. Precious Coral Permit... surrendering to the Regional Administrator any current permit for the precious coral fishery issued under §...

  3. 50 CFR 665.662 - Permits.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... coral MUS in any PRIA precious coral permit area must have a permit issued under § 665.13. (b) Each permit will be valid for fishing only in the permit area specified on the permit. Precious Coral Permit... surrendering to the Regional Administrator any current permit for the precious coral fishery issued under §...

  4. 50 CFR 665.662 - Permits.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... coral MUS in any PRIA precious coral permit area must have a permit issued under § 665.13. (b) Each permit will be valid for fishing only in the permit area specified on the permit. Precious Coral Permit... surrendering to the Regional Administrator any current permit for the precious coral fishery issued under §...

  5. Transgenic Plasmodium parasites stably expressing Plasmodium vivax dihydrofolate reductase-thymidylate synthase as in vitro and in vivo models for antifolate screening

    PubMed Central

    2011-01-01

    Background Plasmodium vivax is the most prevalent cause of human malaria in tropical regions outside the African continent. The lack of a routine continuous in vitro culture of this parasite makes it difficult to develop specific drugs for this disease. To facilitate the development of anti-P. vivax drugs, bacterial and yeast surrogate models expressing the validated P. vivax target dihydrofolate reductase-thymidylate synthase (DHFR-TS) have been generated; however, they can only be used as primary screening models because of significant differences in enzyme expression level and in vivo drug metabolism between the surrogate models and P. vivax parasites. Methods Plasmodium falciparum and Plasmodium berghei parasites were transfected with DNA constructs bearing P. vivax dhfr-ts pyrimethamine sensitive (wild-type) and pyrimethamine resistant (mutant) alleles. Double crossover homologous recombination was used to replace the endogenous dhfr-ts of P. falciparum and P. berghei parasites with P. vivax homologous genes. The integration of Pvdhfr-ts genes via allelic replacement was verified by Southern analysis and the transgenic parasites lines validated as models by standard drug screening assays. Results Transgenic P. falciparum and P. berghei lines stably expressing PvDHFR-TS replacing the endogenous parasite DHFR-TS were obtained. Anti-malarial drug screening assays showed that transgenic parasites expressing wild-type PvDHFR-TS were pyrimethamine-sensitive, whereas transgenic parasites expressing mutant PvDHFR-TS were pyrimethamine-resistant. The growth and sensitivity to other types of anti-malarial drugs in the transgenic parasites were otherwise indistinguishable from the parental parasites. Conclusion With the permanent integration of Pvdhfr-ts gene in the genome, the transgenic Plasmodium lines expressing PvDHFR-TS are genetically stable and will be useful for screening anti-P. vivax compounds targeting PvDHFR-TS. A similar approach could be used to generate

  6. Towards genome-wide experimental genetics in the in vivo malaria model parasite Plasmodium berghei

    PubMed Central

    Matz, Joachim M.; Kooij, Taco W. A.

    2015-01-01

    Plasmodium berghei was identified as a parasite of thicket rats (Grammomys dolichurus) and Anopheles dureni mosquitoes in African highland forests. Successful adaptation to a range of rodent and mosquito species established P. berghei as a malaria model parasite. The introduction of stable transfection technology, permitted classical reverse genetics strategies and thus systematic functional profiling of the gene repertoire. In the past 10 years following the publication of the P. berghei genome sequence, many new tools for experimental genetics approaches have been developed and existing ones have been improved. The infection of mice is the principal limitation towards a genome-wide repository of mutant parasite lines. In the past few years, there have been some promising and most welcome developments that allow rapid selection and isolation of recombinant parasites while simultaneously minimising animal usage. Here, we provide an overview of all the currently available tools and methods. PMID:25789828

  7. Towards genome-wide experimental genetics in the in vivo malaria model parasite Plasmodium berghei.

    PubMed

    Matz, Joachim M; Kooij, Taco W A

    2015-03-01

    Plasmodium berghei was identified as a parasite of thicket rats (Grammomys dolichurus) and Anopheles dureni mosquitoes in African highland forests. Successful adaptation to a range of rodent and mosquito species established P. berghei as a malaria model parasite. The introduction of stable transfection technology, permitted classical reverse genetics strategies and thus systematic functional profiling of the gene repertoire. In the past 10 years following the publication of the P. berghei genome sequence, many new tools for experimental genetics approaches have been developed and existing ones have been improved. The infection of mice is the principal limitation towards a genome-wide repository of mutant parasite lines. In the past few years, there have been some promising and most welcome developments that allow rapid selection and isolation of recombinant parasites while simultaneously minimising animal usage. Here, we provide an overview of all the currently available tools and methods.

  8. Plasmodium falciparum full life cycle and Plasmodium ovale liver stages in humanized mice

    PubMed Central

    Soulard, Valérie; Bosson-Vanga, Henriette; Lorthiois, Audrey; Roucher, Clémentine; Franetich, Jean- François; Zanghi, Gigliola; Bordessoulles, Mallaury; Tefit, Maurel; Thellier, Marc; Morosan, Serban; Le Naour, Gilles; Capron, Frédérique; Suemizu, Hiroshi; Snounou, Georges; Moreno-Sabater, Alicia; Mazier, Dominique

    2015-01-01

    Experimental studies of Plasmodium parasites that infect humans are restricted by their host specificity. Humanized mice offer a means to overcome this and further provide the opportunity to observe the parasites in vivo. Here we improve on previous protocols to achieve efficient double engraftment of TK-NOG mice by human primary hepatocytes and red blood cells. Thus, we obtain the complete hepatic development of P. falciparum, the transition to the erythrocytic stages, their subsequent multiplication, and the appearance of mature gametocytes over an extended period of observation. Furthermore, using sporozoites derived from two P. ovale-infected patients, we show that human hepatocytes engrafted in TK-NOG mice sustain maturation of the liver stages, and the presence of late-developing schizonts indicate the eventual activation of quiescent parasites. Thus, TK-NOG mice are highly suited for in vivo observations on the Plasmodium species of humans. PMID:26205537

  9. Population genetics of Plasmodium falciparum and Plasmodium vivax and asymptomatic malaria in Temotu Province, Solomon Islands

    PubMed Central

    2013-01-01

    Background Temotu Province, Solomon Islands is progressing toward malaria elimination. A baseline survey conducted in 2008 showed that most Plasmodium infections in the province were of low parasite density and asymptomatic infections. To better understand mechanisms underlying these malaria transmission characteristics genetic diversity and relationships among Plasmodium falciparum and Plasmodium vivax populations in the province were examined. Methods Forty-five P. falciparum and 67 P. vivax samples collected in the 2008 baseline survey were successfully genotyped using eight P. falciparum and seven P. vivax microsatellite markers. Genetic diversity, relationships and distribution of both P. falciparum and P. vivax populations were analysed. Results Plasmodium falciparum population exhibited low diversity with 19 haplotypes identified and had closely related clusters indicating clonal expansion. Interestingly, a dominant haplotype was significantly associated with fever and high parasite density. In contrast, the P. vivax population was highly diverse with 58 haplotypes identified that were not closely related. Parasite populations between different islands in the province showed low genetic differentiation. Conclusion The low diversity and clonal population of P. falciparum population may partially account for clinical immunity developed against illness. However, it is possible that importation of a new P. falciparum strain was the major cause of illness. High diversity in P. vivax population and low relatedness between strains suggested clinical immunity to P. vivax may be maintained by different mechanisms. The genetic diversity, population structure and distribution of strains indicate that transmission of P. falciparum was low, but that of P. vivax was still high in 2008. These data will be useful for assessing changes in malaria transmission resulting from interventions. PMID:24261646

  10. Use of a colorimetric (DELI) test for the evaluation of chemoresistance of Plasmodium falciparum and Plasmodium vivax to commonly used anti-plasmodial drugs in the Brazilian Amazon

    PubMed Central

    2013-01-01

    Background The emergence and spread of Plasmodium falciparum and Plasmodium vivax resistance to available anti-malarial drugs represents a major drawback in the control of malaria and its associated morbidity and mortality. The aim of this study was to evaluate the chemoresistance profile of P. falciparum and P. vivax to commonly used anti-plasmodial drugs in a malaria-endemic area in the Brazilian Amazon. Methods The study was carried out in Manaus (Amazonas state), in the Brazilian Amazon. A total of 88 P. falciparum and 178 P. vivax isolates was collected from 2004 to 2007. The sensitivity of P. falciparum isolates was determined to chloroquine, quinine, mefloquine and artesunate and the sensitivity of P. vivax isolates was determined to chloroquine and mefloquine, by using the colorimetric DELI test. Results As expected, a high prevalence of P. falciparum isolates resistant to chloroquine (78.1%) was observed. The prevalence of isolates with profile of resistance or decreased sensitivity for quinine, mefloquine and artesunate was 12.7, 21.2 and 11.7%, respectively. In the case of P. vivax, the prevalence of isolates with profile of resistance for chloroquine and mefloquine was 9.8 and 28%, respectively. No differences in the frequencies of isolates with profile of resistance or geometric mean IC50s were seen when comparing the data obtained in 2004, 2005, 2006 and 2007, for all tested anti-malarials. Conclusions The great majority of P. falciparum isolates in the Brazilian malaria-endemic area remain resistant to chloroquine, and the decreased sensitivity to quinine, mefloquine and artesunate observed in 10–20% of the isolates must be taken with concern, especially for artesunate. Plasmodium vivax isolates also showed a significant proportion of isolates with decreased sensitivity to chloroquine (first-line drug) and mainly to mefloquine. The data presented here also confirm the usefulness of the DELI test to generate results able to impact on public health

  11. Severe Plasmodium falciparum infection mimicking acute myocardial infarction.

    PubMed

    Sulaiman, Helmi; Ismail, Muhammad Dzafir; Jalalonmuhali, Maisarah; Atiya, Nadia; Ponnampalavanar, Sasheela

    2014-08-30

    This case report describes a case of presumed acute myocardial infarction in a returned traveler who was later diagnosed to have severe malaria. Emergency coronary angiography was normal and subsequent peripheral blood film was positive for Plasmodium falciparum.

  12. Colombian Anopheles triannulatus (Diptera: Culicidae) Naturally Infected with Plasmodium spp.

    PubMed Central

    Rosero, Doris A.; Naranjo-Diaz, Nelson; Alvarez, Natalí; Cienfuegos, Astrid V.; Luckhart, Shirley

    2013-01-01

    The role of Anopheles triannulatus as a local vector has not yet been defined for malaria-endemic regions of Colombia. Therefore, the aim of this work was to detect An. triannulatus naturally infected with Plasmodium spp., as an approximation to determining its importance as malaria vector in the country. A total of 510 An. triannulatus were collected in six malaria-endemic localities of NW and SE Colombia from January 2009 to March 2011. In the NW, two specimens were naturally infected; one with Plasmodium vivax VK247, collected biting on humans and the other with Plasmodium falciparum, collected resting on cattle. In the SE, two specimens were positive for P. falciparum. Although these results show An. triannulatus naturally infected with Plasmodium, further studies are recommended to demonstrate the epidemiological importance of this species in malaria-endemic regions of Colombia. PMID:27335865

  13. Plasmodium species: master renovators of their host cells.

    PubMed

    de Koning-Ward, Tania F; Dixon, Matthew W A; Tilley, Leann; Gilson, Paul R

    2016-08-01

    Plasmodium parasites, the causative agents of malaria, have developed elaborate strategies that they use to survive and thrive within different intracellular environments. During the blood stage of infection, the parasite is a master renovator of its erythrocyte host cell, and the changes in cell morphology and function that are induced by the parasite promote survival and contribute to the pathogenesis of severe malaria. In this Review, we discuss how Plasmodium parasites use the protein trafficking motif Plasmodium export element (PEXEL), protease-mediated polypeptide processing, a novel translocon termed the Plasmodium translocon of exported proteins (PTEX) and exomembranous structures to export hundreds of proteins to discrete subcellular locations in the host erythrocytes, which enables the parasite to gain access to vital nutrients and to evade the immune defence mechanisms of the host.

  14. Repeated Plasmodium vivax malaria relapses in a Peruvian sailor.

    PubMed

    McFarland, Adam P; Sanchez, Juan F; Mercado, Alejandro; Ventocilla, Julio A; Cavalcanti, Sofia; Gonzalez, Sofia; Lescano, Andres G

    2015-01-01

    Two Plasmodium vivax recurrences in a Peruvian sailor with weight above the 60 kg (cap for primaquine dosage) highlight the importance of adequate radical cure weight dosage for patient treatment and control efforts, particularly within the military. PMID:26620122

  15. Repeated Plasmodium vivax malaria relapses in a Peruvian sailor.

    PubMed

    McFarland, Adam P; Sanchez, Juan F; Mercado, Alejandro; Ventocilla, Julio A; Cavalcanti, Sofia; Gonzalez, Sofia; Lescano, Andres G

    2015-12-01

    Two Plasmodium vivax recurrences in a Peruvian sailor with weight above the 60 kg (cap for primaquine dosage) highlight the importance of adequate radical cure weight dosage for patient treatment and control efforts, particularly within the military.

  16. Efficient CRISPR-Cas9-mediated genome editing in Plasmodium falciparum.

    PubMed

    Wagner, Jeffrey C; Platt, Randall J; Goldfless, Stephen J; Zhang, Feng; Niles, Jacquin C

    2014-09-01

    Malaria is a major cause of global morbidity and mortality, and new strategies for treating and preventing this disease are needed. Here we show that the Streptococcus pyogenes Cas9 DNA endonuclease and single guide RNAs (sgRNAs) produced using T7 RNA polymerase (T7 RNAP) efficiently edit the Plasmodium falciparum genome. Targeting the genes encoding native knob-associated histidine-rich protein (kahrp) and erythrocyte binding antigen 175 (eba-175), we achieved high (≥ 50-100%) gene disruption frequencies within the usual time frame for generating transgenic parasites.

  17. Plasmodium falciparum Malaria Endemicity in Indonesia in 2010

    PubMed Central

    Elyazar, Iqbal R. F.; Gething, Peter W.; Patil, Anand P.; Rogayah, Hanifah; Kusriastuti, Rita; Wismarini, Desak M.; Tarmizi, Siti N.; Baird, J. Kevin; Hay, Simon I.

    2011-01-01

    Background Malaria control programs require a detailed understanding of the contemporary spatial distribution of infection risk to efficiently allocate resources. We used model based geostatistics (MBG) techniques to generate a contemporary map of Plasmodium falciparum malaria risk in Indonesia in 2010. Methods Plasmodium falciparum Annual Parasite Incidence (PfAPI) data (2006–2008) were used to map limits of P. falciparum transmission. A total of 2,581 community blood surveys of P. falciparum parasite rate (PfPR) were identified (1985–2009). After quality control, 2,516 were included into a national database of age-standardized 2–10 year old PfPR data (PfPR2–10) for endemicity mapping. A Bayesian MBG procedure was used to create a predicted surface of PfPR2–10 endemicity with uncertainty estimates. Population at risk estimates were derived with reference to a 2010 human population count surface. Results We estimate 132.8 million people in Indonesia, lived at risk of P. falciparum transmission in 2010. Of these, 70.3% inhabited areas of unstable transmission and 29.7% in stable transmission. Among those exposed to stable risk, the vast majority were at low risk (93.39%) with the reminder at intermediate (6.6%) and high risk (0.01%). More people in western Indonesia lived in unstable rather than stable transmission zones. In contrast, fewer people in eastern Indonesia lived in unstable versus stable transmission areas. Conclusion While further feasibility assessments will be required, the immediate prospects for sustained control are good across much of the archipelago and medium term plans to transition to the pre-elimination phase are not unrealistic for P. falciparum. Endemicity in areas of Papua will clearly present the greatest challenge. This P. falciparum endemicity map allows malaria control agencies and their partners to comprehensively assess the region-specific prospects for reaching pre-elimination, monitor and evaluate the effectiveness of

  18. Plasmodium Drug Targets Outside the Genetic Control of the Parasite

    PubMed Central

    Sullivan, David J.

    2014-01-01

    Drug development often seeks to find “magic bullets” which target microbiologic proteins while not affecting host proteins. Paul Ehrlich tested methylene blue as an antimalarial but this dye was not superior to quinine. Many successful antimalarial therapies are “magic shotguns” which target many Plasmodium pathways with little interference in host metabolism. Two malaria drug classes, the 8-aminoquinolines and the artemisinins interact with cytochrome P450s and host iron protoporphyrin IX or iron, respectively, to generate toxic metabolites and/or radicals, which kill the parasite by interference with many proteins. The non 8-amino antimalarial quinolines like quinine or piperaquine bind heme to inhibit the process of heme crystallization, which results in multiple enzyme inhibition and membrane dysfunction. The quinolines and artemisinins are rapidly parasiticidal in contrast to metal chelators, which have a slower parasite clearance rate with higher drug concentrations. Iron chelators interfere with the artemisinins but otherwise represent a strategy of targeting multiple enzymes containing iron. Interest has been revived in antineoplastic drugs that target DNA metabolism as antimalarials. Specific drug targeting or investigation of the innate immunity directed to the more permeable trophozoite or schizont infected erythrocyte membrane has been under explored. Novel drug classes in the antimalarial development pipeline which either target multiple proteins or unchangeable cellular targets will slow the pace of drug resistance acquisition. PMID:22973888

  19. Interactive transcriptome analysis of malaria patients and infecting Plasmodium falciparum.

    PubMed

    Yamagishi, Junya; Natori, Anna; Tolba, Mohammed E M; Mongan, Arthur E; Sugimoto, Chihiro; Katayama, Toshiaki; Kawashima, Shuichi; Makalowski, Wojciech; Maeda, Ryuichiro; Eshita, Yuki; Tuda, Josef; Suzuki, Yutaka

    2014-09-01

    To understand the molecular mechanisms of parasitism in vivo, it is essential to elucidate how the transcriptomes of the human hosts and the infecting parasites affect one another. Here we report the RNA-seq analysis of 116 Indonesian patients infected with the malaria parasite Plasmodium falciparum (Pf). We extracted RNAs from their peripheral blood as a mixture of host and parasite transcripts and mapped the RNA-seq tags to the human and Pf reference genomes to separate the respective tags. We were thus able to simultaneously analyze expression patterns in both humans and parasites. We identified human and parasite genes and pathways that correlated with various clinical data, which may serve as primary targets for drug developments. Of particular importance, we revealed characteristic expression changes in the human innate immune response pathway genes including TLR2 and TICAM2 that correlated with the severity of the malaria infection. We also found a group of transcription regulatory factors, JUND, for example, and signaling molecules, TNFAIP3, for example, that were strongly correlated in the expression patterns of humans and parasites. We also identified several genetic variations in important anti-malaria drug resistance-related genes. Furthermore, we identified the genetic variations which are potentially associated with severe malaria symptoms both in humans and parasites. The newly generated data should collectively lay a unique foundation for understanding variable behaviors of the field malaria parasites, which are far more complex than those observed under laboratory conditions.

  20. Rheopathologic Consequence of Plasmodium vivax Rosette Formation.

    PubMed

    Zhang, Rou; Lee, Wenn-Chyau; Lau, Yee-Ling; Albrecht, Letusa; Lopes, Stefanie C P; Costa, Fabio T M; Suwanarusk, Rossarin; Nosten, Francois; Cooke, Brian M; Rénia, Laurent; Russell, Bruce

    2016-08-01

    Malaria parasites dramatically alter the rheological properties of infected red blood cells. In the case of Plasmodium vivax, the parasite rapidly decreases the shear elastic modulus of the invaded RBC, enabling it to avoid splenic clearance. This study highlights correlation between rosette formation and altered membrane deformability of P. vivax-infected erythrocytes, where the rosette-forming infected erythrocytes are significantly more rigid than their non-rosetting counterparts. The adhesion of normocytes to the PvIRBC is strong (mean binding force of 440pN) resulting in stable rosette formation even under high physiological shear flow stress. Rosetting may contribute to the sequestration of PvIRBC schizonts in the host microvasculature or spleen. PMID:27509168

  1. Rheopathologic Consequence of Plasmodium vivax Rosette Formation

    PubMed Central

    Lau, Yee-Ling; Albrecht, Letusa; Lopes, Stefanie C. P.; Costa, Fabio T. M.; Suwanarusk, Rossarin; Nosten, Francois; Cooke, Brian M.; Rénia, Laurent; Russell, Bruce

    2016-01-01

    Malaria parasites dramatically alter the rheological properties of infected red blood cells. In the case of Plasmodium vivax, the parasite rapidly decreases the shear elastic modulus of the invaded RBC, enabling it to avoid splenic clearance. This study highlights correlation between rosette formation and altered membrane deformability of P. vivax-infected erythrocytes, where the rosette-forming infected erythrocytes are significantly more rigid than their non-rosetting counterparts. The adhesion of normocytes to the PvIRBC is strong (mean binding force of 440pN) resulting in stable rosette formation even under high physiological shear flow stress. Rosetting may contribute to the sequestration of PvIRBC schizonts in the host microvasculature or spleen. PMID:27509168

  2. The paradoxical population genetics of Plasmodium falciparum.

    PubMed

    Hartl, Daniel L; Volkman, Sarah K; Nielsen, Kaare M; Barry, Alyssa E; Day, Karen P; Wirth, Dyann F; Winzeler, Elizabeth A

    2002-06-01

    Among the leading causes of death in African children is cerebral malaria caused by the parasitic protozoan Plasmodium falciparum. Endemic forms of this disease are thought to have originated in central Africa 5000-10000 years ago, coincident with the innovation of slash-and-burn agriculture and the diversification of the Anopheles gambiae complex of mosquito vectors. Population genetic studies of P. falciparum have yielded conflicting results. Some evidence suggests that today's population includes multiple ancient lineages pre-dating human speciation. Other evidence suggests that today's population derives from only one, or a small number, of these ancient lineages. Resolution of this issue is important for the evaluation of the long-term efficacy of drug and immunological control strategies. PMID:12036741

  3. Proteasome Inhibitors Block Development of Plasmodium spp.

    PubMed Central

    Gantt, Soren M.; Myung, Joon Mo; Briones, Marcelo R. S.; Li, Wei Dong; Corey, E. J.; Omura, Satoshi; Nussenzweig, Victor; Sinnis, Photini

    1998-01-01

    Proteasomes degrade most of the proteins inside eukaryotic cells, including transcription factors and regulators of cell cycle progression. Here we show that nanomolar concentrations of lactacystin, a specific irreversible inhibitor of the 20S proteasome, inhibit development of the exoerythrocytic and erythrocytic stages of the malaria parasite. Although lactacystin-treated Plasmodium berghei sporozoites are still invasive, their development into exoerythrocytic forms (EEF) is inhibited in vitro and in vivo. Erythrocytic schizogony of P. falciparum in vitro is also profoundly inhibited when drug treatment of the synchronized parasites is prior, but not subsequent, to the initiation of DNA synthesis, suggesting that the inhibitory effect of lactacystin is cell cycle specific. Lactacystin reduces P. berghei parasitemia in rats, but the therapeutic index is very low. Along with other studies showing that lactacystin inhibits stage-specific transformation in Trypanosoma and Entamoeba spp., these findings highlight the potential of proteasome inhibitors as drugs for the treatment of diseases caused by protozoan parasites. PMID:9756786

  4. Development of vaccines for Plasmodium vivax malaria.

    PubMed

    Mueller, Ivo; Shakri, Ahmad Rushdi; Chitnis, Chetan E

    2015-12-22

    Plasmodium vivax continues to cause significant morbidity outside Africa with more than 50% of malaria cases in many parts of South and South-east Asia, Pacific islands, Central and South America being attributed to P. vivax infections. The unique biology of P. vivax, including its ability to form latent hypnozoites that emerge months to years later to cause blood stage infections, early appearance of gametocytes before clinical symptoms are apparent and a shorter development cycle in the vector makes elimination of P. vivax using standard control tools difficult. The availability of an effective vaccine that provides protection and prevents transmission would be a valuable tool in efforts to eliminate P. vivax. Here, we review the latest developments related to P. vivax malaria vaccines and discuss the challenges as well as directions toward the goal of developing highly efficacious vaccines against P. vivax malaria.

  5. Plasmodium vivax genetic diversity: microsatellite length matters.

    PubMed

    Russell, Bruce; Suwanarusk, Rossarin; Lek-Uthai, Usa

    2006-09-01

    The Plasmodium vivax genome is very diverse but has a relatively low abundance of microsatellites. Leclerc et al. had shown that these di-nucleotide repeats have a low level of polymorphism, suggesting a recent bottleneck event in the evolutionary history of P. vivax. By contrast, in a recent paper, Imwong et al. show that there is a very high level of microsatellite diversity. The difference in these results is probably due to the set array lengths chosen by each group. Longer arrays are more diverse than are shorter ones because slippage mutations become exponentially more common with an increase in array length. These studies highlight the need to consider carefully the application and design of studies involving microsatellites.

  6. The paradoxical population genetics of Plasmodium falciparum.

    PubMed

    Hartl, Daniel L; Volkman, Sarah K; Nielsen, Kaare M; Barry, Alyssa E; Day, Karen P; Wirth, Dyann F; Winzeler, Elizabeth A

    2002-06-01

    Among the leading causes of death in African children is cerebral malaria caused by the parasitic protozoan Plasmodium falciparum. Endemic forms of this disease are thought to have originated in central Africa 5000-10000 years ago, coincident with the innovation of slash-and-burn agriculture and the diversification of the Anopheles gambiae complex of mosquito vectors. Population genetic studies of P. falciparum have yielded conflicting results. Some evidence suggests that today's population includes multiple ancient lineages pre-dating human speciation. Other evidence suggests that today's population derives from only one, or a small number, of these ancient lineages. Resolution of this issue is important for the evaluation of the long-term efficacy of drug and immunological control strategies.

  7. Plasmodium malariae blood-stage dynamics.

    PubMed

    McKenzie, F E; Jeffery, G M; Collins, W E

    2001-06-01

    We examine the dynamics of parasitemia, fever, and gametocytemia reflected in the preintervention charts of 180 malaria-naive U.S. neurosyphilis patients infected with the USPHS strain of Plasmodium malariae, for malariatherapy, focusing on the 84 charts for which more than 35 days of patency preceded intervention and daily records encompassed 92% or more of the duration of each infection. Inoculum size did not influence any outcome variable. Fevers (days with temperatures > or =101 F) followed patterns that fit recognized brood structures more often than did our approximations of merogony cycles (via local peaks in parasitemia), but neither closely fit textbook quartan patterns. There were no discernable patterns in gametocytemia. Successful transmission to mosquitoes increased following subcurative drug treatment but did not depend on detectable gametocytemia. PMID:11426728

  8. Avoiding Title V permitting pitfalls

    SciTech Connect

    Laswell, D.L.

    1993-04-01

    Title V of the 1990 Clean Air Act Amendments requires states to implement new air operating permit programs. States have a great deal of flexibility in developing their permit programs. Industry should work now to ensure that state programs contain the favorable aspects of the federal regulations and do not contain more stringent requirements that are not required under the Clean Air Act. This article outlines areas of the permit program that have the potential to handicap industry`s ability to expand.

  9. Dynamics of molecular markers linked to the resistance loci in a mosquito-Plasmodium system.

    PubMed Central

    Yan, Guiyun; Severson, David W

    2003-01-01

    Models on the evolution of resistance to parasitism generally assume fitness tradeoffs between the costs of being parasitized and the costs associated with resistance. This study tested this assumption using the yellow fever mosquito Aedes aegypti and malaria parasite Plasmodium gallinaceum system. Experimental mosquito populations were created by mixing susceptible and resistant strains in equal proportions, and then the dynamics of markers linked to loci for Plasmodium resistance and other unlinked neutral markers were determined over 12 generations. We found that when the mixed population was maintained under parasite-free conditions, the frequencies of alleles specific to the susceptible strain at markers closely linked to the loci for resistance (QTL markers) as well as other unlinked markers increased significantly in the first generation and then fluctuated around equilibrium frequencies for all six markers. However, when the mixed population was exposed to an infected blood meal every generation, allele frequencies at the QTL markers for resistance were not significantly changed. Small population size caused significant random fluctuations of allele frequencies at all marker loci. Consistent allele frequency changes in the QTL markers and other unlinked markers suggest that the reduced fitness in the resistant population has a genome-wide effect on the genetic makeup of the mixed population. Continuous exposure to parasites promoted the maintenance of alleles from the resistant Moyo-R strain in the mixed population. The results are discussed in relation to the proposed malaria control strategy through genetic disruption of vector competence. PMID:12807772

  10. 50 CFR 665.162 - Permits.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... coral MUS in any American Samoa precious coral permit area must have a permit issued under § 665.13. (b) Each permit will be valid for fishing only in the permit area specified on the permit. Precious Coral... upon surrendering to the Regional Administrator any current permit for the precious coral...

  11. 50 CFR 665.262 - Permits.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ...) Any vessel of the United States fishing for, taking, or retaining Hawaii precious coral MUS in any Hawaiian Archipelago precious coral permit area must have a permit issued under § 665.13. (b) Each permit will be valid for fishing only in the permit area specified on the permit. Precious Coral Permit...

  12. 50 CFR 665.262 - Permits.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ...) Any vessel of the United States fishing for, taking, or retaining Hawaii precious coral MUS in any Hawaiian Archipelago precious coral permit area must have a permit issued under § 665.13. (b) Each permit will be valid for fishing only in the permit area specified on the permit. Precious Coral Permit...

  13. 50 CFR 665.162 - Permits.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... coral MUS in any American Samoa precious coral permit area must have a permit issued under § 665.13. (b) Each permit will be valid for fishing only in the permit area specified on the permit. Precious Coral... upon surrendering to the Regional Administrator any current permit for the precious coral...

  14. 50 CFR 665.262 - Permits.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ...) Any vessel of the United States fishing for, taking, or retaining Hawaii precious coral MUS in any Hawaiian Archipelago precious coral permit area must have a permit issued under § 665.13. (b) Each permit will be valid for fishing only in the permit area specified on the permit. Precious Coral Permit...

  15. 50 CFR 665.162 - Permits.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... coral MUS in any American Samoa precious coral permit area must have a permit issued under § 665.13. (b) Each permit will be valid for fishing only in the permit area specified on the permit. Precious Coral... upon surrendering to the Regional Administrator any current permit for the precious coral...

  16. 50 CFR 665.262 - Permits.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ...) Any vessel of the United States fishing for, taking, or retaining Hawaii precious coral MUS in any Hawaiian Archipelago precious coral permit area must have a permit issued under § 665.13. (b) Each permit will be valid for fishing only in the permit area specified on the permit. Precious Coral Permit...

  17. 50 CFR 665.262 - Permits.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ...) Any vessel of the United States fishing for, taking, or retaining Hawaii precious coral MUS in any Hawaiian Archipelago precious coral permit area must have a permit issued under § 665.13. (b) Each permit will be valid for fishing only in the permit area specified on the permit. Precious Coral Permit...

  18. 50 CFR 665.162 - Permits.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... coral MUS in any American Samoa precious coral permit area must have a permit issued under § 665.13. (b) Each permit will be valid for fishing only in the permit area specified on the permit. Precious Coral... upon surrendering to the Regional Administrator any current permit for the precious coral...

  19. 50 CFR 665.162 - Permits.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... coral MUS in any American Samoa precious coral permit area must have a permit issued under § 665.13. (b) Each permit will be valid for fishing only in the permit area specified on the permit. Precious Coral... upon surrendering to the Regional Administrator any current permit for the precious coral...

  20. Permitted water use in Iowa, 1985

    USGS Publications Warehouse

    Runkle, D.L.; Newman, J.L.; Shields, E.M.

    1985-01-01

    This report summarizes where, how much and for what purpose water is allocated for use in Iowa with permits issued by the Department of Water, Air and Waste Management. In Iowa, from a total permitted water use of 855,175.45 million gallons per year, about 58 percent is from surface-water sources and about 42 percent is from ground-water sources. Streams are 80.5 percent of the total surface-water use and wells make up 80.1 percent of the total ground-water use, with 65.4 percent of ground water coming from surficial aquifers. Power generation is the use category that is permitted the largest amount of total water use, 46.6 percent, with surface water being the source of 96.7 percent and 77.9 percent of the surface water is from streams. The public water suppliers' category is the next largest use type with 15.7 percent of the total permitted water. Ground water constitutes 74.4 percent of the public water supplier category with 51.7 percent from surficial aquifers. Surface water makes up 25.6 percent of this category with 83.0 percent of the surface water withdrawn from streams. Mining comprises 13.4 percent of the total water use and is the third largest water-use category. Ground water is the source of 63.3 percent of permitted mining water use with 94.3 percent of this from quarries and sand and gravel pits. Surface water is the source of 36.7 percent of the permitted mining water use with 97.6 percent from streams. Irrigation is the fourth largest permitted use type using 12.0 percent of the total water use. Eighty-eight percent of irrigation is from ground-water sources where surficial aquifers account for 94.7 percent. Streams are 81.1 percent of irrigational surface-water use. Self-supplied industrial users are permitted 10.6 percent of the total permitted water use with 85.5 percent of this from ground-water sources and 14.5 percent from surface-water sources. Of the self-supplied industrial ground-water use, 47.9 percent comes from surficial aquifers and

  1. 40 CFR 49.139 - Rule for non-Title V operating permits.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

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  2. 77 FR 10503 - Fall River Community Hydro Project; Notice of Preliminary Permit Application Accepted for Filing...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-02-22

    ... file a license application during the permit term. A preliminary permit does not authorize the permit... penstock connecting the conduit to the powerhouse; (3) two pump-turbines totaling 900 kilowatts (kW) (1 x 300 kW unit and 1 x 600 kW unit) of generating capacity; and (4) an existing 3-phase power line...

  3. Rediscovery and redescription of Plasmodium pifanoi and description of two additional Plasmodium parasites of Venezuelan lizards.

    PubMed

    Telford, Sam R; Telford, Sam R

    2003-04-01

    Plasmodium pifanoi Scorza and Dagert B., known only from the type host, Ameiva ameiva, is redescribed from Kentropyx calcarata collected in Territorio Amazonas, Venezuela. Schizonts, 6.2 x 4.5 (4-8 x 3-6), produce on average 11.9 (7-16) merozoites. Gametocytes average 12.4 x 6.0 (8-16 x 4-10), with length x width (LW) 72.9 (52-112) and L/W 2.18 (1.1-3.3), and always contain 1-5 prominent vacuoles. Macrogametocytes in active infection are longer than microgametocytes, with greater LW, but gametocytes in chronic infection are not sexually dimorphic in dimension and are slightly smaller. Two additional malarial parasites are described from K. calcarata. Plasmodium lepidoptiformis has small schizonts, 4.6 x 3.2 (3-6 x 2.5-3), that produce 5.1 (4-8) merozoites and commonly resemble a butterfly in appearance. Gametocytes are elongate, 9.0 x 4.3 (7-10 x 3-6), with LW 38.3 (24-51) and L/W 2.2 (1.3-3.3), and sexually dimorphic, with macrogametocytes longer than microgametocytes, with greater LW. Plasmodium minasense calcaratae is characterized by very small, usually fan-shaped, schizonts. 3.4 x 2.6 (2.5-4.5 x 2.0-3.0), that produce 3.9 (3-4) merozoites. Gametocytes are spherical or ovoid, 6.7 x 5.0 (4.5-9.0 x 3.0-7.0), with LW 33.7 (15-54) and L/W 1.4 (1.0-2.3), with no sexual dimorphism in dimensions. PMID:12760655

  4. Maternal-foetal transfer of Plasmodium falciparum and Plasmodium vivax antibodies in a low transmission setting

    PubMed Central

    Charnaud, Sarah C.; McGready, Rose; Herten-Crabb, Asha; Powell, Rosanna; Guy, Andrew; Langer, Christine; Richards, Jack S.; Gilson, Paul R.; Chotivanich, Kesinee; Tsuboi, Takafumi; Narum, David L.; Pimanpanarak, Mupawjay; Simpson, Julie A.; Beeson, James G.; Nosten, François; Fowkes, Freya J. I.

    2016-01-01

    During pregnancy immunolglobulin G (IgG) antibodies are transferred from mother to neonate across the placenta. Studies in high transmission areas have shown transfer of P. falciparum-specific IgG, but the extent and factors influencing maternal-foetal transfer in low transmission areas co-endemic for both P. falciparum and P. vivax are unknown. Pregnant women were screened weekly for Plasmodium infection. Mother-neonate paired serum samples at delivery were tested for IgG to antigens from P. falciparum, P. vivax and other infectious diseases. Antibodies to malarial and non-malarial antigens were highly correlated between maternal and neonatal samples (median [range] spearman ρ = 0.78 [0.57–0.93]), although Plasmodium spp. antibodies tended to be lower in neonates than mothers. Estimated gestational age at last P. falciparum infection, but not P. vivax infection, was positively associated with antibody levels in the neonate (P. falciparum merozoite, spearman ρ median [range] 0.42 [0.33–0.66], PfVAR2CSA 0.69; P. vivax ρ = 0.19 [0.09–0.3]). Maternal-foetal transfer of anti-malarial IgG to Plasmodium spp. antigens occurs in low transmission settings. P. vivax IgG acquisition is not associated with recent exposure unlike P. falciparum IgG, suggesting a difference in acquisition of antibodies. IgG transfer is greatest in the final weeks of pregnancy which has implications for the timing of future malaria vaccination strategies in pregnant women. PMID:26861682

  5. Dimorphism in genes encoding sexual-stage proteins of Plasmodium ovale curtisi and Plasmodium ovale wallikeri☆

    PubMed Central

    Oguike, Mary C.; Sutherland, Colin J.

    2015-01-01

    Plasmodium ovale curtisi and Plasmodium ovale wallikeri are distinct species of malaria parasite which are sympatric throughout the tropics, except for the Americas. Despite this complete overlap in geographic range, these two species do not recombine. Although morphologically very similar, the two taxa must possess distinct characters which prevent recombination between them. We hypothesised that proteins required for sexual reproduction have sufficiently diverged between the two species to prevent recombination in any mosquito blood meal in which gametocytes of both species are ingested. In order to investigate possible barriers to inter-species mating between P. ovale curtisi and P. ovale wallikeri, homologues of genes encoding sexual stage proteins in other plasmodia were identified and compared between the two species. Database searches with motifs for 6-cysteine, Limulus Coagulation factor C domain-containing proteins and other relevant sexual stage proteins in the genus Plasmodium were performed in the available P. ovale curtisi partial genome database (Wellcome Trust Sanger Institute, UK). Sequence fragments obtained were used as the basis for PCR walking along each gene of interest in reference isolates of both P. ovale curtisi and P. ovale wallikeri. Sequence alignment of the homologues of each gene in each species showed complete dimorphism across all isolates. In conclusion, substantial divergence between sexual stage proteins in the two P. ovale spp. was observed, providing further evidence that these do not recombine in nature. Incompatibility of proteins involved in sexual development and fertilisation thus remains a plausible explanation for the observed lack of natural recombination between P. ovale curtisi and P. ovale wallikeri. PMID:25817462

  6. Dimorphism in genes encoding sexual-stage proteins of Plasmodium ovale curtisi and Plasmodium ovale wallikeri.

    PubMed

    Oguike, Mary C; Sutherland, Colin J

    2015-06-01

    Plasmodium ovale curtisi and Plasmodium ovale wallikeri are distinct species of malaria parasite which are sympatric throughout the tropics, except for the Americas. Despite this complete overlap in geographic range, these two species do not recombine. Although morphologically very similar, the two taxa must possess distinct characters which prevent recombination between them. We hypothesised that proteins required for sexual reproduction have sufficiently diverged between the two species to prevent recombination in any mosquito blood meal in which gametocytes of both species are ingested. In order to investigate possible barriers to inter-species mating between P. ovale curtisi and P. ovale wallikeri, homologues of genes encoding sexual stage proteins in other plasmodia were identified and compared between the two species. Database searches with motifs for 6-cysteine, Limulus Coagulation factor C domain-containing proteins and other relevant sexual stage proteins in the genus Plasmodium were performed in the available P. ovale curtisi partial genome database (Wellcome Trust Sanger Institute, UK). Sequence fragments obtained were used as the basis for PCR walking along each gene of interest in reference isolates of both P. ovale curtisi and P. ovale wallikeri. Sequence alignment of the homologues of each gene in each species showed complete dimorphism across all isolates. In conclusion, substantial divergence between sexual stage proteins in the two P. ovale spp. was observed, providing further evidence that these do not recombine in nature. Incompatibility of proteins involved in sexual development and fertilisation thus remains a plausible explanation for the observed lack of natural recombination between P. ovale curtisi and P. ovale wallikeri.

  7. High prevalence and genetic diversity of Plasmodium malariae and no evidence of Plasmodium knowlesi in Bangladesh.

    PubMed

    Fuehrer, Hans-Peter; Swoboda, Paul; Harl, Josef; Starzengruber, Peter; Habler, Verena Elisabeth; Bloeschl, Ingrid; Haque, Rashidul; Matt, Julia; Khan, Wasif Ali; Noedl, Harald

    2014-04-01

    Although the prevalence of malaria remains high in parts of Bangladesh, there continues to be a substantial shortage of information regarding the less common malaria parasites such as Plasmodium malariae or Plasmodium knowlesi. Recent studies indicate that P. malariae may be extremely rare, and so far, there are no data on the presence (or absence) of P. knowlesi in southeastern Bangladesh. Genus- and species-specific nested polymerase chain reaction (PCR) analysis of the small subunit ribosomal RNA gene was performed to assess the presence and prevalence of P. malariae and P. knowlesi in 2,246 samples originating from asymptomatic and febrile participants of a cross-sectional and a febrile illnesses study in the Chittagong Hill Tracts in southeastern Bangladesh. P. malariae was detected in 60 samples (2.7%) corresponding to 8% of the 746 samples giving positive PCR results for Plasmodium sp., mainly because of the high prevalence (9.5%) among asymptomatic study participants testing positive for malaria. Symptomatic cases were more common (4.3% of all symptomatic malaria cases) during the dry season. Parasitemias were low (1,120-2,560/μl in symptomatic and 120-520/μl in asymptomatic carriers). Symptomatic patients presented mild to moderate symptoms like fever, chills, headache, dizziness, fatigue and myalgia.Although both the intermediate as well as the definite host are known to be endemic in southeastern Bangladesh, no evidence for the presence of P. knowlesi was found. We conclude that the role of P. malariae is highly underestimated in rural Bangladesh with major implications for malaria control and elimination strategies. PMID:24578257

  8. Continuous in vitro propagation of the malaria parasite Plasmodium vivax.

    PubMed

    Golenda, C F; Li, J; Rosenberg, R

    1997-06-24

    The difficulty in controlling Plasmodium vivax, the most common cause of human malaria, has been complicated by growing drug resistance. We have established a method to cycle parasite generations in continuous culture using human blood cells. Chesson strain parasites were passaged from owl monkey erythrocytes to human reticulocytes in McCoy's 5A medium modified with L-glutamine with 25 mM Hepes buffer supplemented with 20% AB+ human serum. Reticulocytes were separated by differential centrifugation in homologous plasma from the peripheral blood of a hemochromatosis patient. Parasites were grown during each 48-hr cycle in a static candle jar environment until the beginning of schizogony, at about 36-40 hr, when reticulocytes were added and cultures transferred to a shaker for 10-12 hr. The addition of a concentration of 10% reticulocytes resulted in stabilizing parasite densities between 0.28 and 0.57 after cycle 3 and increasing the total number of parasites at least 2-fold with each generational cycle. Cultured parasites successfully infected an owl monkey. The morphology of cultured parasites was typical of P. vivax, with highly ameboid trophozoites evident; however, infected erythrocytes were enlarged and distorted on thin film preparations. The species identity of cultivated parasites was confirmed by analysis of the A and C 18S rRNA genes from genomic DNA and expression of only the A gene during erythrocytic asexual growth. The ability to culture P. vivax opens new opportunities to develop vaccines, test drugs, and clone parasites for genome sequencing.

  9. Plasmodium dipeptidyl aminopeptidases as malaria transmission-blocking drug targets.

    PubMed

    Tanaka, Takeshi Q; Deu, Edgar; Molina-Cruz, Alvaro; Ashburne, Michael J; Ali, Omar; Suri, Amreena; Kortagere, Sandhya; Bogyo, Matthew; Williamson, Kim C

    2013-10-01

    The Plasmodium falciparum and P. berghei genomes each contain three dipeptidyl aminopeptidase (dpap) homologs. dpap1 and -3 are critical for asexual growth, but the role of dpap2, the gametocyte-specific homolog, has not been tested. If DPAPs are essential for transmission as well as asexual growth, then a DPAP inhibitor could be used for treatment and to block transmission. To directly analyze the role of DPAP2, a dpap2-minus P. berghei (Pbdpap2Δ) line was generated. The Pbdpap2Δ parasites grew normally, differentiated into gametocytes, and generated sporozoites that were infectious to mice when fed to a mosquito. However, Pbdpap1 transcription was >2-fold upregulated in the Pbdpap2Δ clonal lines, possibly compensating for the loss of Pbdpap2. The role of DPAP1 and -3 in the dpap2Δ parasites was then evaluated using a DPAP inhibitor, ML4118S. When ML4118S was added to the Pbdpap2Δ parasites just before a mosquito membrane feed, mosquito infectivity was not affected. To assess longer exposures to ML4118S and further evaluate the role of DPAPs during gametocyte development in a parasite that causes human malaria, the dpap2 deletion was repeated in P. falciparum. Viable P. falciparum dpap2 (Pfdpap2)-minus parasites were obtained that produced morphologically normal gametocytes. Both wild-type and Pfdpap2-negative parasites were sensitive to ML4118S, indicating that, unlike many antimalarials, ML4118S has activity against parasites at both the asexual and sexual stages and that DPAP1 and -3 may be targets for a dual-stage drug that can treat patients and block malaria transmission.

  10. Avian Malaria ( Plasmodium spp.) in Captive Magellanic Penguins ( Spheniscus magellanicus ) from Northern Argentina, 2010.

    PubMed

    Vanstreels, Ralph Eric Thijl; Capellino, Félix; Silveira, Patricia; Braga, Érika M; Rodríguez-Heredia, Sergio Andres; Loureiro, Julio; Catão-Dias, José Luiz

    2016-07-01

    We report two cases of lethal avian malaria in Magellanic Penguins (Spheniscus magellanicus) captive at San Clemente del Tuyú, Argentina, approximately 560 km north of Argentinean breeding colonies of Magellanic Penguins. Blood smears revealed both penguins were concurrently infected by Plasmodium (Haemamoeba) tejerai, Plasmodium (Huffia) sp., and Plasmodium (Novyella) sp. PMID:27285418

  11. Plasmodium vivax trophozoite-stage proteomes

    PubMed Central

    Anderson, D.C.; Lapp, Stacey A.; Akinyi, Sheila; Meyer, Esmeralda V.S.; Barnwell, John W.; Korir-Morrison, Cindy; Galinski, Mary R.

    2015-01-01

    Plasmodium vivax is the causative infectious agent of 80–300 million annual cases of malaria. Many aspects of this parasite’s biology remain unknown. To further elucidate the interaction of P. vivax with its Saimiri boliviensis host, we obtained detailed proteomes of infected red blood cells, representing the trophozoite-enriched stage of development. Data from two of three biological replicate proteomes, emphasized here, were analyzed using five search engines, which enhanced identifications and resulted in the most comprehensive P. vivax proteomes to date, with 1375 P. vivax and 3209 S. boliviensis identified proteins. Ribosome subunit proteins were noted for both P. vivax and S. boliviensis, consistent with P. vivax’s known reticulocyte host–cell specificity. A majority of the host and pathogen proteins identified belong to specific functional categories, and several parasite gene families, while 33% of the P. vivax proteins have no reported function. Hemoglobin was significantly oxidized in both proteomes, and additional protein oxidation and nitration was detected in one of the two proteomes. Detailed analyses of these post-translational modifications are presented. The proteins identified here significantly expand the known P. vivax proteome and complexity of available host protein functionality underlying the host–parasite interactive biology, and reveal unsuspected oxidative modifications that may impact protein function. Biological significance Plasmodium vivax malaria is a serious neglected disease, causing an estimated 80 to 300 million cases annually in 95 countries. Infection can result in significant morbidity and possible death. P. vivax, unlike the much better-studied Plasmodium falciparum species, cannot be grown in long-term culture, has a dormant form in the liver called the hypnozoite stage, has a reticulocyte host–cell preference in the blood, and creates caveolae vesicle complexes at the surface of the infected reticulocyte

  12. Structure and function based design of Plasmodium-selective proteasome inhibitors

    PubMed Central

    Li, Hao; O'Donoghue, Anthony J.; van der Linden, Wouter A.; Xie, Stanley C.; Yoo, Euna; Foe, Ian T.; Tilley, Leann; Craik, Charles S.; da Fonseca, Paula C. A.; Bogyo, Matthew

    2016-01-01

    Plasmodium proteasome is a chemically tractable target that could be exploited by next generation anti-malarial agents. PMID:26863983

  13. Structure- and function-based design of Plasmodium-selective proteasome inhibitors.

    PubMed

    Li, Hao; O'Donoghue, Anthony J; van der Linden, Wouter A; Xie, Stanley C; Yoo, Euna; Foe, Ian T; Tilley, Leann; Craik, Charles S; da Fonseca, Paula C A; Bogyo, Matthew

    2016-02-11

    The proteasome is a multi-component protease complex responsible for regulating key processes such as the cell cycle and antigen presentation. Compounds that target the proteasome are potentially valuable tools for the treatment of pathogens that depend on proteasome function for survival and replication. In particular, proteasome inhibitors have been shown to be toxic for the malaria parasite Plasmodium falciparum at all stages of its life cycle. Most compounds that have been tested against the parasite also inhibit the mammalian proteasome, resulting in toxicity that precludes their use as therapeutic agents. Therefore, better definition of the substrate specificity and structural properties of the Plasmodium proteasome could enable the development of compounds with sufficient selectivity to allow their use as anti-malarial agents. To accomplish this goal, here we use a substrate profiling method to uncover differences in the specificities of the human and P. falciparum proteasome. We design inhibitors based on amino-acid preferences specific to the parasite proteasome, and find that they preferentially inhibit the β2-subunit. We determine the structure of the P. falciparum 20S proteasome bound to the inhibitor using cryo-electron microscopy and single-particle analysis, to a resolution of 3.6 Å. These data reveal the unusually open P. falciparum β2 active site and provide valuable information about active-site architecture that can be used to further refine inhibitor design. Furthermore, consistent with the recent finding that the proteasome is important for stress pathways associated with resistance of artemisinin family anti-malarials, we observe growth inhibition synergism with low doses of this β2-selective inhibitor in artemisinin-sensitive and -resistant parasites. Finally, we demonstrate that a parasite-selective inhibitor could be used to attenuate parasite growth in vivo without appreciable toxicity to the host. Thus, the Plasmodium proteasome is a

  14. Structure- and function-based design of Plasmodium-selective proteasome inhibitors.

    PubMed

    Li, Hao; O'Donoghue, Anthony J; van der Linden, Wouter A; Xie, Stanley C; Yoo, Euna; Foe, Ian T; Tilley, Leann; Craik, Charles S; da Fonseca, Paula C A; Bogyo, Matthew

    2016-02-11

    The proteasome is a multi-component protease complex responsible for regulating key processes such as the cell cycle and antigen presentation. Compounds that target the proteasome are potentially valuable tools for the treatment of pathogens that depend on proteasome function for survival and replication. In particular, proteasome inhibitors have been shown to be toxic for the malaria parasite Plasmodium falciparum at all stages of its life cycle. Most compounds that have been tested against the parasite also inhibit the mammalian proteasome, resulting in toxicity that precludes their use as therapeutic agents. Therefore, better definition of the substrate specificity and structural properties of the Plasmodium proteasome could enable the development of compounds with sufficient selectivity to allow their use as anti-malarial agents. To accomplish this goal, here we use a substrate profiling method to uncover differences in the specificities of the human and P. falciparum proteasome. We design inhibitors based on amino-acid preferences specific to the parasite proteasome, and find that they preferentially inhibit the β2-subunit. We determine the structure of the P. falciparum 20S proteasome bound to the inhibitor using cryo-electron microscopy and single-particle analysis, to a resolution of 3.6 Å. These data reveal the unusually open P. falciparum β2 active site and provide valuable information about active-site architecture that can be used to further refine inhibitor design. Furthermore, consistent with the recent finding that the proteasome is important for stress pathways associated with resistance of artemisinin family anti-malarials, we observe growth inhibition synergism with low doses of this β2-selective inhibitor in artemisinin-sensitive and -resistant parasites. Finally, we demonstrate that a parasite-selective inhibitor could be used to attenuate parasite growth in vivo without appreciable toxicity to the host. Thus, the Plasmodium proteasome is a

  15. Implications of Glutathione Levels in the Plasmodium berghei Response to Chloroquine and Artemisinin

    PubMed Central

    Vega-Rodríguez, Joel; Pastrana-Mena, Rebecca; Crespo-Lladó, Keila N.; Ortiz, José G.; Ferrer-Rodríguez, Iván; Serrano, Adelfa E.

    2015-01-01

    Malaria is one of the most devastating parasitic diseases worldwide. Plasmodium drug resistance remains a major challenge to malaria control and has led to the re-emergence of the disease. Chloroquine (CQ) and artemisinin (ART) are thought to exert their anti-malarial activity inducing cytotoxicity in the parasite by blocking heme degradation (for CQ) and increasing oxidative stress. Besides the contribution of the CQ resistance transporter (PfCRT) and the multidrug resistant gene (pfmdr), CQ resistance has also been associated with increased parasite glutathione (GSH) levels. ART resistance was recently shown to be associated with mutations in the K13-propeller protein. To analyze the role of GSH levels in CQ and ART resistance, we generated transgenic Plasmodium berghei parasites either deficient in or overexpressing the gamma-glutamylcysteine synthetase gene (pbggcs) encoding the rate-limiting enzyme in GSH biosynthesis. These lines produce either lower (pbggcs-ko) or higher (pbggcs-oe) levels of GSH than wild type parasites. In addition, GSH levels were determined in P. berghei parasites resistant to CQ and mefloquine (MQ). Increased GSH levels were detected in both, CQ and MQ resistant parasites, when compared to the parental sensitive clone. Sensitivity to CQ and ART remained unaltered in both pgggcs-ko and pbggcs-oe parasites when tested in a 4 days drug suppressive assay. However, recrudescence assays after the parasites have been exposed to a sub-lethal dose of ART showed that parasites with low levels of GSH are more sensitive to ART treatment. These results suggest that GSH levels influence Plasmodium berghei response to ART treatment. PMID:26010448

  16. The redox systems of Plasmodium falciparum and Plasmodium vivax: comparison, in silico analyses and inhibitor studies.

    PubMed

    Mohring, F; Pretzel, J; Jortzik, E; Becker, K

    2014-01-01

    Plasmodium falciparum is responsible for the most severe form of human malaria. P. vivax, in contrast, is the most widespread malaria parasite with an enormous impact on health and economy, since the infection is characterized by high rates of relapses. Due to the mild course of malaria tertiana and complicated in vitro culturing conditions of P. vivax, most of the research on malaria parasites has focused on P. falciparum so far. The redox metabolism of P. falciparum is a promising target for novel antimalarial drugs, since maintaining a redox equilibrium is of fundamental importance for the parasite. P. falciparum contains a cytosolic glutathione and thioredoxin system, as well as redox systems in the apicoplast and the mitochondrion. In contrast to P. falciparum, little is known about the redox processes in P. vivax so far. This review summarizes the current knowledge of the redox metabolism in malaria parasites and provides a detailed in silico comparison of the known and mostly well characterized redox enzymes from P. falciparum and the largely unknown redox proteins from P. vivax. Known antimalarials at least partially mediating their antiparasitic activity by influencing the redox balance of Plasmodium, including dehydroepiandrosterone, Mannich bases, methylene blue, and naphthoquinones, are discussed. Furthermore, we present novel inhibitors identified via screening of a compound library from the Leibniz Institute for Natural Product Research and Infection Biology, Jena that are active against the redox-related enzymes thioredoxin reductase, glutathione reductase, glutathione-S-transferase, and glucose-6-phosphate dehydrogenase 6- phosphoglucono- lactonase from P. falciparum.

  17. Induction of gene amplification in Plasmodium falciparum

    SciTech Connect

    Rogers, P.L.

    1985-01-01

    Human erythrocytic in vitro cultures of Honduras I strain of the malaria parasite Plasmodium falciparum have been stressed stepwise with increasing concentrations of methotrexate (MTX), a folate antagonist. This selection has produced a strain that is 450 times more resistant to the drug than the original culture. Uptake of sublethal doses of radiolabeled MTX by infected red blood cells was 6-36 times greater in the resistant cultures than in the nonresistant controls. DNA isolated from all of the parasites was probed by hybridization with /sup 35/S-labeled DNA derived from a clone of the yeast thymidylate synthetase (TS) gene. This showed 50 to 100 times more increased hybridization of the TS probe to the DNA from the resistant parasites is direct evidence of gene amplification because DHFR and TS are actually one and the same bifunctional enzyme in P. falciparum. Hence, the evidence presented indicates that induced resistance of the malaria parasite to MTX in this case is due to overproduction of DHFR resulting from amplification of the DHFR-TS gene.

  18. Serum protein concentrations in Plasmodium falciparum malaria.

    PubMed

    Graninger, W; Thalhammer, F; Hollenstein, U; Zotter, G M; Kremsner, P G

    1992-12-01

    In patients with uncomplicated Plasmodium falciparum infection cytokine-mediated serum protein levels of C-reactive protein (CRP), coeruloplasmin (COE), beta 2-microglobulin (B2M), alpha 1-acid glycoprotein (AAG), alpha 1-antitrypsin (AAT), haptoglobin (HPT), prealbumin (PRE), retinol binding protein (RBP), albumin (ALB) and transferrin (TRF) were measured in an endemic area of the Amazonian rain forest. Semi-immune (SI) and nonimmune (NI) patients were investigated. In both patient groups the serum concentrations of CRP, COE and B2M were elevated on admission. In addition AAG and AAT concentrations were increased in NI patients compared to control subjects. Significantly lower serum concentrations of HPT, PRE, RBP, ALB and TRF were seen in both patient groups during the acute phase of the disease, and were more pronounced in NI patients. After a 28-day follow-up, AAT and B2M were normal in SI patients but HPT, AAT and B2M were still significantly altered in NI patients.

  19. Risk factors for UK Plasmodium falciparum cases

    PubMed Central

    2014-01-01

    Background An increasing proportion of malaria cases diagnosed in UK residents with a history of travel to malaria endemic areas are due to Plasmodium falciparum. Methods In order to identify travellers at most risk of acquiring malaria a proportional hazards model was used to estimate the risk of acquiring malaria stratified by purpose of travel and age whilst adjusting for entomological inoculation rate (EIR) and duration of stay in endemic countries. Results Travellers visiting friends and relatives and business travellers were found to have significantly higher hazard of acquiring malaria (adjusted hazard ratio (HR) relative to that of holiday makers 7.4, 95% CI 6.4–8.5, p < 0. 0001 and HR 3.4, 95% CI 2.9-3.8, p < 0. 0001, respectively). All age-groups were at lower risk than children aged 0–15 years. Conclusions These estimates of the increased risk for business travellers and those visiting friends and relatives should be used to inform programmes to improve awareness of the risks of malaria when travelling. PMID:25091803

  20. Temperature alters Plasmodium blocking by Wolbachia

    NASA Astrophysics Data System (ADS)

    Murdock, Courtney C.; Blanford, Simon; Hughes, Grant L.; Rasgon, Jason L.; Thomas, Matthew B.

    2014-02-01

    Very recently, the Asian malaria vector (Anopheles stephensi) was stably transinfected with the wAlbB strain of Wolbachia, inducing refractoriness to the human malaria parasite Plasmodium falciparum. However, conditions in the field can differ substantially from those in the laboratory. We use the rodent malaria P. yoelii, and somatically transinfected An. stephensi as a model system to investigate whether the transmission blocking potential of wAlbB is likely to be robust across different thermal environments. wAlbB reduced malaria parasite prevalence and oocyst intensity at 28°C. At 24°C there was no effect on prevalence but a marked increase in oocyst intensity. At 20°C, wAlbB had no effect on prevalence or intensity. Additionally, we identified a novel effect of wAlbB that resulted in reduced sporozoite development across temperatures, counterbalancing the oocyst enhancement at 24°C. Our results demonstrate complex effects of temperature on the Wolbachia-malaria interaction, and suggest the impacts of transinfection might vary across diverse environments.

  1. Malaria, Plasmodium falciparum and its apicoplast.

    PubMed

    Kalanon, Ming; McFadden, Geoffrey I

    2010-06-01

    Malaria, which is caused by species of the parasite genus Plasmodium, remains a major global health problem. A vestigial plastid homologous with the chloroplasts of plants and algae was discovered in malaria and related parasites from the phylum Apicomplexa and has radically changed our view of the evolutionary origins of these disease-causing protists. We now recognize that this large group of parasites had a photosynthetic ancestry and were converted into parasitism early in the evolution of animals. Apicomplexans have probably been parasitizing the animal kingdom for more than 500 million years. The relic plastid persists in most apicomplexans and is an essential component. Perturbation of apicoplast function or inheritance results in parasite death, making the organelle a promising target for chemotherapy. Plastids, including those of malaria parasites, are essentially reduced endosymbiotic bacteria living inside a eukaryotic host. This means that plastids have bacterial-type metabolic pathways and housekeeping processes, all of which are vulnerable to antibacterial compounds. Indeed, many antibacterials kill malaria parasites by blocking essential processes in the plastid. Furthermore, a range of herbicides that target plastid metabolism of undesired plants are also parasiticidal, making them potential new leads for antimalarial drugs. In the present review, we examine the evolutionary origins of the malaria parasite's plastid by endosymbiosis and outline the recent findings on how the organelle imports nuclear-encoded proteins through a set of translocation machineries in the membranes that bound the organelle.

  2. Diagnosis and treatment of Plasmodium vivax malaria.

    PubMed

    Baird, Kevin J; Maguire, Jason D; Price, Ric N

    2012-01-01

    Infection by Plasmodium vivax poses unique challenges for diagnosis and treatment. Relatively low numbers of parasites in peripheral circulation may be difficult to confirm, and patients infected by dormant liver stages cannot be diagnosed before activation and the ensuing relapse. Radical cure thus requires therapy aimed at both the blood stages of the parasite (blood schizontocidal) and prevention of subsequent relapses (hypnozoitocidal). Chloroquine and primaquine have been the companion therapies of choice for the treatment of vivax malaria since the 1950s. Confirmed resistance to chloroquine occurs in much of the vivax endemic world and demands the investigation of alternative blood schizontocidal companions in radical cure. Such a shift in practice necessitates investigation of the safety and efficacy of primaquine when administered with those therapies, and the toxicity profile of such combination treatments, particularly in patients with glucose-6-phosphate dehydrogenase deficiency. These clinical studies are confounded by the frequency and timing of relapse among strains of P. vivax, and potentially by differing susceptibilities to primaquine. The inability to maintain this parasite in continuous in vitro culture greatly hinders new drug discovery. Development of safe and effective chemotherapies for vivax malaria for the coming decades requires overcoming these challenges. PMID:23199489

  3. Detection of SUMOylation in Plasmodium falciparum.

    PubMed

    Reiter, Katherine H; Matunis, Michael J

    2016-01-01

    Reversible protein modification by small ubiquitin-related modifiers (SUMOs) regulates many cellular processes, including transcription, protein quality control, cell division, and oxidative stress. SUMOylation is therefore essential for normal cell function and represents a potentially valuable target for the development of inhibitors of pathogenic eukaryotic organisms, including the malaria parasite, Plasmodium falciparum (Pf). The specific and essential functions of SUMOylation in Pf, however, remain largely uncharacterized. The further development of antimalarial drugs targeting SUMOylation would benefit significantly from a more detailed understanding of its functions and regulation during the parasite life cycle. The recent development of antibodies specific for Pf SUMO provides a valuable tool to study the functions and regulation of SUMOylation. In preliminary studies, we have used immunoblot analysis to demonstrate that SUMOylation levels vary significantly in parasites during different stages of the red blood cell cycle and also in response to oxidative stress. Owing to the dynamic nature of SUMOylation and to the robust activity of SUMO isopeptidases, analysis of SUMOylation in cultured Pf parasites requires a number of precautions during parasite purification and lysis. Here, we outline methods for preserving SUMO conjugates during isolation of Pf parasites from human red blood cell cultures, and for their detection by immunoblot analysis using PfSUMO-specific antibodies. PMID:27631812

  4. Plasmodium vivax blood-stage dynamics.

    PubMed

    McKenzie, F Ellis; Jeffery, Geoffrey M; Collins, William E

    2002-06-01

    We examine the dynamics of parasitemia and gametocytemia reflected in the preintervention charts of 221 malaria-naive U.S. neurosyphilis patients infected with the St. Elizabeth strain of Plasmodium vivax, for malariatherapy, focusing on the 109 charts for which 15 or more days of patency preceded intervention and daily records encompassed an average 98% of the duration of each infection. Our approximations of merogony cycles (via "local peaks" in parasitemia) seldom fit patterns that correspond to "textbook" tertian brood structures. Peak parasitemia was higher in trophozoite-induced infections than in sporozoite-induced ones. Relative densities of male and female gametocytes appeared to alternate, though without a discernably regular period. Successful transmission to mosquitoes did not depend on detectable gametocytemia or on absence of fever. When gametocytes were detected, transmission success depended on densities of only male gametocytes. Successful feeds occurred on average 4.7 days later in an infection than did failures. Parasitemia was lower in homologous reinfection, gametocytemia lower or absent. PMID:12099421

  5. Plasmodium falciparum Secretome in Erythrocyte and Beyond

    PubMed Central

    Soni, Rani; Sharma, Drista; Bhatt, Tarun K.

    2016-01-01

    Plasmodium falciparum is the causative agent of deadly malaria disease. It is an intracellular eukaryote and completes its multi-stage life cycle spanning the two hosts viz, mosquito and human. In order to habituate within host environment, parasite conform several strategies to evade host immune responses such as surface antigen polymorphism or modulation of host immune system and it is mediated by secretion of proteins from parasite to the host erythrocyte and beyond, collectively known as, malaria secretome. In this review, we will discuss about the deployment of parasitic secretory protein in mechanism implicated for immune evasion, protein trafficking, providing virulence, changing permeability and cyto-adherence of infected erythrocyte. We will be covering the possibilities of developing malaria secretome as a drug/vaccine target. This gathered information will be worthwhile in depicting a well-organized picture for host-pathogen interplay during the malaria infection and may also provide some clues for the development of novel anti-malarial therapies. PMID:26925057

  6. Plasmodium knowlesi: from severe zoonosis to animal model.

    PubMed

    Cox-Singh, Janet; Culleton, Richard

    2015-06-01

    Plasmodium knowlesi malaria is a newly described zoonosis in Southeast Asia. Similarly to Plasmodium falciparum, P. knowlesi can reach high parasitaemia in the human host and both species cause severe and fatal illness. Interpretation of host-parasite interactions in studies of P. knowlesi malaria adds a counterpoint to studies on P. falciparum. However, there is no model system for testing the resulting hypotheses on malaria pathophysiology or for developing new interventions. Plasmodium knowlesi is amenable to genetic manipulation in vitro and several nonhuman primate species are susceptible to experimental infection. Here, we make a case for drawing on P. knowlesi as both a human pathogen and an experimental model to lift the roadblock between malaria research and its translation into human health benefits.

  7. Diagnosis of an imported Plasmodium ovale wallikeri infection in Malaysia.

    PubMed

    Liew, Jonathan Wee Kent; Mahmud, Rohela; Tan, Lian Huat; Lau, Yee Ling

    2016-01-06

    Plasmodium ovale is rare and not exactly known to be autochthonous in Malaysia. There are two distinct forms of the parasite, namely P. ovale curtisi (classic form) and P. ovale wallikeri (variant form). Here, the first sequence confirmed case of an imported P. ovale wallikeri infection in Malaysia is presented. Microscopy found Plasmodium parasites with morphology similar to P. ovale or Plasmodium vivax in the blood films. Further confirmation using polymerase chain reaction (PCR) targeting the small-subunit rRNA gene of the parasite was unsuccessful. Genus-specific PCR was then performed and the product was sequenced and analysed. Sequence analyses confirmed the aetiological agent as P. ovale wallikeri. New species-specific primers (rOVA1v and rOVA2v) were employed and P. ovale wallikeri was finally confirmed. The findings highlight the need to look out for imported malaria infections in Malaysia and the importance of a constantly updated and validated diagnostic technique.

  8. Optimal strategy for controlling the spread of Plasmodium Knowlesi malaria: Treatment and culling

    NASA Astrophysics Data System (ADS)

    Abdullahi, Mohammed Baba; Hasan, Yahya Abu; Abdullah, Farah Aini

    2015-05-01

    Plasmodium Knowlesi malaria is a parasitic mosquito-borne disease caused by a eukaryotic protist of genus Plasmodium Knowlesi transmitted by mosquito, Anopheles leucosphyrus to human and macaques. We developed and analyzed a deterministic Mathematical model for the transmission of Plasmodium Knowlesi malaria in human and macaques. The optimal control theory is applied to investigate optimal strategies for controlling the spread of Plasmodium Knowlesi malaria using treatment and culling as control strategies. The conditions for optimal control of the Plasmodium Knowlesi malaria are derived using Pontryagin's Maximum Principle. Finally, numerical simulations suggested that the combination of the control strategies is the best way to control the disease in any community.

  9. 40 CFR 144.33 - Area permits.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 22 2010-07-01 2010-07-01 false Area permits. 144.33 Section 144.33... INJECTION CONTROL PROGRAM Authorization by Permit § 144.33 Area permits. (a) The Director may issue a permit on an area basis, rather than for each well individually, provided that the permit is for...

  10. 40 CFR 144.33 - Area permits.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 23 2011-07-01 2011-07-01 false Area permits. 144.33 Section 144.33... INJECTION CONTROL PROGRAM Authorization by Permit § 144.33 Area permits. (a) The Director may issue a permit on an area basis, rather than for each well individually, provided that the permit is for...

  11. 40 CFR 144.33 - Area permits.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 24 2013-07-01 2013-07-01 false Area permits. 144.33 Section 144.33... INJECTION CONTROL PROGRAM Authorization by Permit § 144.33 Area permits. (a) The Director may issue a permit on an area basis, rather than for each well individually, provided that the permit is for...

  12. 40 CFR 144.33 - Area permits.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 24 2012-07-01 2012-07-01 false Area permits. 144.33 Section 144.33... INJECTION CONTROL PROGRAM Authorization by Permit § 144.33 Area permits. (a) The Director may issue a permit on an area basis, rather than for each well individually, provided that the permit is for...

  13. 40 CFR 70.6 - Permit content.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 15 2010-07-01 2010-07-01 false Permit content. 70.6 Section 70.6 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) STATE OPERATING PERMIT PROGRAMS § 70.6 Permit content. (a) Standard permit requirements. Each permit issued...

  14. 9 CFR 104.2 - Permit authorized.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... permits for importing biological products. They shall be: (1) U.S. Veterinary Biological Product Permit for Research and Evaluation; (2) U.S. Veterinary Biological Product Permit for Distribution and Sale; or (3) U.S. Veterinary Biological Product Permit for Transit Shipment Only. (b) A permit shall not...

  15. 40 CFR 72.85 - Permit reopenings.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... REGULATION Permit Revisions § 72.85 Permit reopenings. (a) The permitting authority shall reopen an Acid Rain permit for cause whenever: (1) Any additional requirement under the Acid Rain Program becomes applicable... revoked to assure compliance with Acid Rain Program requirements. (b) In reopening an Acid Rain permit...

  16. 40 CFR 72.85 - Permit reopenings.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... REGULATION Permit Revisions § 72.85 Permit reopenings. (a) The permitting authority shall reopen an Acid Rain permit for cause whenever: (1) Any additional requirement under the Acid Rain Program becomes applicable... revoked to assure compliance with Acid Rain Program requirements. (b) In reopening an Acid Rain permit...

  17. 40 CFR 72.85 - Permit reopenings.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... REGULATION Permit Revisions § 72.85 Permit reopenings. (a) The permitting authority shall reopen an Acid Rain permit for cause whenever: (1) Any additional requirement under the Acid Rain Program becomes applicable... revoked to assure compliance with Acid Rain Program requirements. (b) In reopening an Acid Rain permit...

  18. 40 CFR 72.85 - Permit reopenings.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... REGULATION Permit Revisions § 72.85 Permit reopenings. (a) The permitting authority shall reopen an Acid Rain permit for cause whenever: (1) Any additional requirement under the Acid Rain Program becomes applicable... revoked to assure compliance with Acid Rain Program requirements. (b) In reopening an Acid Rain permit...

  19. 40 CFR 72.85 - Permit reopenings.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... REGULATION Permit Revisions § 72.85 Permit reopenings. (a) The permitting authority shall reopen an Acid Rain permit for cause whenever: (1) Any additional requirement under the Acid Rain Program becomes applicable... revoked to assure compliance with Acid Rain Program requirements. (b) In reopening an Acid Rain permit...

  20. Selective Killing of the Human Malaria Parasite Plasmodium falciparum by a Benzylthiazolium dye

    PubMed Central

    Kelly, Jane X.; Winter, Rolf W.; Braun, Theodore P.; Osei-Agyemang, Myralyn; Hinrichs, David J.; Riscoe, Michael K.

    2007-01-01

    Malaria is an infectious disease caused by protozoan parasites of the genus Plasmodium. The most virulent form of the disease is caused by P. falciparum which infects hundreds of millions of people and is responsible for the deaths of 1 to 2 million individuals each year. An essential part of the parasitic process is the remodeling of the red blood cell membrane and its protein constituents to permit a higher flux of nutrients and waste products into or away from the intracellular parasite. Much of this increased permeability is due to a single type of broad specificity channel variously called the new permeation pathway (NPP), the nutrient channel, and the Plasmodial surface anion channel (PSAC). This channel is permeable to a range of low molecular weight solutes both charged and uncharged, with a strong preference for anions. Drugs such as furosemide that are known to block anion-selective channels inhibit PSAC. In this study we have investigated a dye known as benzothiocarboxypurine, BCP, which had been studied as a possible diagnostic aid given its selective uptake by P. falciparum infected red cells. We found that the dye enters parasitized red cells via the furosemide-inhibitable PSAC, forms a brightly fluorescent complex with parasite nucleic acids, and is selectively toxic to infected cells. Our study describes an antimalarial agent that exploits the altered permeability of Plasmodium-infected red cells as a means to killing the parasite and highlights a chemical reagent that may prove useful in high throughput screening of compounds for inhibitors of the channel. PMID:17266952

  1. Elution of Re-188 from W-188/Re-188 generators with salts of weak acids permits efficient concentration to low volumes using a new tandem cation/anion exchange system

    SciTech Connect

    Guhlke, S. |; Beets, A.L.; Knapp, F.F. Jr.

    1997-05-01

    Re-188, available from a W-188/Re-188 generator, is an important therapeutic radioisotope for bone pain palliation, cancer therapy and intravascular brachytherapy, etc. Because of the relatively low specific activity of reactor-produced W-188 (ORNL HFIR, 296-370 MBq mCi/mg W-186 for 2 cycles), methods of concentrating the Re-188 bolus (10-12 mL) from clinical scale (18.5-37 BGq W-188) generators (5-6 gm alumina) are thus very important. We demonstrate for the first time a new strategy of generator elution with salts of weak acids and specific perrhenate anion {open_quotes}trapping{close_quotes} with QMA anion columns. Re-188 perrhenate is efficiently eluted (65-75%) from the alumina-based generator with 0.15-0.3 M ammonium acetate. An acetic acid solution of Re-188 perrhenic acid is obtained by subsequent on-line passage of the generator eluant through a DOWEX AG 50Wx8 (200-400 mesh, H{sup +} form) column. Since acetic acid is not ionized (< 0.001%) at this pH (< pK{sub a} = 4.76) the perrhenate anion is then specifically trapped on a QMA {open_quotes}Light{close_quotes} anion extraction column. QMA elution with 0.9% NaCl, provides Re-188 perrhenate solution in <1 mL. Concentration of 10-20 mL of Re-188 solution (> 15 BGq) in <1 mL has been demonstrated using this simple new approach, which is also effective for concentration of Tc-99m from low specific activity Mo-99 (n,y) generators. The cation/anion tandem system is inexpensive and disposable and use can be easily automated. The availability of this very simple, efficient system is important for broad use of rhenium-188.

  2. The National Solar Permitting Database

    2014-08-31

    "The soft costs of solar—costs not associated with hardware—remain stubbornly high. Among the biggest soft costs are those associated with inefficiencies in local permitting and inspection. A study by the National Renewable Energy Laboratory and Lawrence Berkeley National Laboratory estimates that these costs add an average of $0.22/W per residential installation. This project helps reduce non-hardware/balance of system (BOS) costs by creating and maintaining a free and available site of permitting requirements and solar systemmore » verification software that installers can use to reduce time, capital, and resource investments in tracking permitting requirements. Software tools to identify best permitting practices can enable government stakeholders to optimize their permitting process and remove superfluous costs and requirements. Like ""a Wikipedia for solar permitting"", users can add, edit, delete, and update information for a given jurisdiction. We incentivize this crowdsourcing approach by recognizing users for their contributions in the form of SEO benefits to their company or organization by linking back to users' websites."« less

  3. The National Solar Permitting Database

    SciTech Connect

    Gunderson, Renic

    2014-08-31

    "The soft costs of solar—costs not associated with hardware—remain stubbornly high. Among the biggest soft costs are those associated with inefficiencies in local permitting and inspection. A study by the National Renewable Energy Laboratory and Lawrence Berkeley National Laboratory estimates that these costs add an average of $0.22/W per residential installation. This project helps reduce non-hardware/balance of system (BOS) costs by creating and maintaining a free and available site of permitting requirements and solar system verification software that installers can use to reduce time, capital, and resource investments in tracking permitting requirements. Software tools to identify best permitting practices can enable government stakeholders to optimize their permitting process and remove superfluous costs and requirements. Like ""a Wikipedia for solar permitting"", users can add, edit, delete, and update information for a given jurisdiction. We incentivize this crowdsourcing approach by recognizing users for their contributions in the form of SEO benefits to their company or organization by linking back to users' websites."

  4. Identification of Novel Plasmodium falciparum Hexokinase Inhibitors with Antiparasitic Activity.

    PubMed

    Davis, Mindy I; Patrick, Stephen L; Blanding, Walker M; Dwivedi, Varun; Suryadi, Jimmy; Golden, Jennifer E; Coussens, Nathan P; Lee, Olivia W; Shen, Min; Boxer, Matthew B; Hall, Matthew D; Sharlow, Elizabeth R; Drew, Mark E; Morris, James C

    2016-10-01

    Plasmodium falciparum, the deadliest species of malaria parasites, is dependent on glycolysis for the generation of ATP during the pathogenic red blood cell stage. Hexokinase (HK) catalyzes the first step in glycolysis, transferring the γ-phosphoryl group of ATP to glucose to yield glucose-6-phosphate. Here, we describe the validation of a high-throughput assay for screening small-molecule collections to identify inhibitors of the P. falciparum HK (PfHK). The assay, which employed an ADP-Glo reporter system in a 1,536-well-plate format, was robust with a signal-to-background ratio of 3.4 ± 1.2, a coefficient of variation of 6.8% ± 2.9%, and a Z'-factor of 0.75 ± 0.08. Using this assay, we screened 57,654 molecules from multiple small-molecule collections. Confirmed hits were resolved into four clusters on the basis of structural relatedness. Multiple singleton hits were also identified. The most potent inhibitors had 50% inhibitory concentrations as low as ∼1 μM, and several were found to have low-micromolar 50% effective concentrations against asexual intraerythrocytic-stage P. falciparum parasites. These molecules additionally demonstrated limited toxicity against a panel of mammalian cells. The identification of PfHK inhibitors with antiparasitic activity using this validated screening assay is encouraging, as it justifies additional HTS campaigns with more structurally amenable libraries for the identification of potential leads for future therapeutic development. PMID:27458230

  5. Plasmodium vivax Diversity and Population Structure across Four Continents

    PubMed Central

    Koepfli, Cristian; Rodrigues, Priscila T.; Antao, Tiago; Orjuela-Sánchez, Pamela; Van den Eede, Peter; Gamboa, Dionicia; van Hong, Nguyen; Bendezu, Jorge; Erhart, Annette; Barnadas, Céline; Ratsimbasoa, Arsène; Menard, Didier; Severini, Carlo; Menegon, Michela; Nour, Bakri Y. M.; Karunaweera, Nadira; Mueller, Ivo; Ferreira, Marcelo U.; Felger, Ingrid

    2015-01-01

    Plasmodium vivax is the geographically most widespread human malaria parasite. To analyze patterns of microsatellite diversity and population structure across countries of different transmission intensity, genotyping data from 11 microsatellite markers was either generated or compiled from 841 isolates from four continents collected in 1999–2008. Diversity was highest in South-East Asia (mean allelic richness 10.0–12.8), intermediate in the South Pacific (8.1–9.9) Madagascar and Sudan (7.9–8.4), and lowest in South America and Central Asia (5.5–7.2). A reduced panel of only 3 markers was sufficient to identify approx. 90% of all haplotypes in South Pacific, African and SE-Asian populations, but only 60–80% in Latin American populations, suggesting that typing of 2–6 markers, depending on the level of endemicity, is sufficient for epidemiological studies. Clustering analysis showed distinct clusters in Peru and Brazil, but little sub-structuring was observed within Africa, SE-Asia or the South Pacific. Isolates from Uzbekistan were exceptional, as a near-clonal parasite population was observed that was clearly separated from all other populations (FST>0.2). Outside Central Asia FST values were highest (0.11–0.16) between South American and all other populations, and lowest (0.04–0.07) between populations from South-East Asia and the South Pacific. These comparisons between P. vivax populations from four continents indicated that not only transmission intensity, but also geographical isolation affect diversity and population structure. However, the high effective population size results in slow changes of these parameters. This persistency must be taken into account when assessing the impact of control programs on the genetic structure of parasite populations. PMID:26125189

  6. Plasmodium vivax Diversity and Population Structure across Four Continents.

    PubMed

    Koepfli, Cristian; Rodrigues, Priscila T; Antao, Tiago; Orjuela-Sánchez, Pamela; Van den Eede, Peter; Gamboa, Dionicia; van Hong, Nguyen; Bendezu, Jorge; Erhart, Annette; Barnadas, Céline; Ratsimbasoa, Arsène; Menard, Didier; Severini, Carlo; Menegon, Michela; Nour, Bakri Y M; Karunaweera, Nadira; Mueller, Ivo; Ferreira, Marcelo U; Felger, Ingrid

    2015-01-01

    Plasmodium vivax is the geographically most widespread human malaria parasite. To analyze patterns of microsatellite diversity and population structure across countries of different transmission intensity, genotyping data from 11 microsatellite markers was either generated or compiled from 841 isolates from four continents collected in 1999-2008. Diversity was highest in South-East Asia (mean allelic richness 10.0-12.8), intermediate in the South Pacific (8.1-9.9) Madagascar and Sudan (7.9-8.4), and lowest in South America and Central Asia (5.5-7.2). A reduced panel of only 3 markers was sufficient to identify approx. 90% of all haplotypes in South Pacific, African and SE-Asian populations, but only 60-80% in Latin American populations, suggesting that typing of 2-6 markers, depending on the level of endemicity, is sufficient for epidemiological studies. Clustering analysis showed distinct clusters in Peru and Brazil, but little sub-structuring was observed within Africa, SE-Asia or the South Pacific. Isolates from Uzbekistan were exceptional, as a near-clonal parasite population was observed that was clearly separated from all other populations (FST>0.2). Outside Central Asia FST values were highest (0.11-0.16) between South American and all other populations, and lowest (0.04-0.07) between populations from South-East Asia and the South Pacific. These comparisons between P. vivax populations from four continents indicated that not only transmission intensity, but also geographical isolation affect diversity and population structure. However, the high effective population size results in slow changes of these parameters. This persistency must be taken into account when assessing the impact of control programs on the genetic structure of parasite populations.

  7. Backward bifurcation and optimal control of Plasmodium Knowlesi malaria

    NASA Astrophysics Data System (ADS)

    Abdullahi, Mohammed Baba; Hasan, Yahya Abu; Abdullah, Farah Aini

    2014-07-01

    A deterministic model for the transmission dynamics of Plasmodium Knowlesi malaria with direct transmission is developed. The model is analyzed using dynamical system techniques and it shows that the backward bifurcation occurs for some range of parameters. The model is extended to assess the impact of time dependent preventive (biological and chemical control) against the mosquitoes and vaccination for susceptible humans, while treatment for infected humans. The existence of optimal control is established analytically by the use of optimal control theory. Numerical simulations of the problem, suggest that applying the four control measure can effectively reduce if not eliminate the spread of Plasmodium Knowlesi in a community.

  8. Plasmodium knowlesi as a Threat to Global Public Health

    PubMed Central

    Wesolowski, Roland; Wozniak, Alina; Mila-Kierzenkowska, Celestyna; Szewczyk-Golec, Karolina

    2015-01-01

    Malaria is a tropical disease caused by protozoans of the Plasmodium genus. Delayed diagnosis and misdiagnosis are strongly associated with higher mortality. In recent years, a greater importance is attributed to Plasmodium knowlesi, a species found mainly in Southeast Asia. Routine parasitological diagnostics are associated with certain limitations and difficulties in unambiguous determination of the parasite species based only on microscopic image. Recently, molecular techniques have been increasingly used for predictive diagnosis. The aim of the study is to draw attention to the risk of travelling to knowlesi malaria endemic areas and to raise awareness among personnel involved in the therapeutic process. PMID:26537037

  9. Replication and maintenance of the Plasmodium falciparum apicoplast genome.

    PubMed

    Milton, Morgan E; Nelson, Scott W

    2016-08-01

    Members of the phylum Apicomplexa are responsible for many devastating diseases including malaria (Plasmodium spp.), toxoplasmosis (Toxoplasma gondii), babesiosis (Babesia bovis), and cyclosporiasis (Cyclospora cayetanensis). Most Apicomplexans contain a unique and essential organelle called the apicoplast. Derived from an ancient chloroplast, the apicoplast replicates and maintains a 35 kilobase (kb) circular genome. Due to its essential nature within the parasite, drugs targeted to proteins involved in DNA replication and repair of the apicoplast should be potent and specific. This review summarizes the current knowledge surrounding the replication and repair of the Plasmodium falciparum apicoplast genome and identifies several putative proteins involved in replication and repair pathways. PMID:27338018

  10. Plasmodium AdoMetDC/ODC bifunctional enzyme is essential for male sexual stage development and mosquito transmission

    PubMed Central

    Hart, Robert J.; Ghaffar, Atif; Abdalal, Shaymaa; Perrin, Benjamin

    2016-01-01

    ABSTRACT Polyamines are positively-charged organic molecules that are important for cellular growth and division. Polyamines and their synthesizing enzymes are particularly abundant in rapidly proliferating eukaryotic cells such as parasitic protozoa and cancer cells. Polyamine biosynthesis inhibitors, such as Elfornithine, are now being considered for cancer prevention and have been used effectively against Trypanosoma brucei. Inhibitors of polyamine biosynthesis have caused growth arrest of Plasmodium falciparum blood stages in vitro, but in P. berghei only partial inhibition has been observed. While polyamine biosynthesis enzymes are characterized and conserved in Plasmodium spp., little is known on the biological roles of these enzymes inside malaria parasite hosts. The bifunctional polyamine biosynthesis enzyme S-adenosyl methionine decarboxylase/ornithine decarboxylase (AdoMetDC/ODC) was targeted for deletion in P. yoelii. Deletion of AdoMetDC/ODC significantly reduced blood stage parasitemia but Anopheles transmission was completely blocked. We showed that male gametocytogenesis and male gamete exflagellation were abolished and consequently no ookinetes or oocyst sporozoites could be generated from adometdc/odc(–) parasites. Supplementation of putrescine and spermidine did not rescue the defective phenotypes of male gametocytes and gametes of the knockout parasites. These results highlight the crucial role of polyamine homeostasis in the development and functions of Plasmodium erythrocytic stages in the blood and in the mosquito vector and validate polyamine biosynthesis pathway enzymes as drug targeting candidates for malaria parasite transmission blocking. PMID:27387533

  11. Homology modeling and molecular dynamics simulation of N-myristoyltransferase from Plasmodium falciparum: an insight into novel antimalarial drug design.

    PubMed

    Paul, Paulomi; Chowdhury, Abhishek; Das Talukdar, Anupam; Choudhury, Manabendra Dutta

    2015-03-01

    Malaria is an infectious disease caused by parasites of the genus Plasmodium. It leads to approximately 1 million deaths per annum worldwide, with an increase number of 6.27 million deaths in 2012 alone. Validation of new antimalarial targets is very important in the context of the rise in resistance to current drugs. One such putative target is the enzyme N-myristoyltransferase (NMT), which catalyzes the attachment of the fatty acid myristate to protein substrates (N-myristoylation) for activation. Reports suggests that NMT is an essential and chemically docile target in malaria parasites both in vitro and in vivo, and the selective inhibition of N-myristoylation leads to irreversible failure to form an inner membrane complex—an essential subcellular organelle in the parasite life cycle. In this work, we modeled the three-dimensional structure of Plasmodium falciparum NMT (PfNMT) using Modeler 9.0 taking Plasmodium vivax NMT (PvNMT) as the template. The novelty of the work lies in the selection of template as the similarity of PfNMT with PvNMT was 80.47%, whereas earlier similar work showed template similarity with Candida albicans NMT (CaNMT) and Saccharomyces cerevisiae NMT (ScNMT) to be less than 50%. The generated structure was then validated using various programs such as PROCHECK, RAMPAGE server, CHIMERA and the stability of the model was checked by Gromacs 5.0.

  12. Permitting and licensing new uranium recovery facilities

    SciTech Connect

    Rehmann, M.; Sweeney, K.; Pugsley, C.

    2007-07-01

    With the nuclear renaissance, the uranium mining industry has undergone a dramatic renaissance, as well. This was evidenced with the 2006 National Mining Association (NMA)/Nuclear Regulatory Commission (NRC) workshop drawing its largest attendance ever, with more than 180 attendees representing both established, as well as many new junior firms. And the meeting focused, not on site closure - but on the growing industry and plans for permitting new uranium recovery facilities. With this, the program provided overviews of the programs for permitting and licensing new uranium mines, from both the State and Federal perspectives. A subsequent one-day licensing workshop presented in February 2007 by NRC at its headquarters in Rockville, Maryland drew a crowd of experienced and first-time license applicants. Modern uranium mining is both safer and more environmentally protective than past practices - due largely to the industry's maturing and continuous efforts to improve. This paper will look at the new generation of uranium mining and recovery facilities that are developing in the US, and focus primarily on US permitting and licensing requirements and trends. Understanding these trends is essential to ensuring a vibrant US uranium recovery industry; assured supplies of this important fuel for our energy and the US economy; and environmental protection. (authors)

  13. 40 CFR 72.62 - Draft permit.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... REGULATION Federal Acid Rain Permit Issuance Procedures § 72.62 Draft permit. (a) After the Administrator receives a complete Acid Rain permit application and any supplemental information, the Administrator...

  14. 40 CFR 72.62 - Draft permit.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... REGULATION Federal Acid Rain Permit Issuance Procedures § 72.62 Draft permit. (a) After the Administrator receives a complete Acid Rain permit application and any supplemental information, the Administrator...

  15. 40 CFR 72.62 - Draft permit.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... REGULATION Federal Acid Rain Permit Issuance Procedures § 72.62 Draft permit. (a) After the Administrator receives a complete Acid Rain permit application and any supplemental information, the Administrator...

  16. 40 CFR 72.62 - Draft permit.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... REGULATION Federal Acid Rain Permit Issuance Procedures § 72.62 Draft permit. (a) After the Administrator receives a complete Acid Rain permit application and any supplemental information, the Administrator...

  17. 40 CFR 72.62 - Draft permit.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... REGULATION Federal Acid Rain Permit Issuance Procedures § 72.62 Draft permit. (a) After the Administrator receives a complete Acid Rain permit application and any supplemental information, the Administrator...

  18. Plasmodium falciparum centromeres display a unique epigenetic makeup and cluster prior to and during schizogony.

    PubMed

    Hoeijmakers, Wieteke A M; Flueck, Christian; Françoijs, Kees-Jan; Smits, Arne H; Wetzel, Johanna; Volz, Jennifer C; Cowman, Alan F; Voss, Till; Stunnenberg, Hendrik G; Bártfai, Richárd

    2012-09-01

    Centromeres are essential for the faithful transmission of chromosomes to the next generation, therefore being essential in all eukaryotic organisms. The centromeres of Plasmodium falciparum, the causative agent of the most severe form of malaria, have been broadly mapped on most chromosomes, but their epigenetic composition remained undefined. Here, we reveal that the centromeric histone variant PfCENH3 occupies a 4-4.5 kb region on each P. falciparum chromosome, which is devoid of pericentric heterochromatin but harbours another histone variant, PfH2A.Z. These CENH3 covered regions pinpoint the exact position of the centromere on all chromosomes and revealed that all centromeric regions have similar size and sequence composition. Immunofluorescence assay of PfCENH3 strongly suggests that P. falciparum centromeres cluster to a single nuclear location prior to and during mitosis and cytokinesis but dissociate soon after invasion. In summary, we reveal a dynamic association of Plasmodium centromeres, which bear a unique epigenetic signature and conform to a strict structure. These findings suggest that DNA-associated and epigenetic elements play an important role in centromere establishment in this important human pathogen.

  19. New insights into the Plasmodium vivax transcriptome using RNA-Seq.

    PubMed

    Zhu, Lei; Mok, Sachel; Imwong, Mallika; Jaidee, Anchalee; Russell, Bruce; Nosten, Francois; Day, Nicholas P; White, Nicholas J; Preiser, Peter R; Bozdech, Zbynek

    2016-01-01

    Historically seen as a benign disease, it is now becoming clear that Plasmodium vivax can cause significant morbidity. Effective control strategies targeting P. vivax malaria is hindered by our limited understanding of vivax biology. Here we established the P. vivax transcriptome of the Intraerythrocytic Developmental Cycle (IDC) of two clinical isolates in high resolution by Illumina HiSeq platform. The detailed map of transcriptome generates new insights into regulatory mechanisms of individual genes and reveals their intimate relationship with specific biological functions. A transcriptional hotspot of vir genes observed on chromosome 2 suggests a potential active site modulating immune evasion of the Plasmodium parasite across patients. Compared to other eukaryotes, P. vivax genes tend to have unusually long 5' untranslated regions and also present multiple transcription start sites. In contrast, alternative splicing is rare in P. vivax but its association with the late schizont stage suggests some of its significance for gene function. The newly identified transcripts, including up to 179 vir like genes and 3018 noncoding RNAs suggest an important role of these gene/transcript classes in strain specific transcriptional regulation.

  20. An FtsH protease is recruited to the mitochondrion of Plasmodium falciparum.

    PubMed

    Tanveer, Aiman; Allen, Stacey M; Jackson, Katherine E; Charan, Manish; Ralph, Stuart A; Habib, Saman

    2013-01-01

    The two organelles, apicoplast and mitochondrion, of the malaria parasite Plasmodium falciparum have unique morphology in liver and blood stages; they undergo complex branching and looping prior to division and segregation into daughter merozoites. Little is known about the molecular processes and proteins involved in organelle biogenesis in the parasite. We report the identification of an AAA+/FtsH protease homolog (PfFtsH1) that exhibits ATP- and Zn(2+)-dependent protease activity. PfFtsH1 undergoes processing, forms oligomeric assemblies, and is associated with the membrane fraction of the parasite cell. Generation of a transfectant parasite line with hemagglutinin-tagged PfFtsH1, and immunofluorescence assay with anti-PfFtsH1 Ab demonstrated that the protein localises to P. falciparum mitochondria. Phylogenetic analysis and the single transmembrane region identifiable in PfFtsH1 suggest that it is an i-AAA like inner mitochondrial membrane protein. Expression of PfFtsH1 in Escherichia coli converted a fraction of bacterial cells into division-defective filamentous forms implying a sequestering effect of the Plasmodium factor on the bacterial homolog, indicative of functional conservation with EcFtsH. These results identify a membrane-associated mitochondrial AAA+/FtsH protease as a candidate regulatory protein for organelle biogenesis in P. falciparum.

  1. Artesunate Tolerance in Transgenic Plasmodium falciparum Parasites Overexpressing a Tryptophan-Rich Protein▿†

    PubMed Central

    Deplaine, Guillaume; Lavazec, Catherine; Bischoff, Emmanuel; Natalang, Onguma; Perrot, Sylvie; Guillotte-Blisnick, Micheline; Coppée, Jean-Yves; Pradines, Bruno; Mercereau-Puijalon, Odile; David, Peter H.

    2011-01-01

    Due to their rapid, potent action on young and mature intraerythrocytic stages, artemisinin derivatives are central to drug combination therapies for Plasmodium falciparum malaria. However, the evidence for emerging parasite resistance/tolerance to artemisinins in southeast Asia is of great concern. A better understanding of artemisinin-related drug activity and resistance mechanisms is urgently needed. A recent transcriptome study of parasites exposed to artesunate led us to identify a series of genes with modified levels of expression in the presence of the drug. The gene presenting the largest mRNA level increase, Pf10_0026 (PArt), encoding a hypothetical protein of unknown function, was chosen for further study. Immunodetection with PArt-specific sera showed that artesunate induced a dose-dependent increase of the protein level. Bioinformatic analysis showed that PArt belongs to a Plasmodium-specific gene family characterized by the presence of a tryptophan-rich domain with a novel hidden Markov model (HMM) profile. Gene disruption could not be achieved, suggesting an essential function. Transgenic parasites overexpressing PArt protein were generated and exhibited tolerance to a spike exposure to high doses of artesunate, with increased survival and reduced growth retardation compared to that of wild-type-treated controls. These data indicate the involvement of PArt in parasite defense mechanisms against artesunate. This is the first report of genetically manipulated parasites displaying a stable and reproducible decreased susceptibility to artesunate, providing new possibilities to investigate the parasite response to artemisinins. PMID:21464256

  2. PlasmoView: a web-based resource to visualise global Plasmodium falciparum genomic variation.

    PubMed

    Preston, Mark D; Assefa, Samuel A; Ocholla, Harold; Sutherland, Colin J; Borrmann, Steffen; Nzila, Alexis; Michon, Pascal; Hien, Tran Tinh; Bousema, Teun; Drakeley, Christopher J; Zongo, Issaka; Ouédraogo, Jean-Bosco; Djimde, Abdoulaye A; Doumbo, Ogobara K; Nosten, Francois; Fairhurst, Rick M; Conway, David J; Roper, Cally; Clark, Taane G

    2014-06-01

    Malaria is a global public health challenge, with drug resistance a major barrier to disease control and elimination. To meet the urgent need for better treatments and vaccines, a deeper knowledge of Plasmodium biology and malaria epidemiology is required. An improved understanding of the genomic variation of malaria parasites, especially the most virulent Plasmodium falciparum (Pf) species, has the potential to yield new insights in these areas. High-throughput sequencing and genotyping is generating large amounts of genomic data across multiple parasite populations. The resulting ability to identify informative variants, particularly single-nucleotide polymorphisms (SNPs), will lead to the discovery of intra- and inter-population differences and thus enable the development of genetic barcodes for diagnostic assays and clinical studies. Knowledge of genetic variability underlying drug resistance and other differential phenotypes will also facilitate the identification of novel mutations and contribute to surveillance and stratified medicine applications. The PlasmoView interactive web-browsing tool enables the research community to visualise genomic variation and annotation (eg, biological function) in a geographic setting. The first release contains over 600,000 high-quality SNPs in 631 Pf isolates from laboratory strains and four malaria-endemic regions (West Africa, East Africa, Southeast Asia and Oceania). PMID:24338354

  3. PlasmoView: A Web-based Resource to Visualise Global Plasmodium falciparum Genomic Variation

    PubMed Central

    Preston, Mark D.; Assefa, Samuel A.; Ocholla, Harold; Sutherland, Colin J.; Borrmann, Steffen; Nzila, Alexis; Michon, Pascal; Hien, Tran Tinh; Bousema, Teun; Drakeley, Christopher J.; Zongo, Issaka; Ouédraogo, Jean-Bosco; Djimde, Abdoulaye A.; Doumbo, Ogobara K.; Nosten, Francois; Fairhurst, Rick M.; Conway, David J.; Roper, Cally; Clark, Taane G.

    2014-01-01

    Malaria is a global public health challenge, with drug resistance a major barrier to disease control and elimination. To meet the urgent need for better treatments and vaccines, a deeper knowledge of Plasmodium biology and malaria epidemiology is required. An improved understanding of the genomic variation of malaria parasites, especially the most virulent Plasmodium falciparum (Pf) species, has the potential to yield new insights in these areas. High-throughput sequencing and genotyping is generating large amounts of genomic data across multiple parasite populations. The resulting ability to identify informative variants, particularly single-nucleotide polymorphisms (SNPs), will lead to the discovery of intra- and inter-population differences and thus enable the development of genetic barcodes for diagnostic assays and clinical studies. Knowledge of genetic variability underlying drug resistance and other differential phenotypes will also facilitate the identification of novel mutations and contribute to surveillance and stratified medicine applications. The PlasmoView interactive web-browsing tool enables the research community to visualise genomic variation and annotation (eg, biological function) in a geographic setting. The first release contains over 600 000 high-quality SNPs in 631 Pf isolates from laboratory strains and four malaria-endemic regions (West Africa, East Africa, Southeast Asia and Oceania). PMID:24338354

  4. Conditional Degradation of Plasmodium Calcineurin Reveals Functions in Parasite Colonization of both Host and Vector

    PubMed Central

    Philip, Nisha; Waters, Andrew P.

    2015-01-01

    Summary Functional analysis of essential genes in the malarial parasite, Plasmodium, is hindered by lack of efficient strategies for conditional protein regulation. We report the development of a rapid, specific, and inducible chemical-genetic tool in the rodent malaria parasite, P. berghei, in which endogenous proteins engineered to contain the auxin-inducible degron (AID) are selectively degraded upon adding auxin. Application of AID to the calcium-regulated protein phosphatase, calcineurin, revealed functions in host and vector stages of parasite development. Whereas depletion of calcineurin in late-stage schizonts demonstrated its critical role in erythrocyte attachment and invasion in vivo, stage-specific depletion uncovered roles in gamete development, fertilization, and ookinete-to-oocyst and sporozoite-to-liver stage transitions. Furthermore, AID technology facilitated concurrent generation and phenotyping of transgenic lines, allowing multiple lines to be assessed simultaneously with significant reductions in animal use. This study highlights the broad applicability of AID for functional analysis of proteins across the Plasmodium life cycle. PMID:26118994

  5. Topology and replication of a nuclear episomal plasmid in the rodent malaria Plasmodium berghei

    PubMed Central

    Williamson, Donald H.; Janse, Chris J.; Moore, Peter W.; Waters, Andrew P.; Preiser, Peter R.

    2002-01-01

    The rodent malaria Plasmodium berghei is one of a small number of species of Plasmodium that can currently be genetically transformed through experimentally controlled uptake of exogenous DNA by bloodstage parasites. Circular DNA containing a selectable marker replicates and is maintained under selection pressure in a randomly segregating episomal form during the first weeks after transformation. In this study, using pulsed field gel electrophoresis and ionising radiation, we show that in dividing asexual blood stage parasites the episomes are completely converted, within 2 weeks post-infection, into non-rearranged circular concatamers ranging in size between about 9 and 15 copies of the monomer. These occur as slow-moving aggregates held together by radiation-sensitive linkers consisting partly of single-stranded DNA. The process generating these complexes is not clear but 2D gel analysis showed that Cairns-type replication origins were absent and it seems most likely that the initial concatamerisation takes place using a rolling circle mechanism followed by circularisation through internal recombination. We propose a model in which continued rolling circle replication of the large circular concatamers and the recombinational activity of the tails of the rolling circles could lead to the formation of the large aggregates. PMID:11809885

  6. In Silico Screening on the Three-dimensional Model of the Plasmodium vivax SUB1 Protease Leads to the Validation of a Novel Anti-parasite Compound*

    PubMed Central

    Bouillon, Anthony; Giganti, David; Benedet, Christophe; Gorgette, Olivier; Pêtres, Stéphane; Crublet, Elodie; Girard-Blanc, Christine; Witkowski, Benoit; Ménard, Didier; Nilges, Michael; Mercereau-Puijalon, Odile; Stoven, Véronique; Barale, Jean-Christophe

    2013-01-01

    Widespread drug resistance calls for the urgent development of new antimalarials that target novel steps in the life cycle of Plasmodium falciparum and Plasmodium vivax. The essential subtilisin-like serine protease SUB1 of Plasmodium merozoites plays a dual role in egress from and invasion into host erythrocytes. It belongs to a new generation of attractive drug targets against which specific potent inhibitors are actively searched. We characterize here the P. vivax SUB1 enzyme and show that it displays a typical auto-processing pattern and apical localization in P. vivax merozoites. To search for small PvSUB1 inhibitors, we took advantage of the similarity of SUB1 with bacterial subtilisins and generated P. vivax SUB1 three-dimensional models. The structure-based virtual screening of a large commercial chemical compounds library identified 306 virtual best hits, of which 37 were experimentally confirmed inhibitors and 5 had Ki values of <50 μm for PvSUB1. Interestingly, they belong to different chemical families. The most promising competitive inhibitor of PvSUB1 (compound 2) was equally active on PfSUB1 and displayed anti-P. falciparum and Plasmodium berghei activity in vitro and in vivo, respectively. Compound 2 inhibited the endogenous PfSUB1 as illustrated by the inhibited maturation of its natural substrate PfSERA5 and inhibited parasite egress and subsequent erythrocyte invasion. These data indicate that the strategy of in silico screening of three-dimensional models to select for virtual inhibitors combined with stringent biological validation successfully identified several inhibitors of the PvSUB1 enzyme. The most promising hit proved to be a potent cross-inhibitor of PlasmodiumSUB1, laying the groundwork for the development of a globally active small compound antimalarial. PMID:23653352

  7. The Dynamics of Natural Plasmodium falciparum Infections

    PubMed Central

    Felger, Ingrid; Maire, Martin; Bretscher, Michael T.; Falk, Nicole; Tiaden, André; Sama, Wilson; Beck, Hans-Peter; Owusu-Agyei, Seth; Smith, Thomas A.

    2012-01-01

    Background Natural immunity to Plasmodium falciparum has been widely studied, but its effects on parasite dynamics are poorly understood. Acquisition and clearance rates of untreated infections are key elements of the dynamics of malaria, but estimating these parameters is challenging because of frequent super-infection and imperfect detectability of parasites. Consequently, information on effects of host immune status or age on infection dynamics is fragmentary. Methods An age-stratified cohort of 347 individuals from Northern Ghana was sampled six times at 2 month intervals. High-throughput capillary electrophoresis was used to genotype the msp-2 locus of all P. falciparum infections detected by PCR. Force of infection (FOI) and duration were estimated for each age group using an immigration-death model that allows for imperfect detection of circulating parasites. Results Allowing for imperfect detection substantially increased estimates of FOI and duration. Effects of naturally acquired immunity on the FOI and duration would be reflected in age dependence in these indices, but in our cohort data FOI tended to increase with age in children. Persistence of individual parasite clones was characteristic of all age-groups. Duration peaked in 5–9 year old children (average duration 319 days, 95% confidence interval 318;320). Conclusions The main age-dependence is on parasite densities, with only small age-variations in the FOI and persistence of infections. This supports the hypothesis that acquired immunity controls transmission mainly by limiting blood-stage parasite densities rather than changing rates of acquisition or clearance of infections. PMID:23029082

  8. Discovery of Novel and Ligand-Efficient Inhibitors of Plasmodium falciparum and Plasmodium vivaxN-Myristoyltransferase

    PubMed Central

    2012-01-01

    N-Myristoyltransferase (NMT) is an attractive antiprotozoan drug target. A lead-hopping approach was utilized in the design and synthesis of novel benzo[b]thiophene-containing inhibitors of Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) NMT. These inhibitors are selective against Homo sapiens NMT1 (HsNMT), have excellent ligand efficiency (LE), and display antiparasitic activity in vitro. The binding mode of this series was determined by crystallography and shows a novel binding mode for the benzothiophene ring. PMID:23170970

  9. 40 CFR 52.1233 - Operating permits.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ...) APPROVAL AND PROMULGATION OF IMPLEMENTATION PLANS (CONTINUED) Minnesota § 52.1233 Operating permits. (a) Emission limitations and related provisions which are established in Minnesota permits as...

  10. 40 CFR 52.1233 - Operating permits.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ...) APPROVAL AND PROMULGATION OF IMPLEMENTATION PLANS (CONTINUED) Minnesota § 52.1233 Operating permits. (a) Emission limitations and related provisions which are established in Minnesota permits as...

  11. Plasmodium falciparum and Plasmodium vivax specific lactate dehydrogenase: genetic polymorphism study from Indian isolates.

    PubMed

    Keluskar, Priyadarshan; Singh, Vineeta; Gupta, Purva; Ingle, Sanjay

    2014-08-01

    Control and eradication of malaria is hindered by the acquisition of drug resistance by Plasmodium species. This has necessitated a persistent search for novel drugs and more efficient targets. Plasmodium species specific lactate dehydrogenase is one of the potential therapeutic and diagnostic targets, because of its indispensable role in endoerythrocytic stage of the parasite. A target molecule that is highly conserved in the parasite population can be more effectively used in diagnostics and therapeutics, hence, in the present study polymorphism in PfLDH (Plasmodiumfalciparum specific LDH) and PvLDH (Plasmodiumvivax specific LDH) genes was analyzed using PCR-single strand confirmation polymorphism (PCR-SSCP) and sequencing. Forty-six P. falciparum and thirty-five P. vivax samples were screened from different states of India. Our findings have revealed presence of a single PfLDH genotype and six PvLDH genotypes among the studied samples. Interestingly, along with synonymous substitutions, nonsynonymous substitutions were reported to be present for the first time in the PvLDH genotypes. Further, through amino acid sequence alignment and homology modeling studies we observed that the catalytic residues were conserved in all PvLDH genotypes and the nonsynonymous substitutions have not altered the enzyme structure significantly. Evolutionary genetics studies have confirmed that PfLDH and PvLDH loci are under strong purifying selection. Phylogenetic analysis of the pLDH gene sequences revealed that P. falciparum compared to P. vivax, has recent origin. The study therefore supports PfLDH and PvLDH as suitable therapeutic and diagnostic targets as well as phylogenetic markers to understand the genealogy of malaria species.

  12. Genetic structure of Plasmodium vivax and Plasmodium falciparum in the Bannu district of Pakistan

    PubMed Central

    2010-01-01

    Background Plasmodium vivax and Plasmodium falciparum are the major causative agents of malaria. While knowledge of the genetic structure of malaria parasites is useful for understanding the evolution of parasite virulence, designing anti-malarial vaccines and assessing the impact of malaria control measures, there is a paucity of information on genetic diversity of these two malaria parasites in Pakistan. This study sought to shed some light on the genetic structure of P. vivax and P. falciparum in this understudied region. Methods The genetic diversities of P. vivax and P. falciparum populations from the densely populated, malaria-endemic Bannu district of Pakistan were evaluated by analysis of their merozoite surface protein (msp) genes by PCR-RFLP. Specifically, the Pvmsp-3α and Pvmsp-3β genes of P. vivax and the Pfmsp-1 and Pfmsp-2 genes of P. falciparum were analysed. Results In P. vivax, genotyping of Pvmsp-3α and Pvmsp-3β genes showed a high level of diversity at these loci. Four distinct allele groups: A (1.9 kb), B (1.5 kb), C (1.2 kb), and D (0.3 kb) were detected for Pvmsp-3α, type A being the most prevalent (82%). Conversely, amplification of the P. vivax msp-3β locus produced two allele groups: A (1.7-2.2 kb, 62%) and B (1.4-1.5 kb, 33%), with 5% mixed-strain infections. Restriction analysis of Pvmsp-3α and Pvmsp-3β yielded 12 and 8 distinct alleles, respectively, with a combined mixed genotype prevalence of 20%. In P. falciparum, all three known genotypes of Pfmsp-1 and two of Pfmsp-2 were observed, with MAD20 occurring in 67% and 3D7/IC in 65% of the isolates, respectively. Overall, 24% P. falciparum samples exhibited mixed-strain infections. Conclusion These results indicate that both P. vivax and P. falciparum populations in Pakistan are highly diverse. PMID:20416089

  13. In vitro activity of pyronaridine against multidrug-resistant Plasmodium falciparum and Plasmodium vivax.

    PubMed

    Price, R N; Marfurt, J; Chalfein, F; Kenangalem, E; Piera, K A; Tjitra, E; Anstey, N M; Russell, B

    2010-12-01

    Pyronaridine, a Mannich base antimalarial, has demonstrated high in vivo and in vitro efficacy against chloroquine-resistant Plasmodium falciparum. Although this drug has the potential to become a prominent artemisinin combination therapy, little is known about its efficacy against drug-resistant Plasmodium vivax. The in vitro antimalarial susceptibility of pyronaridine was assessed in multidrug-resistant P. vivax (n = 99) and P. falciparum (n = 90) isolates from Papua, Indonesia, using a schizont maturation assay. The median 50% inhibitory concentration (IC(50)) of pyronaridine was 1.92 nM (range, 0.24 to 13.8 nM) against P. falciparum and 2.58 nM (range, 0.13 to 43.6 nM) against P. vivax, with in vitro susceptibility correlating significantly with chloroquine, amodiaquine, and piperaquine (r(s) [Spearman's rank correlation coefficient] = 0.45 to 0.62; P < 0.001). P. falciparum parasites initially at trophozoite stage had higher IC(50)s of pyronaridine than those exposed at the ring stage (8.9 nM [range, 0.6 to 8.9 nM] versus 1.6 nM [range, 0.6 to 8.9 nM], respectively; P = 0.015), although this did not reach significance for P. vivax (4.7 nM [range, 1.4 to 18.7 nM] versus 2.5 nM [range, 1.4 to 15.6 nM], respectively; P = 0.085). The excellent in vitro efficacy of pyronaridine against both chloroquine-resistant P. vivax and P. falciparum highlights the suitability of the drug as a novel partner for artemisinin-based combination therapy in regions where the two species are coendemic.

  14. Malaria morbidity in Papua Indonesia, an area with multidrug resistant Plasmodium vivax and Plasmodium falciparum

    PubMed Central

    Karyana, Muhammad; Burdarm, Lenny; Yeung, Shunmay; Kenangalem, Enny; Wariker, Noah; Maristela, Rilia; Umana, Ketut Gde; Vemuri, Ram; Okoseray, Maurits J; Penttinen, Pasi M; Ebsworth, Peter; Sugiarto, Paulus; Anstey, Nicholas M; Tjitra, Emiliana; Price, Richard N

    2008-01-01

    Background Multidrug resistance has emerged to both Plasmodium vivax and Plasmodium falciparum and yet the comparative epidemiology of these infections is poorly defined. Methods All laboratory-confirmed episodes of malaria in Timika, Papua, Indonesia, presenting to community primary care clinics and an inpatient facility were reviewed over a two-year period. In addition information was gathered from a house-to-house survey to quantify the prevalence of malaria and treatment-seeking behaviour of people with fever. Results Between January 2004 and December 2005, 99,158 laboratory-confirmed episodes of malaria were reported, of which 58% (57,938) were attributable to P. falciparum and 37% (36,471) to P. vivax. Malaria was most likely to be attributable to pure P. vivax in children under one year of age (55% 2,684/4,889). In the household survey, the prevalence of asexual parasitaemia was 7.5% (290/3,890) for P. falciparum and 6.4% (248/3,890) for P. vivax. The prevalence of P. falciparum infection peaked in young adults aged 15–25 years (9.8% 69/707), compared to P. vivax infection which peaked in children aged 1 to 4 years (9.5% 61/642). Overall 35% (1,813/5,255) of people questioned reported a febrile episode in the preceding month. Of the 60% of people who were estimated to have had malaria, only 39% would have been detected by the surveillance network. The overall incidence of malaria was therefore estimated as 876 per 1,000 per year (Range: 711–906). Conclusion In this region of multidrug-resistant P. vivax and P. falciparum, both species are associated with substantial morbidity, but with significant differences in the age-related risk of infection. PMID:18673572

  15. Plasmodium falciparum and Plasmodium vivax specific lactate dehydrogenase: genetic polymorphism study from Indian isolates.

    PubMed

    Keluskar, Priyadarshan; Singh, Vineeta; Gupta, Purva; Ingle, Sanjay

    2014-08-01

    Control and eradication of malaria is hindered by the acquisition of drug resistance by Plasmodium species. This has necessitated a persistent search for novel drugs and more efficient targets. Plasmodium species specific lactate dehydrogenase is one of the potential therapeutic and diagnostic targets, because of its indispensable role in endoerythrocytic stage of the parasite. A target molecule that is highly conserved in the parasite population can be more effectively used in diagnostics and therapeutics, hence, in the present study polymorphism in PfLDH (Plasmodiumfalciparum specific LDH) and PvLDH (Plasmodiumvivax specific LDH) genes was analyzed using PCR-single strand confirmation polymorphism (PCR-SSCP) and sequencing. Forty-six P. falciparum and thirty-five P. vivax samples were screened from different states of India. Our findings have revealed presence of a single PfLDH genotype and six PvLDH genotypes among the studied samples. Interestingly, along with synonymous substitutions, nonsynonymous substitutions were reported to be present for the first time in the PvLDH genotypes. Further, through amino acid sequence alignment and homology modeling studies we observed that the catalytic residues were conserved in all PvLDH genotypes and the nonsynonymous substitutions have not altered the enzyme structure significantly. Evolutionary genetics studies have confirmed that PfLDH and PvLDH loci are under strong purifying selection. Phylogenetic analysis of the pLDH gene sequences revealed that P. falciparum compared to P. vivax, has recent origin. The study therefore supports PfLDH and PvLDH as suitable therapeutic and diagnostic targets as well as phylogenetic markers to understand the genealogy of malaria species. PMID:24953504

  16. Origin of the human malaria parasite Plasmodium falciparum in gorillas.

    PubMed

    Liu, Weimin; Li, Yingying; Learn, Gerald H; Rudicell, Rebecca S; Robertson, Joel D; Keele, Brandon F; Ndjango, Jean-Bosco N; Sanz, Crickette M; Morgan, David B; Locatelli, Sabrina; Gonder, Mary K; Kranzusch, Philip J; Walsh, Peter D; Delaporte, Eric; Mpoudi-Ngole, Eitel; Georgiev, Alexander V; Muller, Martin N; Shaw, George M; Peeters, Martine; Sharp, Paul M; Rayner, Julian C; Hahn, Beatrice H

    2010-09-23

    Plasmodium falciparum is the most prevalent and lethal of the malaria parasites infecting humans, yet the origin and evolutionary history of this important pathogen remain controversial. Here we develop a single-genome amplification strategy to identify and characterize Plasmodium spp. DNA sequences in faecal samples from wild-living apes. Among nearly 3,000 specimens collected from field sites throughout central Africa, we found Plasmodium infection in chimpanzees (Pan troglodytes) and western gorillas (Gorilla gorilla), but not in eastern gorillas (Gorilla beringei) or bonobos (Pan paniscus). Ape plasmodial infections were highly prevalent, widely distributed and almost always made up of mixed parasite species. Analysis of more than 1,100 mitochondrial, apicoplast and nuclear gene sequences from chimpanzees and gorillas revealed that 99% grouped within one of six host-specific lineages representing distinct Plasmodium species within the subgenus Laverania. One of these from western gorillas comprised parasites that were nearly identical to P. falciparum. In phylogenetic analyses of full-length mitochondrial sequences, human P. falciparum formed a monophyletic lineage within the gorilla parasite radiation. These findings indicate that P. falciparum is of gorilla origin and not of chimpanzee, bonobo or ancient human origin.

  17. Structural Differences Explain Diverse Functions of Plasmodium Actins

    PubMed Central

    Vahokoski, Juha; Martinez, Silvia Muñico; Ignatev, Alexander; Lepper, Simone; Frischknecht, Friedrich; Sidén-Kiamos, Inga; Sachse, Carsten; Kursula, Inari

    2014-01-01

    Actins are highly conserved proteins and key players in central processes in all eukaryotic cells. The two actins of the malaria parasite are among the most divergent eukaryotic actins and also differ from each other more than isoforms in any other species. Microfilaments have not been directly observed in Plasmodium and are presumed to be short and highly dynamic. We show that actin I cannot complement actin II in male gametogenesis, suggesting critical structural differences. Cryo-EM reveals that Plasmodium actin I has a unique filament structure, whereas actin II filaments resemble canonical F-actin. Both Plasmodium actins hydrolyze ATP more efficiently than α-actin, and unlike any other actin, both parasite actins rapidly form short oligomers induced by ADP. Crystal structures of both isoforms pinpoint several structural changes in the monomers causing the unique polymerization properties. Inserting the canonical D-loop to Plasmodium actin I leads to the formation of long filaments in vitro. In vivo, this chimera restores gametogenesis in parasites lacking actin II, suggesting that stable filaments are required for exflagellation. Together, these data underline the divergence of eukaryotic actins and demonstrate how structural differences in the monomers translate into filaments with different properties, implying that even eukaryotic actins have faced different evolutionary pressures and followed different paths for developing their polymerization properties. PMID:24743229

  18. Plasmodium cellular effector mechanisms and the hepatic microenvironment

    PubMed Central

    Frevert, Ute; Krzych, Urszula

    2015-01-01

    Plasmodium falciparum malaria remains one of the most serious health problems globally. Immunization with attenuated parasites elicits multiple cellular effector mechanisms capable of eliminating Plasmodium liver stages. However, malaria liver stage (LS) immunity is complex and the mechanisms effector T cells use to locate the few infected hepatocytes in the large liver in order to kill the intracellular LS parasites remain a mystery to date. Here, we review our current knowledge on the behavior of CD8 effector T cells in the hepatic microvasculature, in malaria and other hepatic infections. Taking into account the unique immunological and lymphogenic properties of the liver, we discuss whether classical granule-mediated cytotoxicity might eliminate infected hepatocytes via direct cell contact or whether cytokines might operate without cell–cell contact and kill Plasmodium LSs at a distance. A thorough understanding of the cellular effector mechanisms that lead to parasite death hence sterile protection is a prerequisite for the development of a successful malaria vaccine to protect the 40% of the world’s population currently at risk of Plasmodium infection. PMID:26074888

  19. 21 CFR 866.3402 - Plasmodium species antigen detection assays.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Plasmodium species antigen detection assays. 866.3402 Section 866.3402 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES IMMUNOLOGY AND MICROBIOLOGY DEVICES Serological Reagents §...

  20. 21 CFR 866.3402 - Plasmodium species antigen detection assays.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Plasmodium species antigen detection assays. 866.3402 Section 866.3402 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES IMMUNOLOGY AND MICROBIOLOGY DEVICES Serological Reagents §...

  1. 21 CFR 866.3402 - Plasmodium species antigen detection assays.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Plasmodium species antigen detection assays. 866.3402 Section 866.3402 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES IMMUNOLOGY AND MICROBIOLOGY DEVICES Serological Reagents §...

  2. 21 CFR 866.3402 - Plasmodium species antigen detection assays.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Plasmodium species antigen detection assays. 866.3402 Section 866.3402 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES IMMUNOLOGY AND MICROBIOLOGY DEVICES Serological Reagents §...

  3. 21 CFR 866.3402 - Plasmodium species antigen detection assays.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Plasmodium species antigen detection assays. 866.3402 Section 866.3402 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES IMMUNOLOGY AND MICROBIOLOGY DEVICES Serological Reagents §...

  4. A bedside dipstick method to detect Plasmodium falciparum.

    PubMed

    Shah, Ira; Deshmukh, C T

    2004-11-01

    We conducted this study to determine efficacy of Parasight-F (an HRP-II antigen dipstick method to detect P. Falciparum) in children. A total of 30 children were enrolled in the age group of 2 months to 12 years whose peripheral smear showed asexual forms of Plasmodium falciparum. All patients were tested for presence of HRP-II antigen of Plasmodium falciparum in their blood by the Parasight-F dipstick test by either an EDTA sample or a finger prick blood sample. The sensitivity of Parasight-F was 83.3 % However, the sensitivity of Parasight-F to detect Plasmodium Falciparum in case of mixed Plasmodium (Vivax + Falciparum) infection was only 25 %. Also, all patients less than 6 months of age had a negative Parasight-F test. Parasitic index, prior treatment with antimalarials or severity of Falciparum malaria have no effect on the sensitivity of Parasight-F test. We conclude that Parasight-F is an effective tool for diagnosis of Plasmoduim falciparum malaria in children. PMID:15591666

  5. Origin of the human malaria parasite Plasmodium falciparum in gorillas

    PubMed Central

    Liu, Weimin; Li, Yingying; Learn, Gerald H.; Rudicell, Rebecca S.; Robertson, Joel D.; Keele, Brandon F.; Ndjango, Jean-Bosco N.; Sanz, Crickette M.; Morgan, David B.; Locatelli, Sabrina; Gonder, Mary K.; Kranzusch, Philip J.; Walsh, Peter D.; Delaporte, Eric; Mpoudi-Ngole, Eitel; Georgiev, Alexander V.; Muller, Martin N.; Shaw, George M.; Peeters, Martine; Sharp, Paul M.; Rayner, Julian C.; Hahn, Beatrice H.

    2010-01-01

    Plasmodium falciparum is the most prevalent and lethal of the malaria parasites infecting humans, yet the origin and evolutionary history of this important pathogen remain controversial. Here, we developed a novel polymerase chain reaction based single genome amplification strategy to identify and characterize Plasmodium spp. DNA sequences in fecal samples of wild-living apes. Among nearly 3,000 specimens collected from field sites throughout central Africa, we found Plasmodium infection in chimpanzees (Pan troglodytes) and western gorillas (Gorilla gorilla), but not in eastern gorillas (Gorilla beringei) or bonobos (Pan paniscus). Ape plasmodial infections were highly prevalent, widely distributed, and almost always comprised of mixed parasite species. Analysis of more than 1,100 mitochondrial, apicoplast and nuclear gene sequences from chimpanzees and gorillas revealed that 99% grouped within one of six host-specific lineages representing distinct Plasmodium species within the subgenus Laverania. One of these from western gorillas was comprised of parasites that were nearly identical to P. falciparum. In phylogenetic analyses of full-length mitochondrial sequences, human P. falciparum formed a monophyletic lineage within the gorilla parasite radiation. These findings indicate that P. falciparum is of gorilla and not of chimpanzee, bonobo or ancient human origin. PMID:20864995

  6. The Permits Game: Conveying the Logic of Marketable Pollution Permits.

    ERIC Educational Resources Information Center

    Walbert, Mark S; Bierma, Thomas J.

    1988-01-01

    Presents an interactive classroom technique to help students understand how the market can be used to arrive at a cost-effective method for pollution control. Emphasizes the understanding of the fundamental ideas that the optimal level of pollution is rarely zero and that marketable pollution permits are efficient means of control. (KO)

  7. Structure, Function and Inhibition of the Phosphoethanolamine Methyltransferases of the Human Malaria Parasites Plasmodium vivax and Plasmodium knowlesi

    SciTech Connect

    Garg, Aprajita; Lukk, Tiit; Kumar, Vidya; Choi, Jae-Yeon; Augagneur, Yoann; Voelker, Dennis R.; Nair, Satish; Mamoun, Choukri Ben

    2015-03-12

    Phosphoethanolamine methyltransferases (PMTs) catalyze the three-step methylation of phosphoethanolamine to form phosphocholine, a critical step in the synthesis of phosphatidylcholine in a select number of eukaryotes including human malaria parasites, nematodes and plants. Genetic studies in the malaria parasite Plasmodium falciparum have shown that the methyltransferase PfPMT plays a critical function in parasite development and differentiation. The presence of PMT orthologs in other malaria parasites that infect humans and their absence in mammals make them ideal targets for the development of selective antimalarials with broad specificity against different Plasmodium species. Here we describe the X-ray structures and biochemical properties of PMT orthologs from Plasmodium vivax and Plasmodium knowlesi and show that both enzymes are inhibited by amodiaquine and NSC158011, two drugs with potent antimalarial activity. Metabolic studies in a yeast mutant that relies on PkPMT or PvPMT for survival demonstrated that these compounds inhibit phosphatidylcholine biosynthesis from ethanolamine. Our structural and functional data provide insights into the mechanism of catalysis and inhibition of PMT enzymes and set the stage for a better design of more specific and selective antimalarial drugs.

  8. Structure, Function and Inhibition of the Phosphoethanolamine Methyltransferases of the Human Malaria Parasites Plasmodium vivax and Plasmodium knowlesi

    DOE PAGES

    Garg, Aprajita; Lukk, Tiit; Kumar, Vidya; Choi, Jae-Yeon; Augagneur, Yoann; Voelker, Dennis R.; Nair, Satish; Mamoun, Choukri Ben

    2015-03-12

    Phosphoethanolamine methyltransferases (PMTs) catalyze the three-step methylation of phosphoethanolamine to form phosphocholine, a critical step in the synthesis of phosphatidylcholine in a select number of eukaryotes including human malaria parasites, nematodes and plants. Genetic studies in the malaria parasite Plasmodium falciparum have shown that the methyltransferase PfPMT plays a critical function in parasite development and differentiation. The presence of PMT orthologs in other malaria parasites that infect humans and their absence in mammals make them ideal targets for the development of selective antimalarials with broad specificity against different Plasmodium species. Here we describe the X-ray structures and biochemical properties ofmore » PMT orthologs from Plasmodium vivax and Plasmodium knowlesi and show that both enzymes are inhibited by amodiaquine and NSC158011, two drugs with potent antimalarial activity. Metabolic studies in a yeast mutant that relies on PkPMT or PvPMT for survival demonstrated that these compounds inhibit phosphatidylcholine biosynthesis from ethanolamine. Our structural and functional data provide insights into the mechanism of catalysis and inhibition of PMT enzymes and set the stage for a better design of more specific and selective antimalarial drugs.« less

  9. Structure, Function and Inhibition of the Phosphoethanolamine Methyltransferases of the Human Malaria Parasites Plasmodium vivax and Plasmodium knowlesi

    PubMed Central

    Garg, Aprajita; Lukk, Tiit; Kumar, Vidya; Choi, Jae-Yeon; Augagneur, Yoann; Voelker, Dennis R.; Nair, Satish; Mamoun, Choukri Ben

    2015-01-01

    Phosphoethanolamine methyltransferases (PMTs) catalyze the three-step methylation of phosphoethanolamine to form phosphocholine, a critical step in the synthesis of phosphatidylcholine in a select number of eukaryotes including human malaria parasites, nematodes and plants. Genetic studies in the malaria parasite Plasmodium falciparum have shown that the methyltransferase PfPMT plays a critical function in parasite development and differentiation. The presence of PMT orthologs in other malaria parasites that infect humans and their absence in mammals make them ideal targets for the development of selective antimalarials with broad specificity against different Plasmodium species. Here we describe the X-ray structures and biochemical properties of PMT orthologs from Plasmodium vivax and Plasmodium knowlesi and show that both enzymes are inhibited by amodiaquine and NSC158011, two drugs with potent antimalarial activity. Metabolic studies in a yeast mutant that relies on PkPMT or PvPMT for survival demonstrated that these compounds inhibit phosphatidylcholine biosynthesis from ethanolamine. Our structural and functional data provide insights into the mechanism of catalysis and inhibition of PMT enzymes and set the stage for a better design of more specific and selective antimalarial drugs. PMID:25761669

  10. Endemicity response timelines for Plasmodium falciparum elimination

    PubMed Central

    Smith, David L; Hay, Simon I

    2009-01-01

    Background The scaling up of malaria control and renewed calls for malaria eradication have raised interest in defining timelines for changes in malaria endemicity. Methods The epidemiological theory for the decline in the Plasmodium falciparum parasite rate (PfPR, the prevalence of infection) following intervention was critically reviewed and where necessary extended to consider superinfection, heterogeneous biting, and aging infections. Timelines for malaria control and elimination under different levels of intervention were then established using a wide range of candidate mathematical models. Analysis focused on the timelines from baseline to 1% and from 1% through the final stages of elimination. Results The Ross-Macdonald model, which ignores superinfection, was used for planning during the Global Malaria Eradication Programme (GMEP). In models that consider superinfection, PfPR takes two to three years longer to reach 1% starting from a hyperendemic baseline, consistent with one of the few large-scale malaria control trials conducted in an African population with hyperendemic malaria. The time to elimination depends fundamentally upon the extent to which malaria transmission is interrupted and the size of the human population modelled. When the PfPR drops below 1%, almost all models predict similar and proportional declines in PfPR in consecutive years from 1% through to elimination and that the waiting time to reduce PfPR from 10% to 1% and from 1% to 0.1% are approximately equal, but the decay rate can increase over time if infections senesce. Conclusion The theory described herein provides simple "rules of thumb" and likely time horizons for the impact of interventions for control and elimination. Starting from a hyperendemic baseline, the GMEP planning timelines, which were based on the Ross-Macdonald model with completely interrupted transmission, were inappropriate for setting endemicity timelines and they represent the most optimistic scenario for

  11. 40 CFR 71.25 - Permit content.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 16 2013-07-01 2013-07-01 false Permit content. 71.25 Section 71.25 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) FEDERAL OPERATING PERMIT PROGRAMS Permits for Early Reductions Sources § 71.25 Permit content. (a) Standard...

  12. 40 CFR 71.25 - Permit content.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 16 2012-07-01 2012-07-01 false Permit content. 71.25 Section 71.25 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) FEDERAL OPERATING PERMIT PROGRAMS Permits for Early Reductions Sources § 71.25 Permit content. (a) Standard...

  13. 40 CFR 71.25 - Permit content.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 15 2010-07-01 2010-07-01 false Permit content. 71.25 Section 71.25 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) FEDERAL OPERATING PERMIT PROGRAMS Permits for Early Reductions Sources § 71.25 Permit content. (a) Standard...

  14. 40 CFR 233.22 - Emergency permits.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 24 2010-07-01 2010-07-01 false Emergency permits. 233.22 Section 233... PROGRAM REGULATIONS Permit Requirements § 233.22 Emergency permits. (a) Notwithstanding any other provision of this part, the Director may issue a temporary emergency permit for a discharge of dredged...

  15. 40 CFR 144.34 - Emergency permits.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 22 2010-07-01 2010-07-01 false Emergency permits. 144.34 Section 144...) UNDERGROUND INJECTION CONTROL PROGRAM Authorization by Permit § 144.34 Emergency permits. (a) Coverage... unless a temporary emergency permit is granted; or (2) A substantial and irretrievable loss of oil or...

  16. 40 CFR 147.2906 - Emergency permits.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 22 2010-07-01 2010-07-01 false Emergency permits. 147.2906 Section...-Class II Wells § 147.2906 Emergency permits. (a) An emergency permit may be issued if: (1) There will be an imminent health hazard unless an emergency permit is issued; or (2) There will be a...

  17. 50 CFR 622.90 - Permits.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ..., DEPARTMENT OF COMMERCE FISHERIES OF THE CARIBBEAN, GULF OF MEXICO, AND SOUTH ATLANTIC Red Drum Fishery of the Gulf of Mexico § 622.90 Permits. (a) Dealer permits and conditions—(1) Permits. For a dealer to first receive Gulf red drum harvested in or from the EEZ, a Gulf and South Atlantic dealer permit must be......

  18. 40 CFR 71.25 - Permit content.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 15 2011-07-01 2011-07-01 false Permit content. 71.25 Section 71.25 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) FEDERAL OPERATING PERMIT PROGRAMS Permits for Early Reductions Sources § 71.25 Permit content. (a) Standard...

  19. 50 CFR 13.27 - Permit suspension.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 50 Wildlife and Fisheries 1 2010-10-01 2010-10-01 false Permit suspension. 13.27 Section 13.27... GENERAL PERMIT PROCEDURES Permit Administration § 13.27 Permit suspension. (a) Criteria for suspension... Government. Such suspension shall remain in effect until the issuing officer determines that the...

  20. 50 CFR 13.27 - Permit suspension.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 50 Wildlife and Fisheries 1 2011-10-01 2011-10-01 false Permit suspension. 13.27 Section 13.27... GENERAL PERMIT PROCEDURES Permit Administration § 13.27 Permit suspension. (a) Criteria for suspension... Government. Such suspension shall remain in effect until the issuing officer determines that the...

  1. 21 CFR 1210.21 - Permit number.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Permit number. 1210.21 Section 1210.21 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) REGULATIONS... IMPORT MILK ACT Permit Control § 1210.21 Permit number. Each permit issued under the Federal Import...

  2. 21 CFR 1210.21 - Permit number.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Permit number. 1210.21 Section 1210.21 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) REGULATIONS... IMPORT MILK ACT Permit Control § 1210.21 Permit number. Each permit issued under the Federal Import...

  3. 21 CFR 1210.21 - Permit number.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Permit number. 1210.21 Section 1210.21 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) REGULATIONS... IMPORT MILK ACT Permit Control § 1210.21 Permit number. Each permit issued under the Federal Import...

  4. 21 CFR 1210.21 - Permit number.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Permit number. 1210.21 Section 1210.21 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) REGULATIONS... IMPORT MILK ACT Permit Control § 1210.21 Permit number. Each permit issued under the Federal Import...

  5. 21 CFR 1210.21 - Permit number.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Permit number. 1210.21 Section 1210.21 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) REGULATIONS... IMPORT MILK ACT Permit Control § 1210.21 Permit number. Each permit issued under the Federal Import...

  6. 40 CFR 71.25 - Permit content.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 16 2014-07-01 2014-07-01 false Permit content. 71.25 Section 71.25 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) FEDERAL OPERATING PERMIT PROGRAMS Permits for Early Reductions Sources § 71.25 Permit content. (a) Standard...

  7. Mitochondrial DNA from the eradicated European Plasmodium vivax and P. falciparum from 70-year-old slides from the Ebro Delta in Spain

    PubMed Central

    Gelabert, Pere; Sandoval-Velasco, Marcela; Olalde, Iñigo; Fregel, Rosa; Rieux, Adrien; Escosa, Raül; Aranda, Carles; Paaijmans, Krijn; Mueller, Ivo; Gilbert, M. Thomas P.; Lalueza-Fox, Carles

    2016-01-01

    Phylogenetic analysis of Plasmodium parasites has indicated that their modern-day distribution is a result of a series of human-mediated dispersals involving transport between Africa, Europe, America, and Asia. A major outstanding question is the phylogenetic affinity of the malaria causing parasites Plasmodium vivax and falciparum in historic southern Europe—where it was endemic until the mid-20th century, after which it was eradicated across the region. Resolving the identity of these parasites will be critical for answering several hypotheses on the malaria dispersal. Recently, a set of slides with blood stains of malaria-affected people from the Ebro Delta (Spain), dated between 1942 and 1944, have been found in a local medical collection. We extracted DNA from three slides, two of them stained with Giemsa (on which Plasmodium parasites could still be seen under the microscope) and another one consisting of dried blood spots. We generated the data using Illumina sequencing after using several strategies aimed at increasing the Plasmodium DNA yield: depletion of the human genomic (g)DNA content through hybridization with human gDNA baits, and capture-enrichment using gDNA derived from P. falciparum. Plasmodium mitochondrial genome sequences were subsequently reconstructed from the resulting data. Phylogenetic analysis of the eradicated European P. vivax mtDNA genome indicates that the European isolate is closely related to the most common present-day American haplotype and likely entered the American continent post-Columbian contact. Furthermore, the European P. falciparum mtDNA indicates a link with current Indian strains that is in agreement with historical accounts. PMID:27671660

  8. [Probable speciations by "host-vector 'fidelity'": 14 species of Plasmodium from magpies].

    PubMed

    Chavatte, J M; Chiron, F; Chabaud, A; Landau, I

    2007-03-01

    33 Magpies resident in two parks close to Paris were investigated for the presence of Plasmodium parasites. The majority of the birds were found to be infected with multiple parasite species. A total of 14 species were observed, and of these 10 were novel and consequently described, and two could not be assigned with confidence. It is hypothesized that the unexpected abundance of species is due to a phenomenon which we term "host-vector 'fidelisation'". Indeed, the combination of the eco-biological characteristics of the host (mating pairs in contiguous, but strictly defined territories) with those of the vector (numerous Aedes species with distinct behavior), would generate fragmentation of the niches. This type of isolation overlays others known for parasitic populations (geographical, circadian, microlocalisations), leading to the formation of independent host-parasite niches which in turn lead to speciation.

  9. Targeting a Novel Plasmodium falciparum Purine Recycling Pathway with Specific Immucillins

    SciTech Connect

    Ting, L; Shi, W; Lewandowicz, A; Singh, V; Mwakingwe, A; Birck, M R; Taylor Ringia, E A; Bench, G; Madrid, D C; Tyler, P C; Evans, G B; Furneaux, R H; Schramm, V L; Kim, K

    2004-05-19

    Plasmodium falciparum is unable to synthesize purine bases and relies upon purine salvage and purine recycling to meet its purine needs. We report that purines formed as products of the polyamine pathway are recycled in a novel pathway in which 5'-methylthioinosine is generated by adenosine deaminase. The action of P. falciparum purine nucleoside phosphorylase is a convergent step of purine salvage, converting both 5'-methylthioinosine and inosine to hypoxanthine. We used accelerator mass spectrometry to verify that 5'-methylthioinosine is an active nucleic acid precursor in P. falciparum. Prior studies have shown that inhibitors of purine salvage enzymes kill malaria, but potent malaria-specific inhibitors of these enzymes have not previously been described. 5'-methylthio-Immucillin-H, a transition state analogue inhibitor that is selective for malarial over human purine nucleoside phosphorylase, kills P. falciparum in culture. Immucillins are currently in clinical trials for other indications and may have application as antimalarials.

  10. Using Amplicon Deep Sequencing to Detect Genetic Signatures of Plasmodium vivax Relapse

    PubMed Central

    Lin, Jessica T.; Hathaway, Nicholas J.; Saunders, David L.; Lon, Chanthap; Balasubramanian, Sujata; Kharabora, Oksana; Gosi, Panita; Sriwichai, Sabaithip; Kartchner, Laurel; Chuor, Char Meng; Satharath, Prom; Lanteri, Charlotte; Bailey, Jeffrey A.; Juliano, Jonathan J.

    2015-01-01

    Plasmodium vivax infections often recur due to relapse of hypnozoites from the liver. In malaria-endemic areas, tools to distinguish relapse from reinfection are needed. We applied amplicon deep sequencing to P. vivax isolates from 78 Cambodian volunteers, nearly one-third of whom suffered recurrence at a median of 68 days. Deep sequencing at a highly variable region of the P. vivax merozoite surface protein 1 gene revealed impressive diversity—generating 67 unique haplotypes and detecting on average 3.6 cocirculating parasite clones within individuals, compared to 2.1 clones detected by a combination of 3 microsatellite markers. This diversity enabled a scheme to classify over half of recurrences as probable relapses based on the low probability of reinfection by multiple recurring variants. In areas of high P. vivax diversity, targeted deep sequencing can help detect genetic signatures of relapse, key to evaluating antivivax interventions and achieving a better understanding of relapse-reinfection epidemiology. PMID:25748326

  11. Using Amplicon Deep Sequencing to Detect Genetic Signatures of Plasmodium vivax Relapse.

    PubMed

    Lin, Jessica T; Hathaway, Nicholas J; Saunders, David L; Lon, Chanthap; Balasubramanian, Sujata; Kharabora, Oksana; Gosi, Panita; Sriwichai, Sabaithip; Kartchner, Laurel; Chuor, Char Meng; Satharath, Prom; Lanteri, Charlotte; Bailey, Jeffrey A; Juliano, Jonathan J

    2015-09-15

    Plasmodium vivax infections often recur due to relapse of hypnozoites from the liver. In malaria-endemic areas, tools to distinguish relapse from reinfection are needed. We applied amplicon deep sequencing to P. vivax isolates from 78 Cambodian volunteers, nearly one-third of whom suffered recurrence at a median of 68 days. Deep sequencing at a highly variable region of the P. vivax merozoite surface protein 1 gene revealed impressive diversity-generating 67 unique haplotypes and detecting on average 3.6 cocirculating parasite clones within individuals, compared to 2.1 clones detected by a combination of 3 microsatellite markers. This diversity enabled a scheme to classify over half of recurrences as probable relapses based on the low probability of reinfection by multiple recurring variants. In areas of high P. vivax diversity, targeted deep sequencing can help detect genetic signatures of relapse, key to evaluating antivivax interventions and achieving a better understanding of relapse-reinfection epidemiology.

  12. Site-specific genome editing in Plasmodium falciparum using engineered zinc-finger nucleases.

    PubMed

    Straimer, Judith; Lee, Marcus C S; Lee, Andrew H; Zeitler, Bryan; Williams, April E; Pearl, Jocelynn R; Zhang, Lei; Rebar, Edward J; Gregory, Philip D; Llinás, Manuel; Urnov, Fyodor D; Fidock, David A

    2012-10-01

    Malaria afflicts over 200 million people worldwide, and its most lethal etiologic agent, Plasmodium falciparum, is evolving to resist even the latest-generation therapeutics. Efficient tools for genome-directed investigations of P. falciparum-induced pathogenesis, including drug-resistance mechanisms, are clearly required. Here we report rapid and targeted genetic engineering of this parasite using zinc-finger nucleases (ZFNs) that produce a double-strand break in a user-defined locus and trigger homology-directed repair. Targeting an integrated egfp locus, we obtained gene-deletion parasites with unprecedented speed (2 weeks), both with and without direct selection. ZFNs engineered against the parasite gene pfcrt, responsible for escape under chloroquine treatment, rapidly produced parasites that carried either an allelic replacement or a panel of specified point mutations. This method will enable a diverse array of genome-editing approaches to interrogate this human pathogen.

  13. Plasmodium knowlesi genome sequences from clinical isolates reveal extensive genomic dimorphism.

    PubMed

    Pinheiro, Miguel M; Ahmed, Md Atique; Millar, Scott B; Sanderson, Theo; Otto, Thomas D; Lu, Woon Chan; Krishna, Sanjeev; Rayner, Julian C; Cox-Singh, Janet

    2015-01-01

    Plasmodium knowlesi is a newly described zoonosis that causes malaria in the human population that can be severe and fatal. The study of P. knowlesi parasites from human clinical isolates is relatively new and, in order to obtain maximum information from patient sample collections, we explored the possibility of generating P. knowlesi genome sequences from archived clinical isolates. Our patient sample collection consisted of frozen whole blood samples that contained excessive human DNA contamination and, in that form, were not suitable for parasite genome sequencing. We developed a method to reduce the amount of human DNA in the thawed blood samples in preparation for high throughput parasite genome sequencing using Illumina HiSeq and MiSeq sequencing platforms. Seven of fifteen samples processed had sufficiently pure P. knowlesi DNA for whole genome sequencing. The reads were mapped to the P. knowlesi H strain reference genome and an average mapping of 90% was obtained. Genes with low coverage were removed leaving 4623 genes for subsequent analyses. Previously we identified a DNA sequence dimorphism on a small fragment of the P. knowlesi normocyte binding protein xa gene on chromosome 14. We used the genome data to assemble full-length Pknbpxa sequences and discovered that the dimorphism extended along the gene. An in-house algorithm was developed to detect SNP sites co-associating with the dimorphism. More than half of the P. knowlesi genome was dimorphic, involving genes on all chromosomes and suggesting that two distinct types of P. knowlesi infect the human population in Sarawak, Malaysian Borneo. We use P. knowlesi clinical samples to demonstrate that Plasmodium DNA from archived patient samples can produce high quality genome data. We show that analyses, of even small numbers of difficult clinical malaria isolates, can generate comprehensive genomic information that will improve our understanding of malaria parasite diversity and pathobiology.

  14. Plasmodium vivax Promiscuous T-Helper Epitopes Defined and Evaluated as Linear Peptide Chimera Immunogens

    PubMed Central

    Caro-Aguilar, Ivette; Rodríguez, Alexandra; Calvo-Calle, J. Mauricio; Guzmán, Fanny; De la Vega, Patricia; Elkin Patarroyo, Manuel; Galinski, Mary R.; Moreno, Alberto

    2002-01-01

    Clinical trials of malaria vaccines have confirmed that parasite-derived T-cell epitopes are required to elicit consistent and long-lasting immune responses. We report here the identification and functional characterization of six T-cell epitopes that are present in the merozoite surface protein-1 of Plasmodium vivax (PvMSP-1) and bind promiscuously to four different HLA-DRB1∗ alleles. Each of these peptides induced lymphoproliferative responses in cells from individuals with previous P. vivax infections. Furthermore, linear-peptide chimeras containing the promiscuous PvMSP-1 T-cell epitopes, synthesized in tandem with the Plasmodium falciparum immunodominant circumsporozoite protein (CSP) B-cell epitope, induced high specific antibody titers, cytokine production, long-lasting immune responses, and immunoglobulin G isotype class switching in BALB/c mice. A linear-peptide chimera containing an allele-restricted P. falciparum T-cell epitope with the CSP B-cell epitope was not effective. Two out of the six promiscuous T-cell epitopes exhibiting the highest anti-peptide response also contain B-cell epitopes. Antisera generated against these B-cell epitopes recognize P. vivax merozoites in immunofluorescence assays. Importantly, the anti-peptide antibodies generated to the CSP B-cell epitope inhibited the invasion of P. falciparum sporozoites into human hepatocytes. These data and the simplicity of design of the chimeric constructs highlight the potential of multimeric, multistage, and multispecies linear-peptide chimeras containing parasite promiscuous T-cell epitopes for malaria vaccine development. PMID:12065487

  15. A new world malaria map: Plasmodium falciparum endemicity in 2010

    PubMed Central

    2011-01-01

    Background Transmission intensity affects almost all aspects of malaria epidemiology and the impact of malaria on human populations. Maps of transmission intensity are necessary to identify populations at different levels of risk and to evaluate objectively options for disease control. To remain relevant operationally, such maps must be updated frequently. Following the first global effort to map Plasmodium falciparum malaria endemicity in 2007, this paper describes the generation of a new world map for the year 2010. This analysis is extended to provide the first global estimates of two other metrics of transmission intensity for P. falciparum that underpin contemporary questions in malaria control: the entomological inoculation rate (PfEIR) and the basic reproductive number (PfR). Methods Annual parasite incidence data for 13,449 administrative units in 43 endemic countries were sourced to define the spatial limits of P. falciparum transmission in 2010 and 22,212 P. falciparum parasite rate (PfPR) surveys were used in a model-based geostatistical (MBG) prediction to create a continuous contemporary surface of malaria endemicity within these limits. A suite of transmission models were developed that link PfPR to PfEIR and PfR and these were fitted to field data. These models were combined with the PfPR map to create new global predictions of PfEIR and PfR. All output maps included measured uncertainty. Results An estimated 1.13 and 1.44 billion people worldwide were at risk of unstable and stable P. falciparum malaria, respectively. The majority of the endemic world was predicted with a median PfEIR of less than one and a median PfRc of less than two. Values of either metric exceeding 10 were almost exclusive to Africa. The uncertainty described in both PfEIR and PfR was substantial in regions of intense transmission. Conclusions The year 2010 has a particular significance as an evaluation milestone for malaria global health policy. The maps presented here

  16. 40 CFR 60.47Da - Commercial demonstration permit.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... (CONTINUED) STANDARDS OF PERFORMANCE FOR NEW STATIONARY SOURCES Standards of Performance for Electric Utility... rolling average basis. (e) Commercial demonstration permits may not exceed the following equivalent MW electrical generation capacity for any one technology category, and the total equivalent MW...

  17. 27 CFR 71.48 - Operating permits and industrial use permits.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... industrial use permits. 71.48 Section 71.48 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX... PERMIT PROCEEDINGS Grounds for Citation § 71.48 Operating permits and industrial use permits. Whenever... industrial use permit: (a) Has not in good faith complied with the provisions of 26 U.S.C. chapter 51...

  18. 27 CFR 71.49a - Applications for operating permits and industrial use permits.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... permits and industrial use permits. 71.49a Section 71.49a Alcohol, Tobacco Products and Firearms ALCOHOL... and industrial use permits. If, on examination of an application for an operating permit or an industrial use permit, the appropriate TTB officer has reason to believe: (a) In case of an application...

  19. 27 CFR 71.49a - Applications for operating permits and industrial use permits.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... permits and industrial use permits. 71.49a Section 71.49a Alcohol, Tobacco Products and Firearms ALCOHOL... and industrial use permits. If, on examination of an application for an operating permit or an industrial use permit, the appropriate TTB officer has reason to believe: (a) In case of an application...

  20. 27 CFR 71.48 - Operating permits and industrial use permits.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... industrial use permits. 71.48 Section 71.48 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX... PERMIT PROCEEDINGS Grounds for Citation § 71.48 Operating permits and industrial use permits. Whenever... industrial use permit: (a) Has not in good faith complied with the provisions of 26 U.S.C. chapter 51...

  1. 27 CFR 71.49a - Applications for operating permits and industrial use permits.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... permits and industrial use permits. 71.49a Section 71.49a Alcohol, Tobacco Products and Firearms ALCOHOL... and industrial use permits. If, on examination of an application for an operating permit or an industrial use permit, the appropriate TTB officer has reason to believe: (a) In case of an application...

  2. 27 CFR 71.48 - Operating permits and industrial use permits.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... industrial use permits. 71.48 Section 71.48 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX... PERMIT PROCEEDINGS Grounds for Citation § 71.48 Operating permits and industrial use permits. Whenever... industrial use permit: (a) Has not in good faith complied with the provisions of 26 U.S.C. chapter 51...

  3. 27 CFR 71.49a - Applications for operating permits and industrial use permits.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... permits and industrial use permits. 71.49a Section 71.49a Alcohol, Tobacco Products and Firearms ALCOHOL... and industrial use permits. If, on examination of an application for an operating permit or an industrial use permit, the appropriate TTB officer has reason to believe: (a) In case of an application...

  4. 27 CFR 71.49a - Applications for operating permits and industrial use permits.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... permits and industrial use permits. 71.49a Section 71.49a Alcohol, Tobacco Products and Firearms ALCOHOL... and industrial use permits. If, on examination of an application for an operating permit or an industrial use permit, the appropriate TTB officer has reason to believe: (a) In case of an application...

  5. 27 CFR 71.48 - Operating permits and industrial use permits.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... industrial use permits. 71.48 Section 71.48 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX... PERMIT PROCEEDINGS Grounds for Citation § 71.48 Operating permits and industrial use permits. Whenever... industrial use permit: (a) Has not in good faith complied with the provisions of 26 U.S.C. chapter 51...

  6. 27 CFR 71.48 - Operating permits and industrial use permits.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... industrial use permits. 71.48 Section 71.48 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX... PERMIT PROCEEDINGS Grounds for Citation § 71.48 Operating permits and industrial use permits. Whenever... industrial use permit: (a) Has not in good faith complied with the provisions of 26 U.S.C. chapter 51...

  7. Plasmodium spp. in raptors on the Eurasian-African migration route.

    PubMed

    Paperna, I; Yosef, R; Landau, I

    2007-12-01

    Examination of blood smears obtained from raptors trapped while on migration at Eilat, Israel, demonstrated Plasmodium infection in Accipiter brevipes and Buteo buteo. The following species are described, from A. brevipes: Plasmodium alloelongatum n. sp., P. accipiteris n. sp. and from B. buteo: P. buteonis n. sp. and Plasmodium sp. for which we lack sufficient data for adequate species description. Overall prevalence of infection with Plasmodium spp. was very low: among 38 examined A. brevipes 5% and among 56 B. buteo 3.6%.

  8. A two-compartment model of osmotic lysis in Plasmodium falciparum-infected erythrocytes.

    PubMed

    Wagner, Marissa A; Andemariam, Biree; Desai, Sanjay A

    2003-01-01

    We recently identified a voltage-dependent anion channel on the surface of human red blood cells (RBCs) infected with the malaria parasite, Plasmodium falciparum. This channel, the plasmodial erythrocyte surface anion channel (PESAC), likely accounts for the increased permeability of infected RBCs to various small solutes, as assessed quantitatively with radioisotope flux and patch-clamp studies. Whereas this increased permeability has also been studied by following osmotic lysis of infected cells in permeant solutes, these experiments have been limited to qualitative comparisons of lysis rates. To permit more quantitative examination of lysis rates, we have developed a mathematical model for osmotic fragility of infected cells based on diffusional uptake via PESAC and the two-compartment geometry of infected RBCs. This model, combined with a simple light scattering assay designed to track osmotic lysis precisely, produced permeability coefficients that match both previous isotope flux and patch-clamp estimates. Our model and light scattering assay also revealed Michaelian kinetics for inhibition of PESAC by furosemide, suggesting a 1:1 stoichiometry for their interaction. PMID:12524269

  9. MOLECULAR SURVEILLANCE OF Plasmodium vivax AND Plasmodium falciparum DHFR MUTATIONS IN ISOLATES FROM SOUTHERN IRAN.

    PubMed

    Sharifi-Sarasiabi, Khojasteh; Haghighi, Ali; Kazemi, Bahram; Taghipour, Niloofar; Mojarad, Ehsan Nazemalhosseini; Gachkar, Latif

    2016-01-01

    In Iran, both Plasmodium vivax and P. falciparum malaria have been detected, but P. vivax is the predominant species. Point mutations in dihydrofolate reductase (dhfr) gene in both Plasmodia are the major mechanisms of pyrimethamine resistance. From April 2007 to June 2009, a total of 134 blood samples in two endemic areas of southern Iran were collected from patients infected with P. vivax and P. falciparum. The isolates were analyzed for P. vivax dihydrofolate reductase (pvdhfr) and P. falciparum dihydrofolate reductase (pfdhfr) point mutations using various PCR-based methods. The majority of the isolates (72.9%) had wild type amino acids at five codons of pvdhfr. Amongst mutant isolates, the most common pvdhfr alleles were double mutant in 58 and 117 amino acids (58R-117N). Triple mutation in 57, 58, and 117 amino acids (57L/58R/117N) was identified for the first time in the pvdhfr gene of Iranian P. vivax isolates. All the P. falciparumsamples analyzed (n = 16) possessed a double mutant pfdhfrallele (59R/108N) and retained a wild-type mutation at position 51. This may be attributed to the fact that the falciparum malaria patients were treated using sulfadoxine-pyrimethamine (SP) in Iran. The presence of mutant haplotypes in P. vivax is worrying, but has not yet reached an alarming threshold regarding drugs such as SP. The results of this study reinforce the importance of performing a molecular surveillance by means of a continuous chemoresistance assessment.

  10. Facing Title V permit constraints

    SciTech Connect

    Patankar, U.M.

    1995-06-01

    The new Title V operating permit requirement under state regulations pursuant to the 1990 Clean Air Act Amendments will cover every emission source at a facility. These rules will significantly affect an operation by setting minimum compliance requirements, mandating periodic compliance certification, prescribing complex monitoring, record keeping and reporting procedures and making state and EPA approval of routine operational changes necessary through a permit amendment. The main concern with Title V is its effect on the operational flexibility of a facility, and individual emission sources within that facility. Unless properly addressed in a permit document, the term operational flexibility, so freely used by regulators in the context of the Title V program, can turn into a misnomer and the ability to operate as before may be significantly compromised under Title V. True operational flexibility is essential for businesses to respond to real changes in the marketplace. In the age of automation, just-in-time inventories and increased competition, flexibility to operate can mean the difference between growth and stagnation.

  11. Authentication codes that permit arbitration

    SciTech Connect

    Simmons, G.J.

    1987-01-01

    Objective of authentication is to detect attempted deceptions in a communications channel. Traditionally this has been restricted to providing the authorized receiver with a capability of detecting unauthentic messages. The known codes have all left open the possibility for either the transmitter to disavow a message that he actually sent to the receiver, i.e., an authentic message, or else for the receiver to falsely attribute a message of his own devising to the transmitter. Of course the party being deceived would know that he was the victim of a deception by the other, but would be unable to ''prove'' this to a third party. Ideally, authentication should provide a means to detect attempted deceptions by insiders (the transmitter or receiver) as well as outsiders (the opponent). It has been an open question of whether it was possible to devise authentication codes that would permit a third party, an arbiter, to decide (in probability) whether the transmitter or the receiver was cheating in the event of a dispute. We answer this question in that both permits the receiver to detect outsider deceptions, as well affirmative by first constructing an example of an authentication code as permitting a designated arbiter to detect insider deceptions and then by generalizing this construction to an infinite class of such codes.

  12. Predictions of avian Plasmodium expansion under climate change

    PubMed Central

    Loiseau, Claire; Harrigan, Ryan J.; Bichet, Coraline; Julliard, Romain; Garnier, Stéphane; Lendvai, Ádám Z.; Chastel, Olivier; Sorci, Gabriele

    2013-01-01

    Vector-borne diseases are particularly responsive to changing environmental conditions. Diurnal temperature variation has been identified as a particularly important factor for the development of malaria parasites within vectors. Here, we conducted a survey across France, screening populations of the house sparrow (Passer domesticus) for malaria (Plasmodium relictum). We investigated whether variation in remotely-sensed environmental variables accounted for the spatial variation observed in prevalence and parasitemia. While prevalence was highly correlated to diurnal temperature range and other measures of temperature variation, environmental conditions could not predict spatial variation in parasitemia. Based on our empirical data, we mapped malaria distribution under climate change scenarios and predicted that Plasmodium occurrence will spread to regions in northern France, and that prevalence levels are likely to increase in locations where transmission already occurs. Our findings, based on remote sensing tools coupled with empirical data suggest that climatic change will significantly alter transmission of malaria parasites. PMID:23350033

  13. Imaging Plasmodium Immunobiology in Liver, Brain, and Lung

    PubMed Central

    Frevert, Ute; Nacer, Adéla; Cabrera, Mynthia; Movila, Alexandru; Leberl, Maike

    2013-01-01

    Plasmodium falciparum malaria is responsible for the deaths of over half a million African children annually. Until a decade ago, dynamic analysis of the malaria parasite was limited to in vitro systems with the typical limitations associated with 2D monocultures or entirely artificial surfaces. Due to extremely low parasite densities, the liver was considered a black box in terms of Plasmodium sporozoite invasion, liver stage development, and merozoite release into the blood. Further, nothing was known about the behavior of blood stage parasites in organs such as brain where clinical signs manifest and the ensuing immune response of the host that may ultimately result in a fatal outcome. The advent of fluorescent parasites, advances in imaging technology, and availability of an ever-increasing number of cellular and molecular probes have helped illuminate many steps along the pathogenetic cascade of this deadly tropical parasite. PMID:24076429

  14. Uncovering the transmission dynamics of Plasmodium vivax using population genetics.

    PubMed

    Barry, Alyssa E; Waltmann, Andreea; Koepfli, Cristian; Barnadas, Celine; Mueller, Ivo

    2015-05-01

    Population genetic analysis of malaria parasites has the power to reveal key insights into malaria epidemiology and transmission dynamics with the potential to deliver tools to support control and elimination efforts. Analyses of parasite genetic diversity have suggested that Plasmodium vivax populations are more genetically diverse and less structured than those of Plasmodium falciparum indicating that P. vivax may be a more ancient parasite of humans and/or less susceptible to population bottlenecks, as well as more efficient at disseminating its genes. These population genetic insights into P. vivax transmission dynamics provide an explanation for its relative resilience to control efforts. Here, we describe current knowledge on P. vivax population genetic structure, its relevance to understanding transmission patterns and relapse and how this information can inform malaria control and elimination programmes.

  15. [Plasmodium vivax, a parasite coming out of the shadows].

    PubMed

    Allgower, Andrea; Taylor, W Robert; Chappuis, François; Eperon, Gilles

    2016-05-01

    Since 2007, the incidence and mortality of malaria caused by Plasmodium falciparum have declined. However, this trend has not been seen with Plasmodium vivax which has biological features. Severe vivax malaria is increasingly reported in endemic countries even though P. vivax has been thought of as a benign disease. Diagnosis is challenging: the usual rapid diagnostic tests are less sensitive in detecting P. vivax and there is no test for the detection of the dormant forms (hypnozoites). The treatment of the acute phase is an artemisinin based combination, e.g. artemetherlumefantrine. Primaquine, which is the only currently available treatment against hypnozoites for the prevention of relapses, may trigger acute haemolytic anaemia in individuals with G6PD deficiency. PMID:27323480

  16. Host AMPK Is a Modulator of Plasmodium Liver Infection.

    PubMed

    Ruivo, Margarida T Grilo; Vera, Iset Medina; Sales-Dias, Joana; Meireles, Patrícia; Gural, Nil; Bhatia, Sangeeta N; Mota, Maria M; Mancio-Silva, Liliana

    2016-09-01

    Manipulation of the master regulator of energy homeostasis AMP-activated protein kinase (AMPK) activity is a strategy used by many intracellular pathogens for successful replication. Infection by most pathogens leads to an activation of host AMPK activity due to the energetic demands placed on the infected cell. Here, we demonstrate that the opposite is observed in cells infected with rodent malaria parasites. Indeed, AMPK activity upon the infection of hepatic cells is suppressed and dispensable for successful infection. By contrast, an overactive AMPK is deleterious to intracellular growth and replication of different Plasmodium spp., including the human malaria parasite, P. falciparum. The negative impact of host AMPK activity on infection was further confirmed in mice under conditions that activate its function. Overall, this work establishes the role of host AMPK signaling as a suppressive pathway of Plasmodium hepatic infection and as a potential target for host-based antimalarial interventions. PMID:27568570

  17. Uncovering the transmission dynamics of Plasmodium vivax using population genetics

    PubMed Central

    Barry, Alyssa E.; Waltmann, Andreea; Koepfli, Cristian; Barnadas, Celine; Mueller, Ivo

    2015-01-01

    Population genetic analysis of malaria parasites has the power to reveal key insights into malaria epidemiology and transmission dynamics with the potential to deliver tools to support control and elimination efforts. Analyses of parasite genetic diversity have suggested that Plasmodium vivax populations are more genetically diverse and less structured than those of Plasmodium falciparum indicating that P. vivax may be a more ancient parasite of humans and/or less susceptible to population bottlenecks, as well as more efficient at disseminating its genes. These population genetic insights into P. vivax transmission dynamics provide an explanation for its relative resilience to control efforts. Here, we describe current knowledge on P. vivax population genetic structure, its relevance to understanding transmission patterns and relapse and how this information can inform malaria control and elimination programmes. PMID:25891915

  18. [Plasmodium falciparum malaria: epidemiology and clinical features at Tarapoto Hospital].

    PubMed

    Calderon, J; Rodriguez, J; Romero, D

    1997-01-01

    A retrospective study was conducted of the clinical records of 41 patients discharged from a hospital in Tarapoto, Peru, between August 1992 and June 1996 following treatment for Plasmodium falciparum malaria. Patients ranged in age from 18 to 65 years; 25 were male. The cases were uniformly distributed throughout the year. The duration of illness averaged 11 days. At admission, 40 patients had fever, 36 had shaking chills, 29 had headache, 21 had nausea and vomiting, 21 had hyporexia, 15 had pallor, and 13 had splenomegaly. 3 of the 16 women were pregnant. 7 patients reported a history of malaria. The admission diagnosis was malaria in 33 cases. 31 patients were treated with chloroquine; 18 were subsequently treated with pyrimethamine-sulfadoxin and 1 received doxycycline. No cases of grave illness or death occurred. The increasing presence of Plasmodium falciparum malaria in the Peruvian lowlands should promote review of the adequacy of control programs.

  19. Recent Title V operating permit program revisions

    SciTech Connect

    Nicewander, M.

    1995-12-31

    The purpose of this paper is to discuss recent EPA proposed regulations regarding required procedures to be incorporated into the state operating permit programs to accommodate permit revisions. The development and implementation of an operating permits program must balance air pollution control requirements with the ability of a source to meet changing market demands. This has been the major item of concern during the operating permits program development. Before discussing the specific procedures for revising operating permits, it is necessary to include some generic background information for familiarization with the operating permits program.

  20. Structure of Plasmodium falciparum ADP-ribosylation factor 1

    SciTech Connect

    Cook, William J.; Smith, Craig D.; Senkovich, Olga; Holder, Anthony A.; Chattopadhyay, Debasish

    2011-09-26

    Vesicular trafficking may play a crucial role in the pathogenesis and survival of the malaria parasite. ADP-ribosylation factors (ARFs) are among the major components of vesicular trafficking pathways in eukaryotes. The crystal structure of ARF1 GTPase from Plasmodium falciparum has been determined in the GDP-bound conformation at 2.5 {angstrom} resolution and is compared with the structures of mammalian ARF1s.

  1. Subinoculation as a technique in the diagnosis of avian plasmodium

    USGS Publications Warehouse

    Herman, C.M.; Knisley, J.O.; Snyder, E.L.

    1966-01-01

    In two successive years, 1964 and 1965, blood subinoculated from wild Canada geese, negative for Plasmodium by examination of peripheral blood smears, into 5-day-old domestic geese produced 60 % infection in the recipients. Prepatent and patent periods, as well as intensity of parasitemia showed much variation. Intramuscular inoculation produced the same prevalence as the intravenous route, but longer prepatent periods and less intensity of parasitemia.

  2. Plasmodium falciparum genetic crosses in a humanized mouse model

    PubMed Central

    Vaughan, Ashley M.; Pinapati, Richard S.; Cheeseman, Ian H.; Camargo, Nelly; Fishbaugher, Matthew; Checkley, Lisa A.; Nair, Shalini; Hutyra, Carolyn A.; Nosten, François H.; Anderson, Timothy J. C.; Ferdig, Michael T.; Kappe, Stefan H. I.

    2015-01-01

    Genetic crosses of phenotypically distinct strains of the human malaria parasite Plasmodium falciparum are a powerful tool for identifying genes controlling drug resistance and other key phenotypes. Previous studies relied on the isolation of recombinant parasites from splenectomized chimpanzees, a research avenue that is no longer available. Here, we demonstrate that human-liver chimeric mice support recovery of recombinant progeny for the identification of genetic determinants of parasite traits and adaptations. PMID:26030447

  3. Fatal Case of Plasmodium vivax Malaria in a Splenectomized Patient.

    PubMed

    Mahmoudvand, H; Farivar, L; Sharifi, I; Harandi, M Fasihi; Moazed, V; Jahanbakhsh, S; Babaei, Z; Zia-Ali, N

    2012-01-01

    Malaria is a major problem in tropical and sub-tropical countries, with high morbidity and mortality. Splenectomy makes patients more susceptible to serious bacterial and parasitic infections. We report for the first time in Iran a fatal case of Plasmodium vivax malaria, confirmed by microscopic and molecular (Semi-nested multiplex PCR) tests in a patient who had undergone splenectomy due to hemolytic anemia. PMID:23109969

  4. Fatal Case of Plasmodium vivax Malaria in a Splenectomized Patient

    PubMed Central

    Mahmoudvand, H; Farivar, L; Sharifi, I; Harandi, M Fasihi; Moazed, V; Jahanbakhsh, S; Babaei, Z; Zia-Ali, N

    2012-01-01

    Malaria is a major problem in tropical and sub-tropical countries, with high morbidity and mortality. Splenectomy makes patients more susceptible to serious bacterial and parasitic infections. We report for the first time in Iran a fatal case of Plasmodium vivax malaria, confirmed by microscopic and molecular (Semi-nested multiplex PCR) tests in a patient who had undergone splenectomy due to hemolytic anemia. PMID:23109969

  5. [A case of Plasmodium vivax malaria with findings of DIC].

    PubMed

    Takaki, K; Aoki, T; Akeda, H; Kajiwara, T; Honda, S; Maeda, Y; Okada, K; Sawae, Y

    1991-04-01

    We reported a rare case of Plasmodium vivax malaria who showed findings of disseminated intravascular coagulation (DIC). A 50-year-old Japanese male was sent to our hospital with the diagnosis of Plasmodium vivax malaria on the 26th of April, 1990. He had stayed in the Solomon Islands from Oct. 1987 to Dec. 1989, and had febrile episodes during his stay in the island. On April 18, 1990, he complained of a high fever with chills, and showed the same episodes on the 20th, 22th and was diagnosed as malaria. He was treated successfully with the sulfadoxine 500 mg and pyrimethamine 25mg (Fansidar), following the normal temperature on the 4th day and disappearance of malarial parasites in the peripheral blood smear on the 6th day. Interestingly, he had thrombocytopenia and a high titer serum level of fibrin degradation product (FDP) supporting the questionable diagnosis of DIC. Even on the 12th day after improved thrombocytopenia by treatment with Gabexate (FOY), the serum level of FDP, D-dimer and thrombin-nati-thrombin (TAT)III complex still remained at high titer levels. One month later he was readmitted for a relapse of Plasmodium vivax malaria, when he showed thrombocytopenia but the serum level of FDP, D-dimer, TAT III complex and PM.alpha 2 PI complex were normal levels. We concluded that the thrombocytopenia and the high titer of FDP at his first admission was a manifestation of DIC. PMID:2071964

  6. Targeting Plasmodium PI(4)K to eliminate malaria.

    PubMed

    McNamara, Case W; Lee, Marcus C S; Lim, Chek Shik; Lim, Siau Hoi; Roland, Jason; Nagle, Advait; Simon, Oliver; Yeung, Bryan K S; Chatterjee, Arnab K; McCormack, Susan L; Manary, Micah J; Zeeman, Anne-Marie; Dechering, Koen J; Kumar, T R Santha; Henrich, Philipp P; Gagaring, Kerstin; Ibanez, Maureen; Kato, Nobutaka; Kuhen, Kelli L; Fischli, Christoph; Rottmann, Matthias; Plouffe, David M; Bursulaya, Badry; Meister, Stephan; Rameh, Lucia; Trappe, Joerg; Haasen, Dorothea; Timmerman, Martijn; Sauerwein, Robert W; Suwanarusk, Rossarin; Russell, Bruce; Renia, Laurent; Nosten, Francois; Tully, David C; Kocken, Clemens H M; Glynne, Richard J; Bodenreider, Christophe; Fidock, David A; Diagana, Thierry T; Winzeler, Elizabeth A

    2013-12-12

    Achieving the goal of malaria elimination will depend on targeting Plasmodium pathways essential across all life stages. Here we identify a lipid kinase, phosphatidylinositol-4-OH kinase (PI(4)K), as the target of imidazopyrazines, a new antimalarial compound class that inhibits the intracellular development of multiple Plasmodium species at each stage of infection in the vertebrate host. Imidazopyrazines demonstrate potent preventive, therapeutic, and transmission-blocking activity in rodent malaria models, are active against blood-stage field isolates of the major human pathogens P. falciparum and P. vivax, and inhibit liver-stage hypnozoites in the simian parasite P. cynomolgi. We show that imidazopyrazines exert their effect through inhibitory interaction with the ATP-binding pocket of PI(4)K, altering the intracellular distribution of phosphatidylinositol-4-phosphate. Collectively, our data define PI(4)K as a key Plasmodium vulnerability, opening up new avenues of target-based discovery to identify drugs with an ideal activity profile for the prevention, treatment and elimination of malaria.

  7. Targeting Plasmodium PI(4)K to eliminate malaria.

    PubMed

    McNamara, Case W; Lee, Marcus C S; Lim, Chek Shik; Lim, Siau Hoi; Roland, Jason; Nagle, Advait; Simon, Oliver; Yeung, Bryan K S; Chatterjee, Arnab K; McCormack, Susan L; Manary, Micah J; Zeeman, Anne-Marie; Dechering, Koen J; Kumar, T R Santha; Henrich, Philipp P; Gagaring, Kerstin; Ibanez, Maureen; Kato, Nobutaka; Kuhen, Kelli L; Fischli, Christoph; Rottmann, Matthias; Plouffe, David M; Bursulaya, Badry; Meister, Stephan; Rameh, Lucia; Trappe, Joerg; Haasen, Dorothea; Timmerman, Martijn; Sauerwein, Robert W; Suwanarusk, Rossarin; Russell, Bruce; Renia, Laurent; Nosten, Francois; Tully, David C; Kocken, Clemens H M; Glynne, Richard J; Bodenreider, Christophe; Fidock, David A; Diagana, Thierry T; Winzeler, Elizabeth A

    2013-12-12

    Achieving the goal of malaria elimination will depend on targeting Plasmodium pathways essential across all life stages. Here we identify a lipid kinase, phosphatidylinositol-4-OH kinase (PI(4)K), as the target of imidazopyrazines, a new antimalarial compound class that inhibits the intracellular development of multiple Plasmodium species at each stage of infection in the vertebrate host. Imidazopyrazines demonstrate potent preventive, therapeutic, and transmission-blocking activity in rodent malaria models, are active against blood-stage field isolates of the major human pathogens P. falciparum and P. vivax, and inhibit liver-stage hypnozoites in the simian parasite P. cynomolgi. We show that imidazopyrazines exert their effect through inhibitory interaction with the ATP-binding pocket of PI(4)K, altering the intracellular distribution of phosphatidylinositol-4-phosphate. Collectively, our data define PI(4)K as a key Plasmodium vulnerability, opening up new avenues of target-based discovery to identify drugs with an ideal activity profile for the prevention, treatment and elimination of malaria. PMID:24284631

  8. Targeting Plasmodium PI(4)K to eliminate malaria

    NASA Astrophysics Data System (ADS)

    McNamara, Case W.; Lee, Marcus C. S.; Lim, Chek Shik; Lim, Siau Hoi; Roland, Jason; Nagle, Advait; Simon, Oliver; Yeung, Bryan K. S.; Chatterjee, Arnab K.; McCormack, Susan L.; Manary, Micah J.; Zeeman, Anne-Marie; Dechering, Koen J.; Kumar, T. R. Santha; Henrich, Philipp P.; Gagaring, Kerstin; Ibanez, Maureen; Kato, Nobutaka; Kuhen, Kelli L.; Fischli, Christoph; Rottmann, Matthias; Plouffe, David M.; Bursulaya, Badry; Meister, Stephan; Rameh, Lucia; Trappe, Joerg; Haasen, Dorothea; Timmerman, Martijn; Sauerwein, Robert W.; Suwanarusk, Rossarin; Russell, Bruce; Renia, Laurent; Nosten, Francois; Tully, David C.; Kocken, Clemens H. M.; Glynne, Richard J.; Bodenreider, Christophe; Fidock, David A.; Diagana, Thierry T.; Winzeler, Elizabeth A.

    2013-12-01

    Achieving the goal of malaria elimination will depend on targeting Plasmodium pathways essential across all life stages. Here we identify a lipid kinase, phosphatidylinositol-4-OH kinase (PI(4)K), as the target of imidazopyrazines, a new antimalarial compound class that inhibits the intracellular development of multiple Plasmodium species at each stage of infection in the vertebrate host. Imidazopyrazines demonstrate potent preventive, therapeutic, and transmission-blocking activity in rodent malaria models, are active against blood-stage field isolates of the major human pathogens P. falciparum and P. vivax, and inhibit liver-stage hypnozoites in the simian parasite P. cynomolgi. We show that imidazopyrazines exert their effect through inhibitory interaction with the ATP-binding pocket of PI(4)K, altering the intracellular distribution of phosphatidylinositol-4-phosphate. Collectively, our data define PI(4)K as a key Plasmodium vulnerability, opening up new avenues of target-based discovery to identify drugs with an ideal activity profile for the prevention, treatment and elimination of malaria.

  9. Regulatory Review of Early Site Permit Applications

    SciTech Connect

    Scott, Michael L.

    2004-07-01

    The U.S. Nuclear Regulatory Commission (NRC) has received and is reviewing three applications for early site permits (ESPs). The ESP process allows early resolution of site-related issues affecting possible construction and operation of a new nuclear power plant. The nuclear industry views a successful and predictable ESP process as an important step in assessing whether to seek authorization to construct and operate a new generation of nuclear power reactors in the United States. Because consideration of ESP applications is a first-of-a-kind activity, a number of issues have emerged prior to and during the reviews of the first three applications. Issues have included the need for design information at the ESP stage, accident analyses, quality assurance, and seismic analyses. The NRC has been working to resolve identified issues to support a Commission decision on whether to issue an ESP approximately 33-37 months after receipt of each ESP application. (authors)

  10. Watershed-based point sources permitting strategy and dynamic permit-trading analysis.

    PubMed

    Ning, Shu-Kuang; Chang, Ni-Bin

    2007-09-01

    Permit-trading policy in a total maximum daily load (TMDL) program may provide an additional avenue to produce environmental benefit, which closely approximates what would be achieved through a command and control approach, with relatively lower costs. One of the important considerations that might affect the effective trading mechanism is to determine the dynamic transaction prices and trading ratios in response to seasonal changes of assimilative capacity in the river. Advanced studies associated with multi-temporal spatially varied trading ratios among point sources to manage water pollution hold considerable potential for industries and policy makers alike. This paper aims to present an integrated simulation and optimization analysis for generating spatially varied trading ratios and evaluating seasonal transaction prices accordingly. It is designed to configure a permit-trading structure basin-wide and provide decision makers with a wealth of cost-effective, technology-oriented, risk-informed, and community-based management strategies. The case study, seamlessly integrating a QUAL2E simulation model with an optimal waste load allocation (WLA) scheme in a designated TMDL study area, helps understand the complexity of varying environmental resources values over space and time. The pollutants of concern in this region, which are eligible for trading, mainly include both biochemical oxygen demand (BOD) and ammonia-nitrogen (NH3-N). The problem solution, as a consequence, suggests an array of waste load reduction targets in a well-defined WLA scheme and exhibits a dynamic permit-trading framework among different sub-watersheds in the study area. Research findings gained in this paper may extend to any transferable dynamic-discharge permit (TDDP) program worldwide.

  11. Protecting capacity against malaria of chemically defined tetramer forms based on the Plasmodium falciparum apical sushi protein as potential vaccine components.

    PubMed

    Vanegas, Magnolia; Bermúdez, Adriana; Guerrero, Yuly Andrea; Cortes-Vecino, Jesús Alfredo; Curtidor, Hernando; Patarroyo, Manuel Elkin; Lozano, José Manuel

    2014-08-15

    Developing novel generations of subunit-based antimalarial vaccines in the form of chemically-defined macromolecule systems for multiple antigen presentation represents a classical problem in the field of vaccine development. Many efforts involving synthesis strategies leading to macromolecule constructs have been based on dendrimer-like systems, the condensation of large building blocks and conventional asymmetric double dimer constructs, all based on lysine cores. This work describes novel symmetric double dimer and condensed linear constructs for presenting selected peptide multi-copies from the apical sushi protein expressed in Plasmodium falciparum. These molecules have been proved to be safe and innocuous, highly antigenic and have shown strong protective efficacy in rodents challenged with two Plasmodium species. Insights into systematic design, synthesis and characterisation have led to such novel antigen systems being used as potential platforms for developing new anti-malarial vaccine candidates.

  12. Protecting capacity against malaria of chemically defined tetramer forms based on the Plasmodium falciparum apical sushi protein as potential vaccine components.

    PubMed

    Vanegas, Magnolia; Bermúdez, Adriana; Guerrero, Yuly Andrea; Cortes-Vecino, Jesús Alfredo; Curtidor, Hernando; Patarroyo, Manuel Elkin; Lozano, José Manuel

    2014-08-15

    Developing novel generations of subunit-based antimalarial vaccines in the form of chemically-defined macromolecule systems for multiple antigen presentation represents a classical problem in the field of vaccine development. Many efforts involving synthesis strategies leading to macromolecule constructs have been based on dendrimer-like systems, the condensation of large building blocks and conventional asymmetric double dimer constructs, all based on lysine cores. This work describes novel symmetric double dimer and condensed linear constructs for presenting selected peptide multi-copies from the apical sushi protein expressed in Plasmodium falciparum. These molecules have been proved to be safe and innocuous, highly antigenic and have shown strong protective efficacy in rodents challenged with two Plasmodium species. Insights into systematic design, synthesis and characterisation have led to such novel antigen systems being used as potential platforms for developing new anti-malarial vaccine candidates. PMID:25063026

  13. 40 CFR 49.155 - Permit requirements.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... digital records for continuous monitoring instrumentation and copies of all reports required by the permit... inspection by use of written, electronic, magnetic and photographic media. (b) Can my permit become...

  14. 45 CFR 670.13 - Permit administration.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... CONSERVATION OF ANTARCTIC ANIMALS AND PLANTS Permits § 670.13 Permit administration. (a) Issuance of the... U.S.C. 1531 et seq.) or any native bird which is protected under the Migratory Bird Treaty Act (16...

  15. 30 CFR 773.17 - Permit conditions.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... the maps submitted with the application and authorized for the term of the permit and that are subject... of this chapter for coal produced under the permit for sale, transfer or use, in the manner...

  16. 30 CFR 773.17 - Permit conditions.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... the maps submitted with the application and authorized for the term of the permit and that are subject... of this chapter for coal produced under the permit for sale, transfer or use, in the manner...

  17. 40 CFR 147.2927 - Permit modification.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... control (see § 147.2926, Permit Transfers); or (iv) Changing quantities or types of injected fluids, provided: (A) The facility can operate within conditions of permit; (B) The facility classification...

  18. 50 CFR 665.462 - Permits.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ..., DEPARTMENT OF COMMERCE (CONTINUED) FISHERIES IN THE WESTERN PACIFIC Mariana Archipelago Fisheries § 665.462... in any Mariana Archipelago precious coral permit area must have a permit issued under § 665.13....

  19. 50 CFR 665.462 - Permits.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ..., DEPARTMENT OF COMMERCE (CONTINUED) FISHERIES IN THE WESTERN PACIFIC Mariana Archipelago Fisheries § 665.462... in any Mariana Archipelago precious coral permit area must have a permit issued under § 665.13....

  20. 50 CFR 665.462 - Permits.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ..., DEPARTMENT OF COMMERCE (CONTINUED) FISHERIES IN THE WESTERN PACIFIC Mariana Archipelago Fisheries § 665.462... in any Mariana Archipelago precious coral permit area must have a permit issued under § 665.13....

  1. 50 CFR 665.462 - Permits.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ..., DEPARTMENT OF COMMERCE (CONTINUED) FISHERIES IN THE WESTERN PACIFIC Mariana Archipelago Fisheries § 665.462... in any Mariana Archipelago precious coral permit area must have a permit issued under § 665.13....

  2. 50 CFR 665.462 - Permits.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ..., DEPARTMENT OF COMMERCE (CONTINUED) FISHERIES IN THE WESTERN PACIFIC Mariana Archipelago Fisheries § 665.462... in any Mariana Archipelago precious coral permit area must have a permit issued under § 665.13....

  3. 78 FR 18420 - Special Permit Applications Actions

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-03-26

    ... Pipeline and Hazardous Materials Safety Administration Special Permit Applications Actions AGENCY: Pipeline and Hazardous Materials Safety Administration (PHMSA), DOT. ACTION: Notice of actions on special... processing of, special permits from the Department of Transportation's Hazardous Material Regulations (49...

  4. Contrasting infection susceptibility of the Japanese macaques and cynomolgus macaques to closely related malaria parasites, Plasmodium vivax and Plasmodium cynomolgi.

    PubMed

    Tachibana, Shin-Ichiro; Kawai, Satoru; Katakai, Yuko; Takahashi, Hideo; Nakade, Toru; Yasutomi, Yasuhiro; Horii, Toshihiro; Tanabe, Kazuyuki

    2015-06-01

    Although the human malaria parasite Plasmodium vivax is closely related to Asian Old World monkey malaria parasites, there are no reports of P. vivax infections in macaques. In this study, we compared the infectivity of P. vivax and Plasmodium cynomolgi in Japanese macaques (Macaca fuscata) and in cynomolgus macaques (Macaca fascicularis). The Japanese macaques were highly susceptible to P. cynomolgi but not to P. vivax, whereas cynomolgus macaques showed mild/limited P. cynomolgi infection and were, also, not susceptible to P. vivax. Serotyping and amino acid sequence comparison of erythrocyte surface Duffy antigen/receptor for chemokines (DARC) indicate that the Japanese macaque DARC sequence is nearly identical to that of rhesus (Macaca mulatta) and cynomolgus macaques. This suggests that the macaques share a common mechanism for preventing P. vivax infection. Comparison of amino acid sequences of the Duffy-binding-like (DBL) domain from several different Plasmodium species suggests that P. vivax DBLs will not bind to macaque DARCs, which can explain the lack of P. vivax infectivity. The DBL sequence analyses also suggest that P. cynomolgi DBLs may target Japanese macaque erythrocytes through a DARC-independent interaction.

  5. Host Defenses in Murine Malaria: Immunological Characteristics of a Protracted State of Immunity to Plasmodium yoelii

    PubMed Central

    Murphy, James R.

    1980-01-01

    Random-bred ICR mice recovered from infection with avirulent Plasmodium yoelii were challenged at various later times with virulent P. yoelii or with another species of Plasmodium, P. berghei, to characterize the immunological nature of the long-term state of immunity generated in response to the avirulent infection. It was found that recovered mice resisted lethal challenge with virulent P. yoelii through at least 416 days after primary infection. However, the quality of this immunity changed as the time after avirulent infection increased. Mice challenged early after recovery were able to prevent the development of patent parasitemia. Later, these immune animals lost this capacity and after challenge infections progressed to patency at the same rate as did nonimmune controls. However, after the establishment of parasitemia, those animals which had encountered the homologous parasite a long time before controlled, and then eliminated, blood infection and survived. The “early” state of immunity was expressed by animals which may have harbored small numbers of viable avirulent parasites and possessed a protective humoral factor which could passively transfer anti-P. yoelii activity to naive recipients. In contrast, animals with “late” immunity showed evidence of neither persisting avirulent parasites nor serum anti-P. yoelii activity. The results support the proposition that immunity to this parasite exists as two distinct but interrelated states of immunological reactivity: an early “active” immunity and a later state which has characteristics suggestive of a state of immunological memory wherewith the animals were capable of anamnestically responding to P. yoelii challenge. Little evidence of heterologous immunity to P. berghei was observed for animals recovered from P. yoelii. PMID:6987179

  6. Killer Bee Molecules: Antimicrobial Peptides as Effector Molecules to Target Sporogonic Stages of Plasmodium

    PubMed Central

    Carter, Victoria; Underhill, Ann; Baber, Ibrahima; Sylla, Lakamy; Baby, Mounirou; Larget-Thiery, Isabelle; Zettor, Agnès; Bourgouin, Catherine; Langel, Ülo; Faye, Ingrid; Otvos, Laszlo; Wade, John D.; Coulibaly, Mamadou B.; Traore, Sekou F.; Tripet, Frederic; Eggleston, Paul; Hurd, Hilary

    2013-01-01

    A new generation of strategies is evolving that aim to block malaria transmission by employing genetically modified vectors or mosquito pathogens or symbionts that express anti-parasite molecules. Whilst transgenic technologies have advanced rapidly, there is still a paucity of effector molecules with potent anti-malaria activity whose expression does not cause detrimental effects on mosquito fitness. Our objective was to examine a wide range of antimicrobial peptides (AMPs) for their toxic effects on Plasmodium and anopheline mosquitoes. Specifically targeting early sporogonic stages, we initially screened AMPs for toxicity against a mosquito cell line and P. berghei ookinetes. Promising candidate AMPs were fed to mosquitoes to monitor adverse fitness effects, and their efficacy in blocking rodent malaria infection in Anopheles stephensi was assessed. This was followed by tests to determine their activity against P. falciparum in An. gambiae, initially using laboratory cultures to infect mosquitoes, then culminating in preliminary assays in the field using gametocytes and mosquitoes collected from the same area in Mali, West Africa. From a range of 33 molecules, six AMPs able to block Plasmodium development were identified: Anoplin, Duramycin, Mastoparan X, Melittin, TP10 and Vida3. With the exception of Anoplin and Mastoparan X, these AMPs were also toxic to an An. gambiae cell line at a concentration of 25 µM. However, when tested in mosquito blood feeds, they did not reduce mosquito longevity or egg production at concentrations of 50 µM. Peptides effective against cultured ookinetes were less effective when tested in vivo and differences in efficacy against P. berghei and P. falciparum were seen. From the range of molecules tested, the majority of effective AMPs were derived from bee/wasp venoms. PMID:24278025

  7. Disease Progression in Plasmodium knowlesi Malaria Is Linked to Variation in Invasion Gene Family Members

    PubMed Central

    Divis, Paul C.; Siner, Angela; Zainudin, Ramlah; Wong, Ing Tien; Lu, Chan Woon; Singh-Khaira, Sarina K.; Millar, Scott B.; Lynch, Sean; Willmann, Matthias; Singh, Balbir; Krishna, Sanjeev; Cox-Singh, Janet

    2014-01-01

    Emerging pathogens undermine initiatives to control the global health impact of infectious diseases. Zoonotic malaria is no exception. Plasmodium knowlesi, a malaria parasite of Southeast Asian macaques, has entered the human population. P. knowlesi, like Plasmodium falciparum, can reach high parasitaemia in human infections, and the World Health Organization guidelines for severe malaria list hyperparasitaemia among the measures of severe malaria in both infections. Not all patients with P. knowlesi infections develop hyperparasitaemia, and it is important to determine why. Between isolate variability in erythrocyte invasion, efficiency seems key. Here we investigate the idea that particular alleles of two P. knowlesi erythrocyte invasion genes, P. knowlesi normocyte binding protein Pknbpxa and Pknbpxb, influence parasitaemia and human disease progression. Pknbpxa and Pknbpxb reference DNA sequences were generated from five geographically and temporally distinct P. knowlesi patient isolates. Polymorphic regions of each gene (approximately 800 bp) were identified by haplotyping 147 patient isolates at each locus. Parasitaemia in the study cohort was associated with markers of disease severity including liver and renal dysfunction, haemoglobin, platelets and lactate, (r = ≥0.34, p = <0.0001 for all). Seventy-five and 51 Pknbpxa and Pknbpxb haplotypes were resolved in 138 (94%) and 134 (92%) patient isolates respectively. The haplotypes formed twelve Pknbpxa and two Pknbpxb allelic groups. Patients infected with parasites with particular Pknbpxa and Pknbpxb alleles within the groups had significantly higher parasitaemia and other markers of disease severity. Our study strongly suggests that P. knowlesi invasion gene variants contribute to parasite virulence. We focused on two invasion genes, and we anticipate that additional virulent loci will be identified in pathogen genome-wide studies. The multiple sustained entries of this diverse pathogen into the

  8. Structurally conserved erythrocyte-binding domain in Plasmodium provides a versatile scaffold for alternate receptor engagement

    PubMed Central

    Gruszczyk, Jakub; Lim, Nicholas T. Y.; Arnott, Alicia; He, Wen-Qiang; Nguitragool, Wang; Roobsoong, Wanlapa; Mok, Yee-Foong; Murphy, James M.; Smith, Katherine R.; Lee, Stuart; Bahlo, Melanie; Mueller, Ivo; Barry, Alyssa E.

    2016-01-01

    Understanding how malaria parasites gain entry into human red blood cells is essential for developing strategies to stop blood stage infection. Plasmodium vivax preferentially invades reticulocytes, which are immature red blood cells. The organism has two erythrocyte-binding protein families: namely, the Duffy-binding protein (PvDBP) and the reticulocyte-binding protein (PvRBP) families. Several members of the PvRBP family bind reticulocytes, specifically suggesting a role in mediating host cell selectivity of P. vivax. Here, we present, to our knowledge, the first high-resolution crystal structure of an erythrocyte-binding domain from PvRBP2a, solved at 2.12 Å resolution. The monomeric molecule consists of 10 α-helices and one short β-hairpin, and, although the structural fold is similar to that of PfRh5—the essential invasion ligand in Plasmodium falciparum—its surface properties are distinct and provide a possible mechanism for recognition of alternate receptors. Sequence alignments of the crystallized fragment of PvRBP2a with other PvRBPs highlight the conserved placement of disulfide bonds. PvRBP2a binds mature red blood cells through recognition of an erythrocyte receptor that is neuraminidase- and chymotrypsin-resistant but trypsin-sensitive. By examining the patterns of sequence diversity within field isolates, we have identified and mapped polymorphic residues to the PvRBP2a structure. Using mutagenesis, we have also defined the critical residues required for erythrocyte binding. Characterization of the structural features that govern functional erythrocyte binding for the PvRBP family provides a framework for generating new tools that block P. vivax blood stage infection. PMID:26715754

  9. Disease progression in Plasmodium knowlesi malaria is linked to variation in invasion gene family members.

    PubMed

    Ahmed, Atique M; Pinheiro, Miguel M; Divis, Paul C; Siner, Angela; Zainudin, Ramlah; Wong, Ing Tien; Lu, Chan Woon; Singh-Khaira, Sarina K; Millar, Scott B; Lynch, Sean; Willmann, Matthias; Singh, Balbir; Krishna, Sanjeev; Cox-Singh, Janet

    2014-08-01

    Emerging pathogens undermine initiatives to control the global health impact of infectious diseases. Zoonotic malaria is no exception. Plasmodium knowlesi, a malaria parasite of Southeast Asian macaques, has entered the human population. P. knowlesi, like Plasmodium falciparum, can reach high parasitaemia in human infections, and the World Health Organization guidelines for severe malaria list hyperparasitaemia among the measures of severe malaria in both infections. Not all patients with P. knowlesi infections develop hyperparasitaemia, and it is important to determine why. Between isolate variability in erythrocyte invasion, efficiency seems key. Here we investigate the idea that particular alleles of two P. knowlesi erythrocyte invasion genes, P. knowlesi normocyte binding protein Pknbpxa and Pknbpxb, influence parasitaemia and human disease progression. Pknbpxa and Pknbpxb reference DNA sequences were generated from five geographically and temporally distinct P. knowlesi patient isolates. Polymorphic regions of each gene (approximately 800 bp) were identified by haplotyping 147 patient isolates at each locus. Parasitaemia in the study cohort was associated with markers of disease severity including liver and renal dysfunction, haemoglobin, platelets and lactate, (r = ≥ 0.34, p =  <0.0001 for all). Seventy-five and 51 Pknbpxa and Pknbpxb haplotypes were resolved in 138 (94%) and 134 (92%) patient isolates respectively. The haplotypes formed twelve Pknbpxa and two Pknbpxb allelic groups. Patients infected with parasites with particular Pknbpxa and Pknbpxb alleles within the groups had significantly higher parasitaemia and other markers of disease severity. Our study strongly suggests that P. knowlesi invasion gene variants contribute to parasite virulence. We focused on two invasion genes, and we anticipate that additional virulent loci will be identified in pathogen genome-wide studies. The multiple sustained entries of this diverse pathogen into the human

  10. A Plasmodium falciparum copper-binding membrane protein with copper transport motifs

    PubMed Central

    2012-01-01

    Background Copper is an essential catalytic co-factor for metabolically important cellular enzymes, such as cytochrome-c oxidase. Eukaryotic cells acquire copper through a copper transport protein and distribute intracellular copper using molecular chaperones. The copper chelator, neocuproine, inhibits Plasmodium falciparum ring-to-trophozoite transition in vitro, indicating a copper requirement for malaria parasite development. How the malaria parasite acquires or secretes copper still remains to be fully elucidated. Methods PlasmoDB was searched for sequences corresponding to candidate P. falciparum copper-requiring proteins. The amino terminal domain of a putative P. falciparum copper transport protein was cloned and expressed as a maltose binding fusion protein. The copper binding ability of this protein was examined. Copper transport protein-specific anti-peptide antibodies were generated in chickens and used to establish native protein localization in P. falciparum parasites by immunofluorescence microscopy. Results Six P. falciparum copper-requiring protein orthologs and a candidate P. falciparum copper transport protein (PF14_0369), containing characteristic copper transport protein features, were identified in PlasmoDB. The recombinant amino terminal domain of the transport protein bound reduced copper in vitro and within Escherichia coli cells during recombinant expression. Immunolocalization studies tracked the copper binding protein translocating from the erythrocyte plasma membrane in early ring stage to a parasite membrane as the parasites developed to schizonts. The protein appears to be a PEXEL-negative membrane protein. Conclusion Plasmodium falciparum parasites express a native protein with copper transporter characteristics that binds copper in vitro. Localization of the protein to the erythrocyte and parasite plasma membranes could provide a mechanism for the delivery of novel anti-malarial compounds. PMID:23190769

  11. Microwave generator

    DOEpatents

    Kwan, T.J.T.; Snell, C.M.

    1987-03-31

    A microwave generator is provided for generating microwaves substantially from virtual cathode oscillation. Electrons are emitted from a cathode and accelerated to an anode which is spaced apart from the cathode. The anode has an annular slit there through effective to form the virtual cathode. The anode is at least one range thickness relative to electrons reflecting from the virtual cathode. A magnet is provided to produce an optimum magnetic field having the field strength effective to form an annular beam from the emitted electrons in substantial alignment with the annular anode slit. The magnetic field, however, does permit the reflected electrons to axially diverge from the annular beam. The reflected electrons are absorbed by the anode in returning to the real cathode, such that substantially no reflexing electrons occur. The resulting microwaves are produced with a single dominant mode and are substantially monochromatic relative to conventional virtual cathode microwave generators. 6 figs.

  12. 76 FR 67181 - Windsor Machinery Co., Inc.; Notice of Preliminary Permit Application Accepted for Filing and...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-10-31

    ... Energy Regulatory Commission Windsor Machinery Co., Inc.; Notice of Preliminary Permit Application..., 2011, Windsor Machinery Co., Inc. filed an application for a preliminary permit, pursuant to section 4... an annual generation of 1,600 megawatt-hours. Applicant Contact: Sarah L. Bower, Windsor Machinery...

  13. 9 CFR 82.12 - Other interstate movements and special permits.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... required for the disposal of dead birds or dead poultry that are infected with END, or dead birds or dead poultry from flocks infected with END, or manure generated by or eggs from birds or poultry infected with... and special permits. (a) A special permit is required for the interstate movement of birds,...

  14. 9 CFR 82.12 - Other interstate movements and special permits.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... required for the disposal of dead birds or dead poultry that are infected with END, or dead birds or dead poultry from flocks infected with END, or manure generated by or eggs from birds or poultry infected with... and special permits. (a) A special permit is required for the interstate movement of birds,...

  15. 9 CFR 82.12 - Other interstate movements and special permits.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... required for the disposal of dead birds or dead poultry that are infected with END, or dead birds or dead poultry from flocks infected with END, or manure generated by or eggs from birds or poultry infected with... and special permits. (a) A special permit is required for the interstate movement of birds,...

  16. 9 CFR 82.12 - Other interstate movements and special permits.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... required for the disposal of dead birds or dead poultry that are infected with END, or dead birds or dead poultry from flocks infected with END, or manure generated by or eggs from birds or poultry infected with... and special permits. (a) A special permit is required for the interstate movement of birds,...

  17. State Waste Discharge Permit application: 200-W Powerhouse Ash Pit

    SciTech Connect

    Atencio, B.P.

    1994-06-01

    As part of the Hanford Federal Facility Agreement and Consent Order negotiations; the US Department of Energy, Richland Operations Office, the US Environmental Protection Agency, and the Washington State Department of Ecology agreed that liquid effluent discharges to the ground on the Hanford Site which affect groundwater or have the potential to affect groundwater would be subject to permitting under the structure of Chapter 173-216 (or 173-218 where applicable) of the Washington Administrative Code, the State Waste Discharge Permit Program. This document constitutes the State Waste Discharge Permit application for the 200-W Powerhouse Ash Pit. The 200-W Powerhouse Ash Waste Water discharges to the 200-W Powerhouse Ash Pit via dedicated pipelines. The 200-W Powerhouse Ash Waste Water is the only discharge to the 200-W Powerhouse Ash Pit. The 200-W Powerhouse is a steam generation facility consisting of a coal-handling and preparation section and boilers.

  18. State Waste Discharge Permit application: 200-E Powerhouse Ash Pit

    SciTech Connect

    Atencio, B.P.

    1994-06-01

    As part of the Hanford Federal Facility Agreement and Consent Order negotiations, the US Department and Energy, Richland Operations Office, the US Environmental Protection Agency, and the Washington State Department of Ecology agreed that liquid effluent discharges to the ground on the Hanford Site which affect groundwater or have the potential to affect groundwater would be subject to permitting under the structure of Chapter 173-216 (or 173-218 where applicable) of the Washington Administrative Code, the State Waste Discharge Permit Program. This document constitutes the State Waste Discharge Permit application for the 200-E Powerhouse Ash Pit. The 200-E Powerhouse Ash Waste Water discharges to the 200-E Powerhouse Ash Pit via dedicated pipelines. The 200-E Ash Waste Water is the only discharge to the 200-E Powerhouse Ash Pit. The 200-E Powerhouse is a steam generation facility consisting of a coal-handling and preparation section and boilers.

  19. 36 CFR 13.188 - Permit terms.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 36 Parks, Forests, and Public Property 1 2010-07-01 2010-07-01 false Permit terms. 13.188 Section....188 Permit terms. The Superintendent shall allow for use and occupancy of a temporary facility only to... Superintendent may also establish permit terms that: (a) Limit use to a specified period, not to exceed...

  20. 36 CFR 13.164 - Permit terms.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 36 Parks, Forests, and Public Property 1 2010-07-01 2010-07-01 false Permit terms. 13.164 Section... PARK SYSTEM UNITS IN ALASKA Cabins Cabin Use for Subsistence Purposes § 13.164 Permit terms. The Superintendent shall, among other conditions, establish terms of a permit that: (a) Allow for use and...

  1. 40 CFR 35.925-6 - Permits.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... ASSISTANCE Grants for Construction of Treatment Works-Clean Water Act § 35.925-6 Permits. That the applicant has, or has applied for, the permit or permits as required by the national pollutant discharge elimination system (NPDES) with respect to existing discharges affected by the proposed project....

  2. 50 CFR 665.203 - Permits.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... and Fisheries FISHERY CONSERVATION AND MANAGEMENT, NATIONAL OCEANIC AND ATMOSPHERIC ADMINISTRATION... required to obtain an MHI non-commercial bottomfish permit or a State of Hawaii Commercial Marine License...) Except as provided in subpart A of 15 CFR part 904, any applicant for a permit or a permit holder...

  3. 40 CFR 147.2924 - Area permits.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 23 2011-07-01 2011-07-01 false Area permits. 147.2924 Section 147... II Wells § 147.2924 Area permits. (a) Area permits may be issued for more than one injection well if... are of similar construction; and (4) All wells are operated by the same owner/operator. (b)...

  4. 40 CFR 147.2924 - Area permits.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 24 2012-07-01 2012-07-01 false Area permits. 147.2924 Section 147... II Wells § 147.2924 Area permits. (a) Area permits may be issued for more than one injection well if... are of similar construction; and (4) All wells are operated by the same owner/operator. (b)...

  5. 40 CFR 147.2924 - Area permits.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 22 2010-07-01 2010-07-01 false Area permits. 147.2924 Section 147... II Wells § 147.2924 Area permits. (a) Area permits may be issued for more than one injection well if... are of similar construction; and (4) All wells are operated by the same owner/operator. (b)...

  6. 40 CFR 147.2924 - Area permits.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 24 2013-07-01 2013-07-01 false Area permits. 147.2924 Section 147... II Wells § 147.2924 Area permits. (a) Area permits may be issued for more than one injection well if... are of similar construction; and (4) All wells are operated by the same owner/operator. (b)...

  7. 50 CFR 648.5 - Operator permits.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ..., that, if the permit is suspended or revoked pursuant to 15 CFR part 904, the operator cannot be aboard... 15 CFR part 904, the Regional Administrator shall issue an operator's permit within 30 days of...). (h) Duration. A permit is valid until it is revoked, suspended or modified under 15 CFR part 904,...

  8. 50 CFR 648.5 - Operator permits.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ..., that, if the permit is suspended or revoked pursuant to 15 CFR part 904, the operator cannot be aboard... 15 CFR part 904, the Regional Administrator shall issue an operator's permit within 30 days of...). (h) Duration. A permit is valid until it is revoked, suspended or modified under 15 CFR part 904,...

  9. 50 CFR 648.5 - Operator permits.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ..., that, if the permit is suspended or revoked pursuant to 15 CFR part 904, the operator cannot be aboard... 15 CFR part 904, the Regional Administrator shall issue an operator's permit within 30 days of...). (h) Duration. A permit is valid until it is revoked, suspended or modified under 15 CFR part 904,...

  10. 50 CFR 648.5 - Operator permits.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ..., that, if the permit is suspended or revoked pursuant to 15 CFR part 904, the operator cannot be aboard... 15 CFR part 904, the Regional Administrator shall issue an operator's permit within 30 days of...). (h) Duration. A permit is valid until it is revoked, suspended or modified under 15 CFR part 904,...

  11. 50 CFR 648.5 - Operator permits.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ..., that, if the permit is suspended or revoked pursuant to 15 CFR part 904, the operator cannot be aboard... 15 CFR part 904, the Regional Administrator shall issue an operator's permit within 30 days of...). (h) Duration. A permit is valid until it is revoked, suspended or modified under 15 CFR part 904,...

  12. 30 CFR 815.2 - Permitting information.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 3 2011-07-01 2011-07-01 false Permitting information. 815.2 Section 815.2... Permitting information. Notwithstanding cross-references in other parts which may be otherwise construed, part 772 establishes the notice and permit information requirements for coal exploration....

  13. 30 CFR 815.2 - Permitting information.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 30 Mineral Resources 3 2012-07-01 2012-07-01 false Permitting information. 815.2 Section 815.2... Permitting information. Notwithstanding cross-references in other parts which may be otherwise construed, part 772 establishes the notice and permit information requirements for coal exploration....

  14. 27 CFR 71.45 - Basic permits.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 2 2013-04-01 2013-04-01 false Basic permits. 71.45... for Citation § 71.45 Basic permits. Whenever the appropriate TTB officer has reason to believe that any person has willfully violated any of the conditions of his basic permit, or has not in fact or...

  15. 27 CFR 71.45 - Basic permits.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 2 2010-04-01 2010-04-01 false Basic permits. 71.45... for Citation § 71.45 Basic permits. Whenever the appropriate TTB officer has reason to believe that any person has willfully violated any of the conditions of his basic permit, or has not in fact or...

  16. 27 CFR 71.45 - Basic permits.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 2 2011-04-01 2011-04-01 false Basic permits. 71.45... for Citation § 71.45 Basic permits. Whenever the appropriate TTB officer has reason to believe that any person has willfully violated any of the conditions of his basic permit, or has not in fact or...

  17. 27 CFR 71.45 - Basic permits.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 2 2012-04-01 2011-04-01 true Basic permits. 71.45... for Citation § 71.45 Basic permits. Whenever the appropriate TTB officer has reason to believe that any person has willfully violated any of the conditions of his basic permit, or has not in fact or...

  18. 27 CFR 71.45 - Basic permits.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 2 2014-04-01 2014-04-01 false Basic permits. 71.45... for Citation § 71.45 Basic permits. Whenever the appropriate TTB officer has reason to believe that any person has willfully violated any of the conditions of his basic permit, or has not in fact or...

  19. 25 CFR 141.12 - Peddler's permits.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 25 Indians 1 2013-04-01 2013-04-01 false Peddler's permits. 141.12 Section 141.12 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR FINANCIAL ACTIVITIES BUSINESS PRACTICES ON THE NAVAJO... boundaries of the Hopi, Navajo, or Zuni reservations without a peddler's permit. The permit shall state...

  20. 25 CFR 141.12 - Peddler's permits.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 25 Indians 1 2011-04-01 2011-04-01 false Peddler's permits. 141.12 Section 141.12 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR FINANCIAL ACTIVITIES BUSINESS PRACTICES ON THE NAVAJO... boundaries of the Hopi, Navajo, or Zuni reservations without a peddler's permit. The permit shall state...

  1. 25 CFR 141.12 - Peddler's permits.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 25 Indians 1 2014-04-01 2014-04-01 false Peddler's permits. 141.12 Section 141.12 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR FINANCIAL ACTIVITIES BUSINESS PRACTICES ON THE NAVAJO... boundaries of the Hopi, Navajo, or Zuni reservations without a peddler's permit. The permit shall state...

  2. 25 CFR 141.12 - Peddler's permits.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 25 Indians 1 2012-04-01 2011-04-01 true Peddler's permits. 141.12 Section 141.12 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR FINANCIAL ACTIVITIES BUSINESS PRACTICES ON THE NAVAJO, HOPI... boundaries of the Hopi, Navajo, or Zuni reservations without a peddler's permit. The permit shall state...

  3. 40 CFR 72.51 - Permit shield.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... REGULATION Acid Rain Permit Contents § 72.51 Permit shield. Each affected unit operated in accordance with the Acid Rain permit that governs the unit and that was issued in compliance with title IV of the Act... operating in compliance with the Acid Rain Program, except as provided in § 72.9(g)(6)....

  4. 40 CFR 72.51 - Permit shield.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... REGULATION Acid Rain Permit Contents § 72.51 Permit shield. Each affected unit operated in accordance with the Acid Rain permit that governs the unit and that was issued in compliance with title IV of the Act... operating in compliance with the Acid Rain Program, except as provided in § 72.9(g)(6)....

  5. 40 CFR 72.51 - Permit shield.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... REGULATION Acid Rain Permit Contents § 72.51 Permit shield. Each affected unit operated in accordance with the Acid Rain permit that governs the unit and that was issued in compliance with title IV of the Act... operating in compliance with the Acid Rain Program, except as provided in § 72.9(g)(6)....

  6. 40 CFR 72.51 - Permit shield.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... REGULATION Acid Rain Permit Contents § 72.51 Permit shield. Each affected unit operated in accordance with the Acid Rain permit that governs the unit and that was issued in compliance with title IV of the Act... operating in compliance with the Acid Rain Program, except as provided in § 72.9(g)(6)....

  7. 40 CFR 72.51 - Permit shield.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... REGULATION Acid Rain Permit Contents § 72.51 Permit shield. Each affected unit operated in accordance with the Acid Rain permit that governs the unit and that was issued in compliance with title IV of the Act... operating in compliance with the Acid Rain Program, except as provided in § 72.9(g)(6)....

  8. 50 CFR 679.4 - Permits.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... programs codified at 50 CFR parts 300 and 679. These permits are listed in the following table. The date of... program permit or card type is: Permit is in effect from issue date through the end of: For more... subpart D of 15 CFR part 904. Such procedures are required for enforcement purposes, not...

  9. 40 CFR 172.5 - The permit.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) PESTICIDE PROGRAMS EXPERIMENTAL USE PERMITS Federal Issuance of Experimental Use Permits § 172.5 The permit. (a) Issuance. The Experimental... health and the environment. (d) Additions. With respect to an experimental use pesticide containing...

  10. 40 CFR 172.5 - The permit.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) PESTICIDE PROGRAMS EXPERIMENTAL USE PERMITS Federal Issuance of Experimental Use Permits § 172.5 The permit. (a) Issuance. The Experimental... health and the environment. (d) Additions. With respect to an experimental use pesticide containing...

  11. 40 CFR 172.5 - The permit.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) PESTICIDE PROGRAMS EXPERIMENTAL USE PERMITS Federal Issuance of Experimental Use Permits § 172.5 The permit. (a) Issuance. The Experimental... health and the environment. (d) Additions. With respect to an experimental use pesticide containing...

  12. 40 CFR 172.5 - The permit.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) PESTICIDE PROGRAMS EXPERIMENTAL USE PERMITS Federal Issuance of Experimental Use Permits § 172.5 The permit. (a) Issuance. The Experimental... health and the environment. (d) Additions. With respect to an experimental use pesticide containing...

  13. 40 CFR 172.5 - The permit.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) PESTICIDE PROGRAMS EXPERIMENTAL USE PERMITS Federal Issuance of Experimental Use Permits § 172.5 The permit. (a) Issuance. The Experimental... health and the environment. (d) Additions. With respect to an experimental use pesticide containing...

  14. 50 CFR 697.5 - Operator permits.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... of this permit, that if the permit is suspended or revoked pursuant to 15 CFR part 904, the operator... provided in subpart D of 15 CFR part 904, the Regional Administrator shall issue an operator's permit... is revoked, suspended, or modified under subpart D of 15 CFR part 904, or otherwise expires, or...

  15. 50 CFR 697.6 - Dealer permits.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... enforcement-related permit sanctions and denials, found at subpart D of 15 CFR part 904. (n) Lobster dealer... provided in subpart D of 15 CFR part 904, the Regional Administrator will issue a permit at any time during... permit is valid until it is revoked, suspended, or modified under 15 CFR part 904, or otherwise...

  16. 50 CFR 697.5 - Operator permits.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... of this permit, that if the permit is suspended or revoked pursuant to 15 CFR part 904, the operator... provided in subpart D of 15 CFR part 904, the Regional Administrator shall issue an operator's permit... is revoked, suspended, or modified under subpart D of 15 CFR part 904, or otherwise expires, or...

  17. 50 CFR 697.6 - Dealer permits.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... enforcement-related permit sanctions and denials, found at subpart D of 15 CFR part 904. (n) Lobster dealer... provided in subpart D of 15 CFR part 904, the Regional Administrator will issue a permit at any time during... permit is valid until it is revoked, suspended, or modified under 15 CFR part 904, or otherwise...

  18. 50 CFR 697.5 - Operator permits.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... of this permit, that if the permit is suspended or revoked pursuant to 15 CFR part 904, the operator... provided in subpart D of 15 CFR part 904, the Regional Administrator shall issue an operator's permit... is revoked, suspended, or modified under subpart D of 15 CFR part 904, or otherwise expires, or...

  19. 50 CFR 697.6 - Dealer permits.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... enforcement-related permit sanctions and denials, found at subpart D of 15 CFR part 904. (n) Lobster dealer... provided in subpart D of 15 CFR part 904, the Regional Administrator will issue a permit at any time during... permit is valid until it is revoked, suspended, or modified under 15 CFR part 904, or otherwise...

  20. 50 CFR 697.5 - Operator permits.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... of this permit, that if the permit is suspended or revoked pursuant to 15 CFR part 904, the operator... provided in subpart D of 15 CFR part 904, the Regional Administrator shall issue an operator's permit... is revoked, suspended, or modified under subpart D of 15 CFR part 904, or otherwise expires, or...

  1. 50 CFR 697.6 - Dealer permits.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... enforcement-related permit sanctions and denials, found at subpart D of 15 CFR part 904. (n) Lobster dealer... provided in subpart D of 15 CFR part 904, the Regional Administrator will issue a permit at any time during... permit is valid until it is revoked, suspended, or modified under 15 CFR part 904, or otherwise...

  2. 50 CFR 697.6 - Dealer permits.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... enforcement-related permit sanctions and denials, found at subpart D of 15 CFR part 904. (n) Lobster dealer... provided in subpart D of 15 CFR part 904, the Regional Administrator will issue a permit at any time during... permit is valid until it is revoked, suspended, or modified under 15 CFR part 904, or otherwise...

  3. 50 CFR 697.5 - Operator permits.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... of this permit, that if the permit is suspended or revoked pursuant to 15 CFR part 904, the operator... provided in subpart D of 15 CFR part 904, the Regional Administrator shall issue an operator's permit... is revoked, suspended, or modified under subpart D of 15 CFR part 904, or otherwise expires, or...

  4. 50 CFR 622.270 - Permits.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ..., DEPARTMENT OF COMMERCE FISHERIES OF THE CARIBBEAN, GULF OF MEXICO, AND SOUTH ATLANTIC Dolphin and Wahoo... while the vessel is at sea or offloading. (4) An owner of a vessel that is required to have a permitted... CFR part 904 is not aboard that vessel. (d) Dealer permits and conditions—(1) Permits. For a dealer...

  5. 50 CFR 660.707 - Permits.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... Permits. (a) General. This section applies to vessels that fish for HMS off or land HMS in the States of... must be registered for use under a HMS permit if that vessel is used: (i) To fish for HMS in the U.S... Tropical Tuna Commission. (2) All permits issued by NMFS in accordance with paragraph (b)(1) of...

  6. 32 CFR 935.11 - Permits.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... CODE Civil Administration Authority § 935.11 Permits. (a) Permits in effect on the dates specified in § 935.4 continue in effect until revoked or rescinded by the Commander. Permits issued by the Commander... consumption. (2) Self-propelled motor vehicles, except aircraft, including attached trailers. (3)...

  7. 33 CFR 126.21 - Permitted transactions.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 33 Navigation and Navigable Waters 2 2010-07-01 2010-07-01 false Permitted transactions. 126.21 Section 126.21 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) WATERFRONT FACILITIES HANDLING OF DANGEROUS CARGO AT WATERFRONT FACILITIES § 126.21 Permitted transactions. All permits issued pursuant to §...

  8. 33 CFR 126.21 - Permitted transactions.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 33 Navigation and Navigable Waters 2 2011-07-01 2011-07-01 false Permitted transactions. 126.21 Section 126.21 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) WATERFRONT FACILITIES HANDLING OF DANGEROUS CARGO AT WATERFRONT FACILITIES § 126.21 Permitted transactions. All permits issued pursuant to §...

  9. 25 CFR 173.7 - Permits, transferable.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 25 Indians 1 2014-04-01 2014-04-01 false Permits, transferable. 173.7 Section 173.7 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR LAND AND WATER CONCESSIONS, PERMITS AND LEASES ON LANDS WITHDRAWN OR ACQUIRED IN CONNECTION WITH INDIAN IRRIGATION PROJECTS § 173.7 Permits, transferable....

  10. 25 CFR 173.7 - Permits, transferable.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 25 Indians 1 2012-04-01 2011-04-01 true Permits, transferable. 173.7 Section 173.7 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR LAND AND WATER CONCESSIONS, PERMITS AND LEASES ON LANDS WITHDRAWN OR ACQUIRED IN CONNECTION WITH INDIAN IRRIGATION PROJECTS § 173.7 Permits, transferable....

  11. 25 CFR 173.7 - Permits, transferable.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 25 Indians 1 2010-04-01 2010-04-01 false Permits, transferable. 173.7 Section 173.7 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR LAND AND WATER CONCESSIONS, PERMITS AND LEASES ON LANDS WITHDRAWN OR ACQUIRED IN CONNECTION WITH INDIAN IRRIGATION PROJECTS § 173.7 Permits, transferable....

  12. 25 CFR 173.7 - Permits, transferable.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 25 Indians 1 2011-04-01 2011-04-01 false Permits, transferable. 173.7 Section 173.7 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR LAND AND WATER CONCESSIONS, PERMITS AND LEASES ON LANDS WITHDRAWN OR ACQUIRED IN CONNECTION WITH INDIAN IRRIGATION PROJECTS § 173.7 Permits, transferable....

  13. 25 CFR 173.7 - Permits, transferable.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 25 Indians 1 2013-04-01 2013-04-01 false Permits, transferable. 173.7 Section 173.7 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR LAND AND WATER CONCESSIONS, PERMITS AND LEASES ON LANDS WITHDRAWN OR ACQUIRED IN CONNECTION WITH INDIAN IRRIGATION PROJECTS § 173.7 Permits, transferable....

  14. 40 CFR 70.6 - Permit content.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... increases in emissions that are authorized by allowances acquired pursuant to the acid rain program... and air pollution control equipment), practices, or operations regulated or required under the permit... the general permit. General permits shall not be authorized for affected sources under the acid...

  15. 40 CFR 70.6 - Permit content.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... increases in emissions that are authorized by allowances acquired pursuant to the acid rain program... and air pollution control equipment), practices, or operations regulated or required under the permit... the general permit. General permits shall not be authorized for affected sources under the acid...

  16. 40 CFR 70.6 - Permit content.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... increases in emissions that are authorized by allowances acquired pursuant to the acid rain program... and air pollution control equipment), practices, or operations regulated or required under the permit... the general permit. General permits shall not be authorized for affected sources under the acid...

  17. 36 CFR 13.186 - Permit issuance.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 36 Parks, Forests, and Public Property 1 2011-07-01 2011-07-01 false Permit issuance. 13.186 Section 13.186 Parks, Forests, and Public Property NATIONAL PARK SERVICE, DEPARTMENT OF THE INTERIOR... § 13.186 Permit issuance. (a) In making a decision on a permit application, the Superintendent...

  18. 30 CFR 774.13 - Permit revisions.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 3 2010-07-01 2010-07-01 false Permit revisions. 774.13 Section 774.13 Mineral Resources OFFICE OF SURFACE MINING RECLAMATION AND ENFORCEMENT, DEPARTMENT OF THE INTERIOR SURFACE COAL...; RENEWAL; TRANSFER, ASSIGNMENT, OR SALE OF PERMIT RIGHTS; POST-PERMIT ISSUANCE REQUIREMENTS; AND...

  19. 30 CFR 774.15 - Permit renewals.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 3 2010-07-01 2010-07-01 false Permit renewals. 774.15 Section 774.15 Mineral Resources OFFICE OF SURFACE MINING RECLAMATION AND ENFORCEMENT, DEPARTMENT OF THE INTERIOR SURFACE COAL...; RENEWAL; TRANSFER, ASSIGNMENT, OR SALE OF PERMIT RIGHTS; POST-PERMIT ISSUANCE REQUIREMENTS; AND...

  20. Sequential Plasmodium chabaudi and Plasmodium berghei infections provide a novel model of severe malarial anemia.

    PubMed

    Harris, Juliana V; Bohr, Tiffany M; Stracener, Catherine; Landmesser, Mary E; Torres, Vladimir; Mbugua, Amos; Moratz, Chantal; Stoute, José A

    2012-09-01

    Lack of an adequate animal model of Plasmodium falciparum severe malarial anemia (SMA) has hampered the understanding of this highly lethal condition. We developed a model of SMA by infecting C57BL/6 mice with P. chabaudi followed after recovery by P. berghei infection. P. chabaudi/P. berghei-infected mice had an initial 9- to 10-day phase of relatively low parasitemia and severe anemia, followed by a second phase of hyperparasitemia, more profound anemia, reticulocytosis, and death 14 to 21 days after infection. P. chabaudi/P. berghei-infected animals had more intense splenic hematopoiesis, higher interleukin-10 (IL-10)/tumor necrosis factor alpha and IL-12/gamma interferon (IFN-γ) ratios, and higher antibody levels against P. berghei and P. chabaudi antigens than P. berghei-infected or P. chabaudi-recovered animals. Early treatment with chloroquine or artesunate did not prevent the anemia, suggesting that the bulk of red cell destruction was not due to the parasite. Red cells from P. chabaudi/P. berghei-infected animals had increased surface IgG and C3 by flow cytometry. However, C3(-/-) mice still developed anemia. Tracking of red cells labeled ex vivo and in vivo and analysis of frozen tissue sections by immunofluorescence microscopy showed that red cells from P. chabaudi/P. berghei-infected animals were removed at an accelerated rate in the liver by erythrophagocytosis. This model is practical and reproducible, and its similarities with P. falciparum SMA in humans makes it an appealing system with which to study the pathogenesis of this condition and explore potential immunomodulatory interventions.

  1. Human Plasmodium knowlesi Infection Detected by Rapid Diagnostic Tests for Malaria

    PubMed Central

    van Hellemond, Jaap J.; Rutten, Marijke; Koelewijn, Rob; Zeeman, Anne-Marie; Verweij, Jaco J.; Wismans, Pieter J.; Kocken, Clemens H.

    2009-01-01

    We describe a PCR-confirmed case of Plasmodium knowlesi infection with a high parasitemia level and clinical signs of severe malaria in a migrant worker from Malaysian Borneo in the Netherlands. Investigations showed that commercially available rapid antigen tests for detection of human Plasmodium infections can detect P. knowlesi infections in humans. PMID:19788819

  2. Copper pathways in Plasmodium falciparum infected erythrocytes indicate an efflux role for the copper P-ATPase.

    PubMed

    Rasoloson, Dominique; Shi, Lirong; Chong, Curtis R; Kafsack, Bjorn F; Sullivan, David J

    2004-08-01

    Copper, like iron, is a transition metal that can generate oxygen radicals by the Fenton reaction. The Plasmodium parasite invades an erythrocyte host cell containing 20 microM copper, of which 70% is contained in the Cu/Zn SOD (cuprozinc superoxide dismutase). In the present study, we follow the copper pathways in the Plasmodium-infected erythrocyte. Metal-determination analysis shows that the total copper content of Percoll-purified trophozoite-stage-infected erythrocytes is 66% that of uninfected erythrocytes. This decrease parallels the decrease seen in Cu/Zn SOD levels in parasite-infected erythrocytes. Neocuproine, an intracellular copper chelator, arrests parasites at the ring-to-trophozoite stage transition and also specifically decreases intraparasitic levels of Cu/Zn SOD and catalase. Up to 150 microM BCS (2,9-dimethyl-4,7-diphenyl-1,10-phenanthrolinedisulphonic acid), an extracellular copper chelator, has no effect on parasite growth. We characterized a single copy PfCuP-ATPase (Plasmodium falciparum copper P-ATPase) transporter, which, like the Crypto-sporidium parvum copper P-ATPase, has a single copper-binding domain: 'Met-Xaa-Cys-Xaa-Xaa-Cys'. Recombinant expression of the N-terminal metal-binding domain reveals that the protein specifically binds reduced copper. Transcription of the PfCuP-ATPase gene is the highest at late ring stage/early trophozoite, and is down-regulated in the presence of neocuproine. Immunofluorescence and electron microscopy indicate the transporter to be both in the parasite and on the erythrocyte membrane. Both the decrease in total copper and the location of the PfCuP-ATPase gene indicate a copper-efflux pathway from the infected erythrocyte.

  3. Loop-Mediated Isothermal Amplification Assay for Identification of Five Human Plasmodium Species in Malaysia.

    PubMed

    Lau, Yee-Ling; Lai, Meng-Yee; Fong, Mun-Yik; Jelip, Jenarun; Mahmud, Rohela

    2016-02-01

    The lack of rapid, affordable, and accurate diagnostic tests represents the primary hurdle affecting malaria surveillance in resource- and expertise-limited areas. Loop-mediated isothermal amplification (LAMP) is a sensitive, rapid, and cheap diagnostic method. Five species-specific LAMP assays were developed based on 18S rRNA gene. Sensitivity and specificity of LAMP results were calculated as compared with microscopic examination and nested polymerase chain reaction. LAMP reactions were highly sensitive with the detection limit of one copy for Plasmodium vivax, Plasmodium falciparum, and Plasmodium malariae and 10 copies for Plasmodium knowlesi and Plasmodium ovale. LAMP positively detected all human malaria species in all positive samples (N = 134; sensitivity = 100%) within 35 minutes. All negative samples were not amplified by LAMP (N = 67; specificity = 100%). LAMP successfully detected two samples with very low parasitemia. LAMP may offer a rapid, simple, and reliable test for the diagnosis of malaria in areas where malaria is prevalent.

  4. 33 CFR Appendix A to Part 331 - Administrative Appeal Process for Permit Denials and Proffered Permits

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... Permit Denials and Proffered Permits A Appendix A to Part 331 Navigation and Navigable Waters CORPS OF ENGINEERS, DEPARTMENT OF THE ARMY, DEPARTMENT OF DEFENSE ADMINISTRATIVE APPEAL PROCESS Pt. 331, App. A Appendix A to Part 331—Administrative Appeal Process for Permit Denials and Proffered Permits ER28MR00.000...

  5. 40 CFR 72.32 - Permit application shield and binding effect of permit application.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) PERMITS REGULATION Acid Rain Permit Applications § 72.32... submits a timely and complete Acid Rain permit application, the owners and operators of the affected... requirement to have an Acid Rain permit under § 72.9(a)(2) and § 72.30(a); provided that any delay in...

  6. 40 CFR 72.32 - Permit application shield and binding effect of permit application.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) PERMITS REGULATION Acid Rain Permit Applications § 72.32... submits a timely and complete Acid Rain permit application, the owners and operators of the affected... requirement to have an Acid Rain permit under § 72.9(a)(2) and § 72.30(a); provided that any delay in...

  7. 40 CFR 72.32 - Permit application shield and binding effect of permit application.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) PERMITS REGULATION Acid Rain Permit Applications § 72.32... submits a timely and complete Acid Rain permit application, the owners and operators of the affected... requirement to have an Acid Rain permit under § 72.9(a)(2) and § 72.30(a); provided that any delay in...

  8. 40 CFR 72.32 - Permit application shield and binding effect of permit application.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) PERMITS REGULATION Acid Rain Permit Applications § 72.32... submits a timely and complete Acid Rain permit application, the owners and operators of the affected... requirement to have an Acid Rain permit under § 72.9(a)(2) and § 72.30(a); provided that any delay in...

  9. 40 CFR 72.32 - Permit application shield and binding effect of permit application.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) PERMITS REGULATION Acid Rain Permit Applications § 72.32... submits a timely and complete Acid Rain permit application, the owners and operators of the affected... requirement to have an Acid Rain permit under § 72.9(a)(2) and § 72.30(a); provided that any delay in...

  10. 76 FR 81932 - Auction of FM Broadcast Construction Permits; Revised Construction Permit Number in Auction 93

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-29

    ... COMMISSION Auction of FM Broadcast Construction Permits; Revised Construction Permit Number in Auction 93... the construction permit number for one of the FM broadcast construction permits for Auction 93. FOR...'s Electronic Comment Filing System (ECFS) Web page at http://www.fcc.gov/cgb/ecfs/ . ] 1....

  11. 50 CFR 13.25 - Transfer of permits and scope of permit authorization.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 50 Wildlife and Fisheries 1 2010-10-01 2010-10-01 false Transfer of permits and scope of permit authorization. 13.25 Section 13.25 Wildlife and Fisheries UNITED STATES FISH AND WILDLIFE SERVICE, DEPARTMENT OF... OF WILDLIFE AND PLANTS GENERAL PERMIT PROCEDURES Permit Administration § 13.25 Transfer of...

  12. Federal Environmental Permitting Handbook. Environmental Guidance

    SciTech Connect

    Not Available

    1991-05-01

    The handbook consists of eight chapters addressing permitting and licensing requirements under the Resource Conservation and Recovery Act (RCRA), the Comprehensive Environmental Response, Compensation, and Liability Act of 1980, as amended by the Superfund Amendments and Reauthorization Act of 1986 (CERCLA/SARA), the Atomic Energy Act (AEA), the Clean Air Act (CAA), the Clean Water Act (CWA), the Federal Insectide, Fungicide, and Rodenticide Act (FIFRA), the Safe Drinking Water Act (SDWA), and the Toxic Substances Control Act (TSCA). Each chapter consists of: (1) an introduction to the statute and permitting requirements; (2) a diagram illustrating the relationship between permitting requirements under the statute being discussed and permitting requirements from other environmental statutes which may have to be addressed when applying for a particular permit (e.g., when applying for a RCRA permit, permits and permit applications under the CWA, CAA, SDWA, etc. would have to be listed in the RCRA permit application); and, (3) a compilation of the permitting requirements for the regulatory program resulting from the statute. In addition, the Handbook contains a permitting keyword index and a listing of hotline telephone numbers for each of the statutes.

  13. Reducing concentrated animal feeding operations permitting requirements.

    PubMed

    Centner, T J; Newton, G L

    2011-12-01

    Many owners and operators of concentrated animal feeding operations (CAFO) need to secure National Pollutant Discharge Elimination System permits from the federal or state permitting authority. Because of the expense and inconvenience of permit applications, farm groups have challenged revisions to the federal CAFO Rule as well as state regulations claiming selected provisions exceeded the authority of the permitting agency. In 2011, 2 courts responded with decisions that clarify federal and state permitting regulations. Another goal of agricultural groups is to change the regulatory authority of the state from an environmental agency to a department of agriculture. These developments suggest that by altering the permitting authority, CAFO owners and operators may alleviate some of the burdens of the permitting process. PMID:21821805

  14. Annual Hanford Site Environmental Permitting Status Report

    SciTech Connect

    HOMAN, N.A.

    2000-10-01

    The information contained in, and/or referenced in, this Annual Hanford Site Environmental Permitting Status Report addresses Permit Condition II.W (Other Permits and/or Approvals) of the Dangerous Waste Portion of the Resource Conservation and Recovery Act Permit for the Treatment, Storage, and Disposal of Dangerous Waste, issued by the Washington State Department of Ecology (WA7890008967). Condition II.W specifies that the Permittees are responsible for obtaining all other applicable federal, state, and local permits authorizing the development and operation of the Hanford Facility. This status report also addresses Permit Condition I.E.22, as interpreted in Section 12.1.25 of the Hanford Facility Dangerous Waste Permit Application, General Information Portion (DOE/RL-91-28, Rev. 4), that states this report will be prepared annually and a copy of this report will be placed in the Facility Operating Record, General Information file by October 1 of each year.

  15. Homology-Based Prediction of Potential Protein–Protein Interactions between Human Erythrocytes and Plasmodium falciparum

    PubMed Central

    Ramakrishnan, Gayatri; Srinivasan, Narayanaswamy; Padmapriya, Ponnan; Natarajan, Vasant

    2015-01-01

    Plasmodium falciparum, a causative agent of malaria, is a well-characterized obligate intracellular parasite known for its ability to remodel host cells, particularly erythrocytes, to successfully persist in the host environment. However, the current levels of understanding from the laboratory experiments on the host–parasite interactions and the strategies pursued by the parasite to remodel host erythrocytes are modest. Several computational means developed in the recent past to predict host–parasite/pathogen interactions have generated testable hypotheses on feasible protein–protein interactions. We demonstrate the utility of protein structure-based protocol in the recognition of potential interacting proteins across P. falciparum and host erythrocytes. In concert with the information on the expression and subcellular localization of host and parasite proteins, we have identified 208 biologically feasible interactions potentially brought about by 59 P. falciparum and 30 host erythrocyte proteins. For selected cases, we have evaluated the physicochemical viability of the predicted interactions in terms of surface complementarity, electrostatic complementarity, and interaction energies at protein interface regions. Such careful inspection of molecular and mechanistic details generates high confidence on the predicted host–parasite protein–protein interactions. The predicted host–parasite interactions generate many experimentally testable hypotheses that can contribute to the understanding of possible mechanisms undertaken by the parasite in host erythrocyte remodeling. Thus, the key protein players recognized in P. falciparum can be explored for their usefulness as targets for chemotherapeutic intervention. PMID:26740742

  16. Regular production of infective sporozoites of Plasmodium falciparum and P. vivax in laboratory-bred Anopheles albimanus.

    PubMed

    Hurtado, S; Salas, M L; Romero, J F; Zapata, J C; Ortiz, H; Arevalo-Herrera, M; Herrera, S

    1997-01-01

    One of the major constraints for studies on the sporogonic cycle of the parasites causing human malaria, and on the protective efficacy of pre-erythrocytic vaccines, is the scarcity of laboratory-reared Anopheles mosquitoes as a source of infective sporozoites. The aim of the present study was to reproduce the life-cycles of Plasmodium falciparum and P. vivax in the laboratory and so develop the ability to produce infective sporozoites of these two species regularly under laboratory conditions. Colonized Anopheles albimanus, of Buenaventura and Tecojate strains, were infected by feeding either on Plasmodium-infected blood, from human patients or experimentally inoculated Aotus monkeys, or on gametocytes of the P. falciparum NF-54 isolate grown in vitro. The monkeys were infected with the blood stages of a Colombian P. vivax isolate and then, after recovery, with the Santa Lucia strain of P. falciparum from El Salvador. Although both of the mosquito strains used were successfully infected with both parasite species, the Buenaventura strain of mosquito was generally more susceptible to infection than the Tecojate strain, and particularly to infection with the parasites from the patients, who lived where this strain of mosquitoes was originally isolated. Monkeys injected intravenously with the P. vivax sporozoites produced in the mosquitoes developed patent sexual and asexual parasitaemias; the gametocytes that developed could then be used to infect mosquitoes, allowing the development of more sporozoites. However, experimental infections failed to establish after the P. falciparum sporozoites were used to inoculate monkeys. The ability to reproduce the complete life cycle of P. vivax in the laboratory, from human to mosquito and then to monkey, should greatly facilitate many studies on vivax malaria and on the efficacy of candidate malaria vaccines. The availability of the sporogonic cycles of P. falciparum from three different sources should also permit a variety of

  17. A World Malaria Map: Plasmodium falciparum Endemicity in 2007

    PubMed Central

    Hay, Simon I; Guerra, Carlos A; Gething, Peter W; Patil, Anand P; Tatem, Andrew J; Noor, Abdisalan M; Kabaria, Caroline W; Manh, Bui H; Elyazar, Iqbal R. F; Brooker, Simon; Smith, David L; Moyeed, Rana A; Snow, Robert W

    2009-01-01

    Background Efficient allocation of resources to intervene against malaria requires a detailed understanding of the contemporary spatial distribution of malaria risk. It is exactly 40 y since the last global map of malaria endemicity was published. This paper describes the generation of a new world map of Plasmodium falciparum malaria endemicity for the year 2007. Methods and Findings A total of 8,938 P. falciparum parasite rate (PfPR) surveys were identified using a variety of exhaustive search strategies. Of these, 7,953 passed strict data fidelity tests for inclusion into a global database of PfPR data, age-standardized to 2–10 y for endemicity mapping. A model-based geostatistical procedure was used to create a continuous surface of malaria endemicity within previously defined stable spatial limits of P. falciparum transmission. These procedures were implemented within a Bayesian statistical framework so that the uncertainty of these predictions could be evaluated robustly. The uncertainty was expressed as the probability of predicting correctly one of three endemicity classes; previously stratified to be an informative guide for malaria control. Population at risk estimates, adjusted for the transmission modifying effects of urbanization in Africa, were then derived with reference to human population surfaces in 2007. Of the 1.38 billion people at risk of stable P. falciparum malaria, 0.69 billion were found in Central and South East Asia (CSE Asia), 0.66 billion in Africa, Yemen, and Saudi Arabia (Africa+), and 0.04 billion in the Americas. All those exposed to stable risk in the Americas were in the lowest endemicity class (PfPR2−10 ≤ 5%). The vast majority (88%) of those living under stable risk in CSE Asia were also in this low endemicity class; a small remainder (11%) were in the intermediate endemicity class (PfPR2−10 > 5 to < 40%); and the remaining fraction (1%) in high endemicity (PfPR2−10 ≥ 40%) areas. High endemicity was widespread in the

  18. Comparison of the Performances of Five Primer Sets for the Detection and Quantification of Plasmodium in Anopheline Vectors by Real-Time PCR

    PubMed Central

    Chaumeau, V.; Andolina, C.; Fustec, B.; Tuikue Ndam, N.; Brengues, C.; Herder, S.; Cerqueira, D.; Chareonviriyaphap, T.; Nosten, F.; Corbel, V.

    2016-01-01

    Quantitative real-time polymerase chain reaction (qrtPCR) has made a significant improvement for the detection of Plasmodium in anopheline vectors. A wide variety of primers has been used in different assays, mostly adapted from molecular diagnosis of malaria in human. However, such an adaptation can impact the sensitivity of the PCR. Therefore we compared the sensitivity of five primer sets with different molecular targets on blood stages, sporozoites and oocysts standards of Plasmodium falciparum (Pf) and P. vivax (Pv). Dilution series of standard DNA were used to discriminate between methods at low concentrations of parasite and to generate standard curves suitable for the absolute quantification of Plasmodium sporozoites. Our results showed that the best primers to detect blood stages were not necessarily the best ones to detect sporozoites. Absolute detection threshold of our qrtPCR assay varied between 3.6 and 360 Pv sporozoites and between 6 and 600 Pf sporozoites per mosquito according to the primer set used in the reaction mix. In this paper, we discuss the general performance of each primer set and highlight the need to use efficient detection methods for transmission studies. PMID:27441839

  19. Comparison of the Performances of Five Primer Sets for the Detection and Quantification of Plasmodium in Anopheline Vectors by Real-Time PCR.

    PubMed

    Chaumeau, V; Andolina, C; Fustec, B; Tuikue Ndam, N; Brengues, C; Herder, S; Cerqueira, D; Chareonviriyaphap, T; Nosten, F; Corbel, V

    2016-01-01

    Quantitative real-time polymerase chain reaction (qrtPCR) has made a significant improvement for the detection of Plasmodium in anopheline vectors. A wide variety of primers has been used in different assays, mostly adapted from molecular diagnosis of malaria in human. However, such an adaptation can impact the sensitivity of the PCR. Therefore we compared the sensitivity of five primer sets with different molecular targets on blood stages, sporozoites and oocysts standards of Plasmodium falciparum (Pf) and P. vivax (Pv). Dilution series of standard DNA were used to discriminate between methods at low concentrations of parasite and to generate standard curves suitable for the absolute quantification of Plasmodium sporozoites. Our results showed that the best primers to detect blood stages were not necessarily the best ones to detect sporozoites. Absolute detection threshold of our qrtPCR assay varied between 3.6 and 360 Pv sporozoites and between 6 and 600 Pf sporozoites per mosquito according to the primer set used in the reaction mix. In this paper, we discuss the general performance of each primer set and highlight the need to use efficient detection methods for transmission studies. PMID:27441839

  20. Evidence for the Contribution of the Hemozoin Synthesis Pathway of the Murine Plasmodium yoelii to the Resistance to Artemisinin-Related Drugs

    PubMed Central

    Nicolau-Travers, Marie-Laure; Iriart, Xavier; Njomnang Soh, Patrice; Bousejra-ElGarah, Fatima; Meunier, Bernard; Berry, Antoine; Benoit-Vical, Françoise

    2012-01-01

    Plasmodium falciparum malaria is a major global health problem, causing approximately 780,000 deaths each year. In response to the spreading of P. falciparum drug resistance, WHO recommended in 2001 to use artemisinin derivatives in combination with a partner drug (called ACT) as first-line treatment for uncomplicated falciparum malaria, and most malaria-endemic countries have since changed their treatment policies accordingly. Currently, ACT are often the last treatments that can effectively and rapidly cure P. falciparum infections permitting to significantly decrease the mortality and the morbidity due to malaria. However, alarming signs of emerging resistance to artemisinin derivatives along the Thai-Cambodian border are of major concern. Through long-term in vivo pressures, we have been able to select a murine malaria model resistant to artemisinins. We demonstrated that the resistance of Plasmodium to artemisinin-based compounds depends on alterations of heme metabolism and on a loss of hemozoin formation linked to the down-expression of the recently identified Heme Detoxification Protein (HDP). These artemisinins resistant strains could be able to detoxify the free heme by an alternative catabolism pathway involving glutathione (GSH)-mediation. Finally, we confirmed that artemisinins act also like quinolines against Plasmodium via hemozoin production inhibition. The work proposed here described the mechanism of action of this class of molecules and the resistance to artemisinins of this model. These results should help both to reinforce the artemisinins activity and avoid emergence and spread of endoperoxides resistance by focusing in adequate drug partners design. Such considerations appear crucial in the current context of early artemisinin resistance in Asia. PMID:22403683

  1. Evaluation of the Sensitivity of a pLDH-Based and an Aldolase-Based Rapid Diagnostic Test for Diagnosis of Uncomplicated and Severe Malaria Caused by PCR-Confirmed Plasmodium knowlesi, Plasmodium falciparum, and Plasmodium vivax

    PubMed Central

    William, Timothy; Grigg, Matthew J.; Piera, Kim; Yeo, Tsin W.; Anstey, Nicholas M.

    2013-01-01

    Plasmodium knowlesi can cause severe and fatal human malaria in Southeast Asia. Rapid diagnosis of all Plasmodium species is essential for initiation of effective treatment. Rapid diagnostic tests (RDTs) are sensitive for detection of uncomplicated and severe falciparum malaria but have not been systematically evaluated in knowlesi malaria. At a tertiary referral hospital in Sabah, Malaysia, we prospectively evaluated the sensitivity of two combination RDTs for the diagnosis of uncomplicated and severe malaria from all three potentially fatal Plasmodium species, using a pan-Plasmodium lactate dehydrogenase (pLDH)-P. falciparum histidine-rich protein 2 (PfHRP2) RDT (First Response) and a pan-Plasmodium aldolase-PfHRP2 RDT (ParaHIT). Among 293 hospitalized adults with PCR-confirmed Plasmodium monoinfection, the sensitivity of the pLDH component of the pLDH-PfHRP2 RDT was 74% (95/129; 95% confidence interval [CI], 65 to 80%), 91% (110/121; 95% CI, 84 to 95%), and 95% (41/43; 95% CI, 85 to 99%) for PCR-confirmed P. knowlesi, P. falciparum, and P. vivax infections, respectively, and 88% (30/34; 95% CI, 73 to 95%), 90% (38/42; 95% CI, 78 to 96%), and 100% (12/12; 95% CI, 76 to 100%) among patients tested before antimalarial treatment was begun. Sensitivity in severe malaria was 95% (36/38; 95% CI, 83 to 99), 100% (13/13; 95% CI, 77 to 100), and 100% (7/7; 95% CI, 65 to 100%), respectively. The aldolase component of the aldolase-PfHRP2 RDT performed poorly in all Plasmodium species. The pLDH-based RDT was highly sensitive for the diagnosis of severe malaria from all species; however, neither the pLDH- nor aldolase-based RDT demonstrated sufficiently high overall sensitivity for P. knowlesi. More sensitive RDTs are needed in regions of P. knowlesi endemicity. PMID:23345297

  2. Evaluation of the sensitivity of a pLDH-based and an aldolase-based rapid diagnostic test for diagnosis of uncomplicated and severe malaria caused by PCR-confirmed Plasmodium knowlesi, Plasmodium falciparum, and Plasmodium vivax.

    PubMed

    Barber, Bridget E; William, Timothy; Grigg, Matthew J; Piera, Kim; Yeo, Tsin W; Anstey, Nicholas M

    2013-04-01

    Plasmodium knowlesi can cause severe and fatal human malaria in Southeast Asia. Rapid diagnosis of all Plasmodium species is essential for initiation of effective treatment. Rapid diagnostic tests (RDTs) are sensitive for detection of uncomplicated and severe falciparum malaria but have not been systematically evaluated in knowlesi malaria. At a tertiary referral hospital in Sabah, Malaysia, we prospectively evaluated the sensitivity of two combination RDTs for the diagnosis of uncomplicated and severe malaria from all three potentially fatal Plasmodium species, using a pan-Plasmodium lactate dehydrogenase (pLDH)-P. falciparum histidine-rich protein 2 (PfHRP2) RDT (First Response) and a pan-Plasmodium aldolase-PfHRP2 RDT (ParaHIT). Among 293 hospitalized adults with PCR-confirmed Plasmodium monoinfection, the sensitivity of the pLDH component of the pLDH-PfHRP2 RDT was 74% (95/129; 95% confidence interval [CI], 65 to 80%), 91% (110/121; 95% CI, 84 to 95%), and 95% (41/43; 95% CI, 85 to 99%) for PCR-confirmed P. knowlesi, P. falciparum, and P. vivax infections, respectively, and 88% (30/34; 95% CI, 73 to 95%), 90% (38/42; 95% CI, 78 to 96%), and 100% (12/12; 95% CI, 76 to 100%) among patients tested before antimalarial treatment was begun. Sensitivity in severe malaria was 95% (36/38; 95% CI, 83 to 99), 100% (13/13; 95% CI, 77 to 100), and 100% (7/7; 95% CI, 65 to 100%), respectively. The aldolase component of the aldolase-PfHRP2 RDT performed poorly in all Plasmodium species. The pLDH-based RDT was highly sensitive for the diagnosis of severe malaria from all species; however, neither the pLDH- nor aldolase-based RDT demonstrated sufficiently high overall sensitivity for P. knowlesi. More sensitive RDTs are needed in regions of P. knowlesi endemicity.

  3. [Monkey malaria (Plasmodium knowlesi infection) after travelling to Thailand].

    PubMed

    Kroidl, Inge; Seilmaier, Michael; Berens-Riha, Nicole; Bretzel, Gisela; Wendtner, Clemens; Löscher, Thomas

    2015-05-01

    A case of malaria caused by Plasmodium knowlesi is described in a 52-year-old female German traveler after returning from Thailand. P. knowlesi is a parasite of macaques in Southeast Asia and has been recognized in recent years as an important and probably increasing cause of human malaria in some areas. At least 16 cases in international travelers have been published so far. This includes four cases imported to Germany. All German patients visited forested areas in Southern Thailand inhabited by the natural monkey host prior to their illness. Most cases diagnosed in endemic areas present as mild disease. However in some patients P. knowlesi may take a severe and life-threatening course. Diagnosis is usually is based on microscopy whereas rapid tests are not reliable. However, microscopic differentiation of P. knowlesi from other plasmodium species (eg, P. malariae, P. falciparum) is difficult, especially when parasitemia is low. Thus PCR methods are required for definite species determination. Changing endemicity as well as changing tourism patterns such as the trend towards eco-tourism might increase the risk of infection for travelers even in areas which are considered as low endemic for malaria. Malaria has to be considered in all febrile patients returning from endemic areas. In Southeast Asia this has to include Plasmodium knowlesi infection. Especially if microscopy suggests P. falciparum/P. malariae double infection, or when results indicate P. malariae but the clinical presentation differs from that of quartan malaria (eg, daily fever), diagnostic procedures for P. knowlesi should be initiated. Currently available rapid diagnostic tests are not reliable for the detection of P. knowlesi. The definite diagnosis of P. knowlesi infection usually requires PCR techniques Changing tourism patterns such as the trend towards eco-tourism might increase the risk of infection for travelers even in low prevalence areas. PMID:26080720

  4. Multiplicity of Infection and Disease Severity in Plasmodium vivax

    PubMed Central

    Pacheco, M. Andreína; Lopez-Perez, Mary; Vallejo, Andrés F.; Herrera, Sócrates; Arévalo-Herrera, Myriam; Escalante, Ananias A.

    2016-01-01

    Background Multiplicity of infection (MOI) refers to the average number of distinct parasite genotypes concurrently infecting a patient. Although several studies have reported on MOI and the frequency of multiclonal infections in Plasmodium falciparum, there is limited data on Plasmodium vivax. Here, MOI and the frequency of multiclonal infections were studied in areas from South America where P. vivax and P. falciparum can be compared. Methodology/Principal Findings As part of a passive surveillance study, 1,328 positive malaria patients were recruited between 2011 and 2013 in low transmission areas from Colombia. Of those, there were only 38 P. vivax and 24 P. falciparum clinically complicated cases scattered throughout the time of the study. Samples from uncomplicated cases were matched in time and location with the complicated cases in order to compare the circulating genotypes for these two categories. A total of 92 P. vivax and 57 P. falciparum uncomplicated cases were randomly subsampled. All samples were genotyped by using neutral microsatellites. Plasmodium vivax showed more multiclonal infections (47.7%) than P. falciparum (14.8%). Population genetics and haplotype network analyses did not detect differences in the circulating genotypes between complicated and uncomplicated cases in each parasite. However, a Fisher exact test yielded a significant association between having multiclonal P. vivax infections and complicated malaria. No association was found for P. falciparum infections. Conclusion The association between multiclonal infections and disease severity in P. vivax is consistent with previous observations made in rodent malaria. The contrasting pattern between P. vivax and P. falciparum could be explained, at least in part, by the fact that P. vivax infections have lineages that were more distantly related among them than in the case of the P. falciparum multiclonal infections. Future research should address the possible role that acquired

  5. Clinical and Laboratory Features of Human Plasmodium knowlesi Infection

    PubMed Central

    Daneshvar, Cyrus; Davis, Timothy M. E.; Cox-Singh, Janet; Rafa’ee, Mohammad Zakri; Zakaria, Siti Khatijah; Divis, Paul C. S.; Singh, Balbir

    2010-01-01

    Background Plasmodium knowlesi is increasingly recognized as a cause of human malaria in Southeast Asia but there are no detailed prospective clinical studies of naturally acquired infections. Methods In a systematic study of the presentation and course of patients with acute P. knowlesi infection, clinical and laboratory data were collected from previously untreated, nonpregnant adults admitted to the hospital with polymerase chain reaction–confirmed acute malaria at Kapit Hospital (Sarawak, Malaysia) from July 2006 through February 2008. Results Of 152 patients recruited, 107 (70%) had P. knowlesi infection, 24 (16%) had Plasmodium falciparum infection, and 21 (14%) had Plasmodium vivax. Patients with P. knowlesi infection presented with a nonspecific febrile illness, had a baseline median parasitemia value at hospital admission of 1387 parasites/μL (interquartile range, 6–222,570 parasites/μL), and all were thrombocytopenic at hospital admission or on the following day. Most (93.5%) of the patients with P. knowlesi infection had uncomplicated malaria that responded to chloroquine and primaquine treatment. Based on World Health Organization criteria for falciparum malaria, 7 patients with P. knowlesi infection (6.5%) had severe infections at hospital admission. The most frequent complication was respiratory distress, which was present at hospital admission in 4 patients and developed after admission in an additional 3 patients. P. knowlesi parasitemia at hospital admission was an independent determinant of respiratory distress, as were serum creatinine level, serum bilirubin, and platelet count at admission (P < .002 for each). Two patients with knowlesi malaria died, representing a case fatality rate of 1.8% (95% confidence interval, 0.2%–6.6%). Conclusions Knowlesi malaria causes a wide spectrum of disease. Most cases are uncomplicated and respond promptly to treatment, but approximately 1 in 10 patients develop potentially fatal complications. PMID

  6. Virulence and transmission success of the malarial parasite Plasmodium falciparum

    PubMed Central

    Hayward, Rhian E.; Tiwari, Bela; Piper, Karen P.; Baruch, Dror I.; Day, Karen P.

    1999-01-01

    Virulence of Plasmodium falciparum is associated with the expression of variant surface antigens designated PfEMP1 (P. falciparum erythrocyte membrane protein 1) that are encoded by a family of var genes. Data presented show that the transmission stages of P. falciparum also express PfEMP1 variants. Virulence in this host–parasite system can be considered a variable outcome of optimizing the production of sexual transmission stages from the population of disease-inducing asexual stages. Immunity to PfEMP1 will contribute to the regulation of this trade-off by controlling the parasite population with potential to produce mature transmission stages. PMID:10200302

  7. Three species of Plasmodium from Canada geese, Branta canadensis

    USGS Publications Warehouse

    Herman, C.M.; Barrow, J.H.

    1967-01-01

    Studies on Canada geese at the Seney National Wildlife Refuge in northern Michigan during the past few years have uncovered at least three species of Plasmodium: P circumflexum, P. relictum, and P. vaughani. Although rarely observed in direct blood smears from the wild hosts, isodiagnosis, using primarily domestic geese as recipients, revealed a prevalence of 60 percent in random samplings of the population. P. circumflexum is the most prevalent and mixed infections have been noted. In experimental infections, induced by blood inoculation, the malaria produced by P. circumflexum produces about a 70 percent mortality in Canada geese and about a 10 percent mortality in domestic geese.

  8. Intraerythrocytic stages of Plasmodium falciparum biosynthesize vitamin E.

    PubMed

    Sussmann, Rodrigo A C; Angeli, Cláudia B; Peres, Valnice J; Kimura, Emilia A; Katzin, Alejandro M

    2011-12-15

    The 2-C-methyl-D-erythritol-4-phosphate and shikimate pathways were found to be active in Plasmodium falciparum and both can result in vitamin E biosynthesis in plants and algae. This study biochemically confirmed vitamin E biosynthesis in the malaria parasite, which can be inhibited by usnic acid. Furthermore, we found evidence pointing to a role of this vitamin in infected erythrocytes. These findings not only contribute to current understanding of P. falciparum biology but also reveal a pathway that could serve as a chemotherapeutic target.

  9. An Autochthonous Case of Severe Plasmodium knowlesi Malaria in Thailand

    PubMed Central

    Nakaviroj, Surat; Kobasa, Teerayot; Teeranaipong, Phairote; Putaporntip, Chaturong; Jongwutiwes, Somchai

    2015-01-01

    A 58-year-old Thai man was infected with Plasmodium knowlesi in Chantaburi Province, eastern Thailand. In addition to pyrexia, the patient developed hypotension, renal failure, jaundice, and severe thrombocytopenia. The parasitemia at the time of admission was 16.67% or ∼503,400 parasites/μL. With artesunate treatment and supportive care, the patient recovered uneventfully. The occurrence of complicated knowlesi malaria in a low-endemic area underscores the risk of high morbidity from this simian malaria. PMID:25535314

  10. [Artemisinin resistance in Plasmodium falciparum: global status and basic research].

    PubMed

    Zhao, Shao-min; Wang, Man-yuan

    2014-10-01

    Artemisinin-resistant Plasmodium falciparum has been identified by WHO in the Greater Mekong subregion. While there is no report on artemisinin resistance in Africa and South America by now, related surveillance measures have been taken place. The genes related artemisinin-resistance has been identified and the molecular markers will be used for large-scale surveillance efforts to contain artemisinin resistance. The emergence and spread of artemisinin resistance worldwide is a present danger and needs more attention. This article reviews the progress of artemisininresistance malaria parasites and artemisinin-based combination therapies. PMID:25726605

  11. The epidemiology of Plasmodium falciparum gametocytes: weapons of mass dispersion.

    PubMed

    Drakeley, Chris; Sutherland, Colin; Bousema, J Teun; Sauerwein, Robert W; Targett, Geoffrey A T

    2006-09-01

    Much of the epidemiology of Plasmodium falciparum in Sub-Saharan Africa focuses on the prevalence patterns of asexual parasites in people of different ages, whereas the gametocytes that propagate the disease are often neglected. One expected benefit of the widespread introduction of artemisinin-based combination therapy for malaria is a reduction in gametocyte carriage. However, the factors that affect the transmission of parasites from humans to mosquitoes show complex dynamics in relation to the intensity and seasonality of malaria transmission, and thus such benefits might not be automatic. Here, we review data on gametocyte carriage in the context of the development of naturally acquired immunity and population infectivity. PMID:16846756

  12. Plasmodium knowlesi Sporozoite Antigen: Expression by Infectious Recombinant Vaccinia Virus

    NASA Astrophysics Data System (ADS)

    Smith, Geoffrey L.; Godson, G. Nigel; Nussenzweig, Victor; Nussenzweig, Ruth S.; Barnwell, John; Moss, Bernard

    1984-04-01

    The gene coding for the circumsporozoite antigen of the malaria parasite Plasmodium knowlesi was inserted into the vaccinia virus genome under the control of a defined vaccinia virus promoter. Cells infected with the recombinant virus synthesized polypeptides of 53,000 to 56,000 daltons that reacted with monoclonal antibody against the repeating epitope of the malaria protein. Furthermore, rabbits vaccinated with the recombinant virus produced antibodies that bound specifically to sporozoites. These data provide evidence for expression of a cloned malaria gene in mammalian cells and illustrate the potential of vaccinia virus recombinants as live malaria vaccines.

  13. A Stem Cell Strategy Identifies Glycophorin C as a Major Erythrocyte Receptor for the Rodent Malaria Parasite Plasmodium berghei

    PubMed Central

    Yiangou, Loukia; Montandon, Ruddy; Modrzynska, Katarzyna; Rosen, Barry; Bushell, Wendy; Hale, Christine; Billker, Oliver; Rayner, Julian C.

    2016-01-01

    The clinical complications of malaria are caused by the parasite expansion in the blood. Invasion of erythrocytes is a complex process that depends on multiple receptor-ligand interactions. Identification of host receptors is paramount for fighting the disease as it could reveal new intervention targets, but the enucleated nature of erythrocytes makes genetic approaches impossible and many receptors remain unknown. Host-parasite interactions evolve rapidly and are therefore likely to be species-specific. As a results, understanding of invasion receptors outside the major human pathogen Plasmodium falciparum is very limited. Here we use mouse embryonic stem cells (mESCs) that can be genetically engineered and differentiated into erythrocytes to identify receptors for the rodent malaria parasite Plasmodium berghei. Two proteins previously implicated in human malaria infection: glycophorin C (GYPC) and Band-3 (Slc4a1) were deleted in mESCs to generate stable cell lines, which were differentiated towards erythropoiesis. In vitro infection assays revealed that while deletion of Band-3 has no effect, absence of GYPC results in a dramatic decrease in invasion, demonstrating the crucial role of this protein for P. berghei infection. This stem cell approach offers the possibility of targeting genes that may be essential and therefore difficult to disrupt in whole organisms and has the potential to be applied to a variety of parasites in diverse host cell types. PMID:27362409

  14. Marketable permits, market power, and cheating

    SciTech Connect

    Egteren, H. van; Weber, M.

    1996-03-01

    Marketable pollution permits are gaining acceptance in government policy circles, and initial estimates of the potential cost savings over command and control regulations were deemed significant and achievable with minimal information requirements on the part of reglators. However, the original promise of marketable permit systems has not been fulfilled. Significant gains in pollution reduction have not been achieved while emissions permits have become costly liabilities to firms. This paper combines the theoretical challeges of two groups to consider the impact of market power on equilibrium permit prices and levels of compliance. Results indicate that when a firm has market power in the permit market, the intial allocation is fundamental in determining prices and levels of compliance for all participants in the permit market. Furthermore, the exercise of market power and its corresponding impact on the equilibrium level of compliance is a significant factor in determining total social costs.

  15. African apes as reservoirs of Plasmodium falciparum and the origin and diversification of the Laverania subgenus.

    PubMed

    Duval, Linda; Fourment, Mathieu; Nerrienet, Eric; Rousset, Dominique; Sadeuh, Serge A; Goodman, Steven M; Andriaholinirina, Nicole V; Randrianarivelojosia, Milijaona; Paul, Richard E; Robert, Vincent; Ayala, Francisco J; Ariey, Frédéric

    2010-06-01

    We investigated two mitochondrial genes (cytb and cox1), one plastid gene (tufA), and one nuclear gene (ldh) in blood samples from 12 chimpanzees and two gorillas from Cameroon and one lemur from Madagascar. One gorilla sample is related to Plasmodium falciparum, thus confirming the recently reported presence in gorillas of this parasite. The second gorilla sample is more similar to the recently defined Plasmodium gaboni than to the P. falciparum-Plasmodium reichenowi clade, but distinct from both. Two chimpanzee samples are P. falciparum. A third sample is P. reichenowi and two others are P. gaboni. The other chimpanzee samples are different from those in the ape clade: two are Plasmodium ovale, and one is Plasmodium malariae. That is, we have found three human Plasmodium parasites in chimpanzees. Four chimpanzee samples were mixed: one species was P. reichenowi; the other species was P. gaboni in three samples and P. ovale in the fourth sample. The lemur sample, provisionally named Plasmodium malagasi, is a sister lineage to the large cluster of primate parasites that does not include P. falciparum or ape parasites, suggesting that the falciparum + ape parasite cluster (Laverania clade) may have evolved from a parasite present in hosts not ancestral to the primates. If malignant malaria were eradicated from human populations, chimpanzees, in addition to gorillas, might serve as a reservoir for P. falciparum. PMID:20498054

  16. Detection of avian Plasmodium spp. DNA sequences from mosquitoes captured in Minami Daito Island of Japan.

    PubMed

    Ejiri, Hiroko; Sato, Yukita; Sasaki, Emi; Sumiyama, Daisuke; Tsuda, Yoshio; Sawabe, Kyoko; Matsui, Shin; Horie, Sayaka; Akatani, Kana; Takagi, Masaoki; Omori, Sumie; Murata, Koichi; Yukawa, Masayoshi

    2008-11-01

    Several species of birds in Minami Daito Island, an oceanic island located in the far south from the main islands of Japan, were found to be infected with avian Plasmodium. However, no vector species of the avian malaria in this island have been revealed yet. To speculate potential vectors, we collected mosquitoes there and investigated using a PCR procedure whether the mosquitoes harbor avian malaria or not. Totally 1,264 mosquitoes including 9 species were collected during March 2006 to February 2007. The mosquitoes collected were stored every species, sampled date and location for DNA extraction. Fifteen out of 399 DNA samples showed positive for the partial mtDNA cytb gene of avian Plasmodium. Estimated minimum infection rate among collected mosquitoes was 1.2% in this study. Four species of mosquitoes; Aedes albopictus, Culex quinquefasciatus, Lutzia fuscanus and Mansonia sp. had avian Plasmodium gene sequences. Detected DNA sequences from A. albopictus and L. fuscanus were identical to an avian Plasmodium lineage detected in bull-headed shrike (Lanius bucephalus) captured in the island. Different sequences were detected from C. quinquefasciatus, which were corresponding to an avian Plasmodium from a sparrow (Passer montanus) and Plasmodium gallinaceum. Our results suggest that A. albopictus, Lutzia fuscanus, C. quinquefasciatus, and Mansonia sp. could be potential vectors of avian malaria in Minami Daito Island. This study was the first report of molecular detection of avian Plasmodium from mosquitoes in Japan.

  17. Extracellular ATP triggers proteolysis and cytosolic Ca2+ rise in Plasmodium berghei and Plasmodium yoelii malaria parasites

    PubMed Central

    2012-01-01

    Background Plasmodium has a complex cell biology and it is essential to dissect the cell-signalling pathways underlying its survival within the host. Methods Using the fluorescence resonance energy transfer (FRET) peptide substrate Abz-AIKFFARQ-EDDnp and Fluo4/AM, the effects of extracellular ATP on triggering proteolysis and Ca2+ signalling in Plasmodium berghei and Plasmodium yoelii malaria parasites were investigated. Results The protease activity was blocked in the presence of the purinergic receptor blockers suramin (50 μM) and PPADS (50 μM) or the extracellular and intracellular calcium chelators EGTA (5 mM) and BAPTA/AM (25, 100, 200 and 500 μM), respectively for P. yoelii and P. berghei. Addition of ATP (50, 70, 200 and 250 μM) to isolated parasites previously loaded with Fluo4/AM in a Ca2+-containing medium led to an increase in cytosolic calcium. This rise was blocked by pre-incubating the parasites with either purinergic antagonists PPADS (50 μM), TNP-ATP (50 μM) or the purinergic blockers KN-62 (10 μM) and Ip5I (10 μM). Incubating P. berghei infected cells with KN-62 (200 μM) resulted in a changed profile of merozoite surface protein 1 (MSP1) processing as revealed by western blot assays. Moreover incubating P. berghei for 17 h with KN-62 (10 μM) led to an increase in rings forms (82% ± 4, n = 11) and a decrease in trophozoite forms (18% ± 4, n = 11). Conclusions The data clearly show that purinergic signalling modulates P. berghei protease(s) activity and that MSP1 is one target in this pathway. PMID:22420332

  18. 40 CFR 124.6 - Draft permits.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... CFR § 52.21; (iv) 404 permits, permit conditions under §§ 233.7 and 233.8; (v) NPDES permits, effluent....25 (NPDES), 145.11 (UIC), 233.26 (404), and 271.14 (RCRA).) Once an application is complete, the... §§ 123.25 (NPDES), 145.11 (UIC), 233.26 (404), and 271.14 (RCRA).) If the Director decides to prepare...

  19. 40 CFR 124.6 - Draft permits.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... CFR § 52.21; (iv) 404 permits, permit conditions under §§ 233.7 and 233.8; (v) NPDES permits, effluent....25 (NPDES), 145.11 (UIC), 233.26 (404), and 271.14 (RCRA).) Once an application is complete, the... §§ 123.25 (NPDES), 145.11 (UIC), 233.26 (404), and 271.14 (RCRA).) If the Director decides to prepare...

  20. 40 CFR 124.6 - Draft permits.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... CFR § 52.21; (iv) 404 permits, permit conditions under §§ 233.7 and 233.8; (v) NPDES permits, effluent....25 (NPDES), 145.11 (UIC), 233.26 (404), and 271.14 (RCRA).) Once an application is complete, the... §§ 123.25 (NPDES), 145.11 (UIC), 233.26 (404), and 271.14 (RCRA).) If the Director decides to prepare...

  1. 40 CFR 124.6 - Draft permits.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... CFR § 52.21; (iv) 404 permits, permit conditions under §§ 233.7 and 233.8; (v) NPDES permits, effluent....25 (NPDES), 145.11 (UIC), 233.26 (404), and 271.14 (RCRA).) Once an application is complete, the... §§ 123.25 (NPDES), 145.11 (UIC), 233.26 (404), and 271.14 (RCRA).) If the Director decides to prepare...

  2. 40 CFR 124.6 - Draft permits.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... CFR § 52.21; (iv) 404 permits, permit conditions under §§ 233.7 and 233.8; (v) NPDES permits, effluent....25 (NPDES), 145.11 (UIC), 233.26 (404), and 271.14 (RCRA).) Once an application is complete, the... §§ 123.25 (NPDES), 145.11 (UIC), 233.26 (404), and 271.14 (RCRA).) If the Director decides to prepare...

  3. 27 CFR 19.684 - Automatic termination of permits.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... Changes to Permit Information § 19.684 Automatic termination of permits. (a) Permits not transferable. An alcohol fuel plant permit is not transferable and, except as otherwise provided in paragraph (b) of...

  4. A kinetic fluorescence assay reveals unusual features of Ca++ uptake in Plasmodium falciparum-infected erythrocytes

    PubMed Central

    2014-01-01

    Background To facilitate development within erythrocytes, malaria parasites increase their host cell uptake of diverse solutes including Ca++. The mechanism and molecular basis of increased Ca++ permeability remains less well studied than that of other solutes. Methods Based on an appropriate Ca++ affinity and its greater brightness than related fluorophores, Fluo-8 was selected and used to develop a robust fluorescence-based assay for Ca++ uptake by human erythrocytes infected with Plasmodium falciparum. Results Both uninfected and infected cells exhibited a large Ca++-dependent fluorescence signal after loading with the Fluo-8 dye. Probenecid, an inhibitor of erythrocyte organic anion transporters, abolished the fluorescence signal in uninfected cells; in infected cells, this agent increased fluorescence via mechanisms that depend on parasite genotype. Kinetic fluorescence measurements in 384-well microplates revealed that the infected cell Ca++ uptake is not mediated by the plasmodial surface anion channel (PSAC), a parasite nutrient channel at the host membrane; it also appears to be distinct from mammalian Ca++ channels. Imaging studies confirmed a low intracellular Ca++ in uninfected cells and higher levels in both the host and parasite compartments of infected cells. Parasite growth inhibition studies revealed a conserved requirement for extracellular Ca++. Conclusions Nondestructive loading of Fluo-8 into human erythrocytes permits measurement of Ca++ uptake kinetics. The greater Ca++ permeability of cells infected with malaria parasites is apparent when probenecid is used to inhibit Fluo-8 efflux at the host membrane. This permeability is mediated by a distinct pathway and may be essential for intracellular parasite development. The miniaturized assay presented here should help clarify the precise transport mechanism and may identify inhibitors suitable for antimalarial drug development. PMID:24885754

  5. 36 CFR 1001.6 - Permits.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... authorized by regulations set forth in this chapter, the Executive Director may issue a permit to authorize..., natural or cultural resources, scientific research, implementation of management responsibilities,...

  6. 36 CFR 1001.6 - Permits.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... authorized by regulations set forth in this chapter, the Executive Director may issue a permit to authorize..., natural or cultural resources, scientific research, implementation of management responsibilities,...

  7. 36 CFR 1001.6 - Permits.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... authorized by regulations set forth in this chapter, the Executive Director may issue a permit to authorize..., natural or cultural resources, scientific research, implementation of management responsibilities,...

  8. Annual Hanford Site environmental permitting status report

    SciTech Connect

    Thompson, S.A.

    1996-10-01

    This Annual Hanford Site Environmental Permitting Status Report (Status Report) was prepared in response to requirements prescribed in U.S. Department of Energy (DOE) Order 5400.2A, `Environmental Compliance Issue Coordination`. This Order, canceled in April 1996, required that information on existing and anticipated environmental permitting for DOE facilities be submitted (or updated) annually by October 1 of each calendar year. Although the Order was canceled, the need for this Status Report still remains. For example, the Washington State Department of Ecology`s (Ecology) Dangerous Waste Permit Application Requirements (Publication Number 95-402, June 1996), Checklist Section J, calls for current information on existing and anticipated environmental permitting. As specified in the Hanford Facility Dangerous Waste Permit Application, General Information Portion (DOE/RL-91-28), this Status Report serves as the vehicle for meeting this requirement for the Hanford Facility. This Status Report includes information on all existing and anticipated environmental permitting. Environmental permitting required by the Resource Conservation and Recovery Act (RCRA) of 1976, the Hazardous and Solid Waste Amendments (HSWA) of 1984, and non-RCRA permitting (solid waste handling, Clean Air Act Amendments of 1990, Clean Water Act Amendments of 1987, Washington State waste discharge, and onsite sewage system) are addressed. Information on RCRA and non-RCRA permitting is included and is current as of July 31, 1996.

  9. 36 CFR 20.2 - Permits; conditions.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... Michigan laws, and related regulations prescribed by the Michigan Department of Conservation, governing... permit. Only nets and gear approved by the Michigan Department of Conservation shall be used....

  10. Malaria vaccines: identifying Plasmodium falciparum liver-stage targets.

    PubMed

    Longley, Rhea J; Hill, Adrian V S; Spencer, Alexandra J

    2015-01-01

    The development of a highly efficacious and durable vaccine for malaria remains a top priority for global health researchers. Despite the huge rise in recognition of malaria as a global health problem and the concurrent rise in funding over the past 10-15 years, malaria continues to remain a widespread burden. The evidence of increasing resistance to anti-malarial drugs and insecticides is a growing concern. Hence, an efficacious and durable preventative vaccine for malaria is urgently needed. Vaccines are one of the most cost-effective tools and have successfully been used in the prevention and control of many diseases, however, the development of a vaccine for the Plasmodium parasite has proved difficult. Given the early success of whole sporozoite mosquito-bite delivered vaccination strategies, we know that a vaccine for malaria is an achievable goal, with sub-unit vaccines holding great promise as they are simple and cheap to both manufacture and deploy. However a major difficulty in development of sub-unit vaccines lies within choosing the appropriate antigenic target from the 5000 or so genes expressed by the parasite. Given the liver-stage of malaria represents a bottle-neck in the parasite's life cycle, there is widespread agreement that a multi-component sub-unit malaria vaccine should preferably contain a liver-stage target. In this article we review progress in identifying and screening Plasmodium falciparum liver-stage targets for use in a malaria vaccine. PMID:26441899

  11. A Comprehensive Analysis of Plasmodium Circumsporozoite Protein Binding to Hepatocytes.

    PubMed

    Zhao, Jinghua; Bhanot, Purnima; Hu, Junjie; Wang, Qian

    2016-01-01

    Circumsporozoite protein (CSP) is the dominant protein on the surface of Plasmodium sporozoites and plays a critical role in the invasion by sporozoites of hepatocytes. Contacts between CSP and heparin sulfate proteoglycans (HSPGs) lead to the attachment of sporozoites to hepatocytes and trigger signaling events in the parasite that promote invasion of hepatocytes. The precise sequence elements in CSP that bind HSPGs have not been identified. We performed a systematic in vitro analysis to dissect the association between Plasmodium falciparum CSP (PfCSP) and hepatocytes. We demonstrate that interactions between PfCSP and heparin or a cultured hepatoma cell line, HepG2, are mediated primarily by a lysine-rich site in the amino terminus of PfCSP. Importantly, the carboxyl terminus of PfCSP facilitates heparin-binding by the amino-terminus but does not interact directly with heparin. These findings provide insights into how CSP recognizes hepatocytes and useful information for further functional studies of CSP. PMID:27560376

  12. [Maternal death from severe malaria due to Plasmodium vivax].

    PubMed

    Arróspide, Nancy; Espinoza, Máximo Manuel; Miranda-Choque, Edwin; Mayta-Tristán, Percy; Legua, Pedro; Cabezas, César

    2016-06-01

    Here we describe the case of a 19-year-old woman, in her 29th week of gestation, who was from Llumpe (Ancash, Peru) and had a history of traveling to Chanchamayo (Junín, Peru) and Rinconada (Ancash, Peru). The patient presented at Chacas Hospital (Chacas, Ancash, Peru) with general malaise, dehydration, respiratory distress, jaundice, the sensation of thermal rise, and abdominal pain. Analysis of blood smears revealed 60% hemoparasites. She was transferred to Ramos Guardia Hospital (Huaraz, Peru) where she presented increasing respiratory distress, choluria, hematuria, and decreased urine output, moreover she was positive for Plasmodium. From there she was transferred to Cayetano Heredia Hospital (Lima, Peru), where she was admitted to the intensive care unit (ICU) with multiple organ failure, stillbirth, and leading to death. She underwent mechanical ventilation, was administered clindamycin, and was prescribed quinine, which she did not received due a lack by availability. The evolution of the illness was torpid, and she ultimately developed multiple organ failure and died. Plasmodium vivax infection was confirmed. Accordingly, we emphasize the importance of improving our diagnostic capabilities and management techniques to enable clinicians to provide adequate and timely treatment. PMID:27656940

  13. Targeting molecular interactions essential for Plasmodium sexual reproduction

    PubMed Central

    Vega-Rodriguez, Joel; Perez-Barreto, Davinia; Ruiz-Reyes, Antonio; Jacobs-Lorena, Marcelo

    2015-01-01

    Summary Malaria remains one of the most devastating infectious diseases, killing up to a million people every year. Whereas much progress has been made in understanding the life cycle of the parasite in the human host and in the mosquito vector, significant gaps of knowledge remain. Fertilization of malaria parasites, a process that takes place in the lumen of the mosquito midgut, is poorly understood and the molecular interactions (receptor–ligand) required for Plasmodium fertilization remain elusive. By use of a phage display library, we identified FG1 (Female Gamete peptide 1), a peptide that binds specifically to the surface of female Plasmodium berghei gametes. Importantly, FG1 but not a scrambled version of the peptide, strongly reduces P. berghei oocyst formation by interfering with fertilization. In addition, FG1 also inhibits P. falciparum oocyst formation suggesting that the peptide binds to a molecule on the surface of the female gamete whose structure is conserved. Identification of the molecular interactions disrupted by the FG1 peptide may lead to the development of novel malaria transmission-blocking strategies. PMID:25944054

  14. Late relapse of imported Plasmodium ovale malaria: a case report.

    PubMed

    Siala, Emna; Gastli, Mondher; Essid, Rym; Jemal, Sana; Ben Abdallah, Rym; Ben Abda, Imène; Aoun, Karim; Bouratbine, Aida

    2015-06-01

    We report the first case of an imported Plasmodium ovale relapse in a Tunisian man who developed malaria three years after leaving sub- Saharan Africa. A 29-year-old Tunisian man consulted in September 2011 because of a fever, myalgia, and headache that had begun eight days earlier and persisted despite treatment with oral antibiotics. On questioning, the patient stated that he had resided three years ago for six months in Ivory Coast, where he acquired malaria. He was treated with artemether-lumefantrine. The patient said he had no recent travel to any other malaria-endemic area and had not received a blood transfusion. A first microscopy of peripheral blood smears was negative for malaria parasites. The diagnosis was established 17 days after onset of symptoms. A repeat microscopic examination of blood smears confirmed the presence of Plasmodium ovale with a parasitemia lower than 0.1%. The patient was treated with artemether lumefantrine, followed by primaquine. This case emphasizes the possibility of relapse of some plasmodial species. It highlights the importance of repeating microscopic examination of blood when the diagnosis of malaria is suspected. PMID:26644094

  15. A Comprehensive Analysis of Plasmodium Circumsporozoite Protein Binding to Hepatocytes

    PubMed Central

    Zhao, Jinghua; Bhanot, Purnima; Hu, Junjie; Wang, Qian

    2016-01-01

    Circumsporozoite protein (CSP) is the dominant protein on the surface of Plasmodium sporozoites and plays a critical role in the invasion by sporozoites of hepatocytes. Contacts between CSP and heparin sulfate proteoglycans (HSPGs) lead to the attachment of sporozoites to hepatocytes and trigger signaling events in the parasite that promote invasion of hepatocytes. The precise sequence elements in CSP that bind HSPGs have not been identified. We performed a systematic in vitro analysis to dissect the association between Plasmodium falciparum CSP (PfCSP) and hepatocytes. We demonstrate that interactions between PfCSP and heparin or a cultured hepatoma cell line, HepG2, are mediated primarily by a lysine-rich site in the amino terminus of PfCSP. Importantly, the carboxyl terminus of PfCSP facilitates heparin-binding by the amino-terminus but does not interact directly with heparin. These findings provide insights into how CSP recognizes hepatocytes and useful information for further functional studies of CSP. PMID:27560376

  16. Innate immunity induced by Plasmodium liver infection inhibits malaria reinfections.

    PubMed

    Liehl, Peter; Meireles, Patrícia; Albuquerque, Inês S; Pinkevych, Mykola; Baptista, Fernanda; Mota, Maria M; Davenport, Miles P; Prudêncio, Miguel

    2015-03-01

    Following transmission through a mosquito bite to the mammalian host, Plasmodium parasites first invade and replicate inside hepatocytes before infecting erythrocytes and causing malaria. The mechanisms limiting Plasmodium reinfections in humans living in regions of malaria endemicity have mainly been explored by studying the resistance induced by the blood stage of infection. However, epidemiologic studies have suggested that in high-transmission areas, preerythrocytic stages also activate host resistance to reinfection. This, along with the recent discovery that liver infections trigger a specific and effective type I interferon (IFN) response, prompted us to hypothesize that this pre-erythrocyte-stage-induced resistance is linked to liver innate immunity. Here, we combined experimental approaches and mathematical modeling to recapitulate field studies and understand the molecular basis behind such resistance. We present a newly established mouse reinfection model and demonstrate that rodent malaria liver-stage infection inhibits reinfection. This protection relies on the activation of innate immunity and involves the type I IFN response and the antimicrobial cytokine gamma IFN (IFN-γ). Importantly, mathematical simulations indicate that the predictions based on our experimental murine reinfection model fit available epidemiological data. Overall, our study revealed that liver-stage-induced innate immunity may contribute to the preerythrocytic resistance observed in humans in regions of malaria hyperendemicity.

  17. Pfcrt Gene in Plasmodium falciparum Field Isolates from Muzaffargarh, Pakistan

    PubMed Central

    Sahar, Sumrin; Tanveer, Akhtar; Ali, Akbar; Bilal, Hazrat; Muhammad Saleem, Rana

    2015-01-01

    Background: 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. Methods: Overall, 10,372 blood films of suspected malarial patients were examined microscopically from rural health center Sinawan, district Muzaffargarh, Pakistan from November 2008 to November 2010. P. falciparum positive samples (both whole blood and FTA blood spotted cards) were used for DNA extraction. Nested PCR was used to amplify the pfcrt (codon 72–76) gene fragment. Sequencing was carried out to find the haplotypes in the amplified fragment of pfcrt gene. Result: Over all slide positivity rate (SPR), P. vivax and P. falciparum positivity rate was 21.40 %, 19.37 % and 2.03% respectively. FTA blood spotted cards were equally efficient in the blood storage for PCR and sequencing. Analysis of sequencing results of pfcrt showed only one type of haplotype SagtVMNT (AGTGTAATGAATACA) from codon 72–76 in all samples. Conclusion: The results show high prevalence of CQ resistance and AQ resistant genes. AQ is not recommended to be used as a partner drug in ACT in this locality, so as to ward off future catastrophes. PMID:26623432

  18. Plasmodium vivax: clinical spectrum, risk factors and pathogenesis.

    PubMed

    Anstey, Nicholas M; Douglas, Nicholas M; Poespoprodjo, Jeanne R; Price, Ric N

    2012-01-01

    Vivax malaria was historically described as 'benign tertian malaria' because individual clinical episodes were less likely to cause severe illness than Plasmodium falciparum. Despite this, Plasmodium vivax was, and remains, responsible for major morbidity and significant mortality in vivax-endemic areas. Single infections causing febrile illness in otherwise healthy individuals rarely progress to severe disease. Nevertheless, in the presence of co-morbidities, P. vivax can cause severe illness and fatal outcomes. Recurrent or chronic infections in endemic areas can cause severe anaemia and malnutrition, particularly in early childhood. Other severe manifestations include acute lung injury, acute kidney injury and uncommonly, coma. Multiorgan failure and shock are described but further studies are needed to investigate the role of bacterial and other co-infections in these syndromes. In pregnancy, P. vivax infection can cause maternal anaemia, miscarriage, low birth weight and congenital malaria. Compared to P. falciparum, P. vivax has a greater capacity to elicit an inflammatory response, resulting in a lower pyrogenic threshold. Conversely, cytoadherence of P. vivax to endothelial cells is less frequent and parasite sequestration is not thought to be a significant cause of severe illness in vivax malaria. With a predilection for young red cells, P. vivax does not result in the high parasite biomass associated with severe disease in P. falciparum, but a four to fivefold greater removal of uninfected red cells from the circulation relative to P. falciparum is associated with a similar risk of severe anaemia. Mechanisms underlying the pathogenesis of severe vivax syndromes remain incompletely understood.

  19. Human cytotoxic T lymphocytes against the Plasmodium falciparum circumsporozoite protein.

    PubMed Central

    Malik, A; Egan, J E; Houghten, R A; Sadoff, J C; Hoffman, S L

    1991-01-01

    Cytotoxic T lymphocytes (CTL) against the circumsporozoite (CS) protein of malaria sporozoites protect against malaria in rodents. Although there is interest in developing human vaccines that induce CTL against the Plasmodium falciparum CS protein, humans have never been shown to produce CTL against any Plasmodium species protein or other parasite protein. We report that when peripheral blood mononuclear cells (PBMC) from three of four volunteers immunized with irradiated P. falciparum sporozoites were stimulated in vitro with a recombinant vaccinia virus expressing the P. falciparum CS protein or a peptide including only amino acids 368-390 of the P. falciparum CS protein [CS-(368-390)], the PBMC lysed autologous Epstein-Barr virus-transformed B cells transfected with the P. falciparum CS protein gene or incubated with CS-(368-390) tricosapeptide. Activity was antigen specific, genetically restricted, and dependent on CD8+ T cells. In one volunteer, seven peptides reflecting amino acids 311-400 were tested, and, as in B10.BR mice, CTL activity was only associated with the CS-(368-390) peptide. Development of an assay for studying human CTL against the CS and other malaria proteins and a method for constructing target cells by direct gene transfection provide a foundation for studying the role of CTL in protection against malaria. PMID:1707538

  20. A novel Sushi domain-containing protein of Plasmodium falciparum.

    PubMed

    O'Keeffe, Aisling H; Green, Judith L; Grainger, Munira; Holder, Anthony A

    2005-03-01

    Using bioinformatics analyses of the completed malaria genome sequence, we have identified a novel protein with a potential role in erythrocyte invasion. The protein (PFD0295c, ) has a predicted signal sequence and transmembrane domain and a sequence near the C-terminus of the protein shows significant similarity with Sushi domains. These domains, which exist in a wide variety of complement and adhesion proteins, have previously been shown to be involved in protein-protein and protein-ligand interactions. Orthologous genes have also been identified in the genomes of several other Plasmodium species, suggesting a conserved function for this protein in Plasmodium. Our results show that this protein is located in apical organelles and we have therefore designated the protein apical Sushi protein (ASP). We show that the expression of ASP is tightly regulated in the intraerythrocytic stages of the parasite and that it undergoes post-translational proteolytic processing. Based on our observations of timing of expression, location and proteolytic processing, we propose a role for ASP in erythrocyte invasion.

  1. [Maternal death from severe malaria due to Plasmodium vivax].

    PubMed

    Arróspide, Nancy; Espinoza, Máximo Manuel; Miranda-Choque, Edwin; Mayta-Tristán, Percy; Legua, Pedro; Cabezas, César

    2016-06-01

    Here we describe the case of a 19-year-old woman, in her 29th week of gestation, who was from Llumpe (Ancash, Peru) and had a history of traveling to Chanchamayo (Junín, Peru) and Rinconada (Ancash, Peru). The patient presented at Chacas Hospital (Chacas, Ancash, Peru) with general malaise, dehydration, respiratory distress, jaundice, the sensation of thermal rise, and abdominal pain. Analysis of blood smears revealed 60% hemoparasites. She was transferred to Ramos Guardia Hospital (Huaraz, Peru) where she presented increasing respiratory distress, choluria, hematuria, and decreased urine output, moreover she was positive for Plasmodium. From there she was transferred to Cayetano Heredia Hospital (Lima, Peru), where she was admitted to the intensive care unit (ICU) with multiple organ failure, stillbirth, and leading to death. She underwent mechanical ventilation, was administered clindamycin, and was prescribed quinine, which she did not received due a lack by availability. The evolution of the illness was torpid, and she ultimately developed multiple organ failure and died. Plasmodium vivax infection was confirmed. Accordingly, we emphasize the importance of improving our diagnostic capabilities and management techniques to enable clinicians to provide adequate and timely treatment.

  2. Proteome mapping of Plasmodium: identification of the P. yoelii remodellome

    PubMed Central

    Siau, Anthony; Huang, Ximei; Weng, Mei; Sze, Siu Kwan; Preiser, Peter R.

    2016-01-01

    Plasmodium associated virulence in the host is linked to extensive remodelling of the host erythrocyte by parasite proteins that form the “remodellome”. However, without a common motif or structure available to identify these proteins, little is known about the proteins that are destined to reside in the parasite periphery, the host-cell cytoplasm and/or the erythrocyte membrane. Here, the subcellular fractionation of erythrocytic P. yoelii at trophozoite and schizont stage along with label-free quantitative LC-MS/MS analysis of the whole proteome, revealed a proteome of 1335 proteins. Differential analysis of the relative abundance of these proteins across the subcellular compartments allowed us to map their locations, independently of their predicted features. These results, along with literature data and in vivo validation of 61 proteins enabled the identification of a remodellome of 184 proteins. This approach identified a significant number of conserved remodelling proteins across plasmodium that likely represent key conserved functions in the parasite and provides new insights into parasite evolution and biology. PMID:27503796

  3. DNA Cloning of Plasmodium falciparum Circumsporozoite Gene: Amino Acid Sequence of Repetitive Epitope

    NASA Astrophysics Data System (ADS)

    Enea, Vincenzo; Ellis, Joan; Zavala, Fidel; Arnot, David E.; Asavanich, Achara; Masuda, Aoi; Quakyi, Isabella; Nussenzweig, Ruth S.

    1984-08-01

    A clone of complementary DNA encoding the circumsporozoite (CS) protein of the human malaria parasite Plasmodium falciparum has been isolated by screening an Escherichia coli complementary DNA library with a monoclonal antibody to the CS protein. The DNA sequence of the complementary DNA insert encodes a four-amino acid sequence: proline-asparagine-alanine-asparagine, tandemly repeated 23 times. The CS β -lactamase fusion protein specifically binds monoclonal antibodies to the CS protein and inhibits the binding of these antibodies to native Plasmodium falciparum CS protein. These findings provide a basis for the development of a vaccine against Plasmodium falciparum malaria.

  4. Immunisation against a serine protease inhibitor reduces intensity of Plasmodium berghei infection in mosquitoes.

    PubMed

    Williams, Andrew R; Zakutansky, Sara E; Miura, Kazutoyo; Dicks, Matthew D J; Churcher, Thomas S; Jewell, Kerry E; Vaughan, Aisling M; Turner, Alison V; Kapulu, Melissa C; Michel, Kristin; Long, Carole A; Sinden, Robert E; Hill, Adrian V S; Draper, Simon J; Biswas, Sumi

    2013-10-01

    The mosquito innate immune response is able to clear the majority of Plasmodium parasites. This immune clearance is controlled by a number of regulatory molecules including serine protease inhibitors (serpins). To determine whether such molecules could represent a novel target for a malaria transmission-blocking vaccine, we vaccinated mice with Anopheles gambiae serpin-2. Antibodies against Anopheles gambiae serpin-2 significantly reduced the infection of a heterologous Anopheles species (Anopheles stephensi) by Plasmodium berghei, however this effect was not observed with Plasmodium falciparum. Therefore, this approach of targeting regulatory molecules of the mosquito immune system may represent a novel approach to transmission-blocking malaria vaccines.

  5. Case history review--demilitarization combustion permits.

    PubMed

    Gaborek, B J

    2000-02-01

    In May 1993, Administrative Browner of the U.S. Environmental Protection Agency (USEPA) announced that an indirect exposure health risk assessment was required for all hazardous waste combustion facilities seeking a Resource Conservation and Recovery Act permit. These types of risk assessments evaluate the health and environmental effects from inhalation of emissions (direct exposure) and from contact with environmental media and consumption of food products impacted by the emissions (indirect exposure). Completion of an indirect exposure risk assessment is often complicated by the various methodologies available for generating results and by the requirements of the regulating community. To minimize this complexity and to maximize consistency between risk assessments, the USEPA developed a number of detailed guidance documents. Site-specific conditions and toxicological data gaps, however, continue to present challenges not addressed by these guidance documents. This paper presents some of the specific challenges encountered by the U.S. Army Center for Health Promotion and Preventive Medicine when performing indirect exposure health risk assessments for several demilitarization combustion facilities.

  6. 40 CFR 144.31 - Application for a permit; authorization by permit.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... is located on Indian lands. (6) A listing of all permits or construction approvals received or.... (vii) Ocean dumping permits under the Marine Protection Research and Sanctuaries Act. (viii) Dredge...

  7. 40 CFR 144.31 - Application for a permit; authorization by permit.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... is located on Indian lands. (6) A listing of all permits or construction approvals received or.... (vii) Ocean dumping permits under the Marine Protection Research and Sanctuaries Act. (viii) Dredge...

  8. 40 CFR 144.31 - Application for a permit; authorization by permit.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... is located on Indian lands. (6) A listing of all permits or construction approvals received or.... (vii) Ocean dumping permits under the Marine Protection Research and Sanctuaries Act. (viii) Dredge...

  9. 30 CFR 947.773 - Requirements for permits and permit processing.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... regulations: (1) Department of Ecology: Surface Water Rights Permit, RCW 90.03.250 Dam Safety Approval, RCW 90... deny a permit application to the Washington Department of Natural Resources, the Department of...

  10. 30 CFR 947.773 - Requirements for permits and permit processing.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... regulations: (1) Department of Ecology: Surface Water Rights Permit, RCW 90.03.250 Dam Safety Approval, RCW 90... deny a permit application to the Washington Department of Natural Resources, the Department of...

  11. 30 CFR 947.773 - Requirements for permits and permit processing.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... regulations: (1) Department of Ecology: Surface Water Rights Permit, RCW 90.03.250 Dam Safety Approval, RCW 90... deny a permit application to the Washington Department of Natural Resources, the Department of...

  12. 30 CFR 947.773 - Requirements for permits and permit processing.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... regulations: (1) Department of Ecology: Surface Water Rights Permit, RCW 90.03.250 Dam Safety Approval, RCW 90... deny a permit application to the Washington Department of Natural Resources, the Department of...

  13. 30 CFR 947.773 - Requirements for permits and permit processing.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... regulations: (1) Department of Ecology: Surface Water Rights Permit, RCW 90.03.250 Dam Safety Approval, RCW 90... deny a permit application to the Washington Department of Natural Resources, the Department of...

  14. 30 CFR 921.773 - Requirements for permits and permit processing.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... issued by the Secretary pursuant to 30 CFR part 773 and applicable permits issued pursuant to the laws of... shall have the locations of the proposed permit boundaries, topsoil storage areas, sediment...

  15. 30 CFR 921.773 - Requirements for permits and permit processing.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... issued by the Secretary pursuant to 30 CFR part 773 and applicable permits issued pursuant to the laws of... shall have the locations of the proposed permit boundaries, topsoil storage areas, sediment...

  16. 40 CFR 52.681 - Permits to construct and tier II operating permits.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... of the SIP. (b) Operating Permits authorizing the use of alternative emission limits (bubbles) under... credits in a bubble pursuant to IDAPA 58.01.01.461), and Tier II Operating Permits authorizing...

  17. 40 CFR 52.681 - Permits to construct and tier II operating permits.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... of the SIP. (b) Operating Permits authorizing the use of alternative emission limits (bubbles) under... credits in a bubble pursuant to IDAPA 58.01.01.461), and Tier II Operating Permits authorizing...

  18. 40 CFR 52.681 - Permits to construct and tier II operating permits.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... of the SIP. (b) Operating Permits authorizing the use of alternative emission limits (bubbles) under... credits in a bubble pursuant to IDAPA 58.01.01.461), and Tier II Operating Permits authorizing...

  19. 40 CFR 52.681 - Permits to construct and tier II operating permits.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... of the SIP. (b) Operating Permits authorizing the use of alternative emission limits (bubbles) under... credits in a bubble pursuant to IDAPA 58.01.01.461), and Tier II Operating Permits authorizing...

  20. 40 CFR 52.681 - Permits to construct and tier II operating permits.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... of the SIP. (b) Operating Permits authorizing the use of alternative emission limits (bubbles) under... credits in a bubble pursuant to IDAPA 58.01.01.461), and Tier II Operating Permits authorizing...

  1. Antibody responses to Plasmodium falciparum and Plasmodium vivax blood-stage and sporozoite antigens in the postpartum period

    PubMed Central

    McLean, Alistair R. D.; Boel, Machteld E.; McGready, Rose; Ataide, Ricardo; Drew, Damien; Tsuboi, Takafumi; Beeson, James G.; Nosten, François; Simpson, Julie A.; Fowkes, Freya J. I.

    2016-01-01

    During pregnancy a variety of immunological changes occur to accommodate the fetus. It is unknown whether these changes continue to affect humoral immunity postpartum or how quickly they resolve. IgG levels were measured to P. falciparum and P. vivax antigens in 201 postpartum and 201 controls over 12 weeks. Linear mixed-effects models assessed antibody maintenance over time and the effect of microscopically confirmed Plasmodium spp. infection on antibody levels, and whether this was different in postpartum women compared with control women. Postpartum women had reduced Plasmodium spp. antibody levels compared to controls at baseline. Over 12 weeks, mean antibody levels in postpartum women increased to levels observed in control women. Microscopically confirmed P. falciparum and P. vivax infections during follow-up were associated with an increase in species-specific antibodies with similar magnitudes of boosting observed in postpartum and control women. Antibodies specific for pregnancy-associated, VAR2CSA-expressing parasites did not rapidly decline postpartum and did not boost in response to infection in either postpartum or control women. After pregnancy, levels of malaria-specific antibodies were reduced, but recovered to levels seen in control women. There was no evidence of an impaired ability to mount a boosting response in postpartum women. PMID:27558000

  2. Functional Antibodies against VAR2CSA in Nonpregnant Populations from Colombia Exposed to Plasmodium falciparum and Plasmodium vivax

    PubMed Central

    Doritchamou, Justin; Arango, Eliana M.; Cabrera, Ana; Arroyo, Maria Isabel; Kain, Kevin C.; Ndam, Nicaise Tuikue; Maestre, Amanda

    2014-01-01

    In pregnancy, parity-dependent immunity is observed in response to placental infection with Plasmodium falciparum. Antibodies recognize the surface antigen, VAR2CSA, expressed on infected red blood cells and inhibit cytoadherence to the placental tissue. In most settings of malaria endemicity, antibodies against VAR2CSA are predominantly observed in multigravid women and infrequently in men, children, and nulligravid women. However, in Colombia, we detected antibodies against multiple constructs of VAR2CSA among men and children with acute P. falciparum and Plasmodium vivax infection. The majority of men and children (>60%) had high levels of IgGs against three recombinant domains of VAR2CSA: DBL5ε, DBL3X, and ID1-ID2. Surprisingly, these antibodies were observed only in pregnant women, men, and children exposed either to P. falciparum or to P. vivax. Moreover, the anti-VAR2CSA antibodies are of high avidity and efficiently inhibit adherence of infected red blood cells to chondroitin sulfate A in vitro, suggesting that they are specific and functional. These unexpected results suggest that there may be genotypic or phenotypic differences in the parasites of this region or in the host response to either P. falciparum or P. vivax infection outside pregnancy. These findings may hold significant clinical relevance to the pathophysiology and outcome of malaria infections in this region. PMID:24686068

  3. Prevalence of mutation and phenotypic expression associated with sulfadoxine-pyrimethamine resistance in Plasmodium falciparum and Plasmodium vivax.

    PubMed

    Zakai, Haytham A; Khan, Wajihullah; Asma, Umme

    2013-09-01

    Therapeutic efficacy of sulfadoxine-pyrimethamine (SP), which is commonly used to treat falciparum malaria, was assessed in isolates of Plasmodium falciparum (Welch, 1897) and Plasmodium vivax (Grassi et Feletti, 1890) ofAligarh, Uttar Pradesh, North India and Taif, Saudi Arabia during 2011-2012. Both the species showed mutations in dihydrofolate reductase (DHFR) enzyme as they have common biochemical drug targets. Mutation rate for pfdhfr was higher compared to pvdhfr because the drug was mainly given to treat falciparum malaria. Since both the species coexist, P. vivax was also exposed to SP due to faulty species diagnosis or medication without specific diagnosis. Low level of mutations against SP in P. falciparum of Saudi isolates indicates that the SP combination is still effective for the treatment of falciparum malaria. Since SP is used as first-line of treatment because of high level of resistance against chloroquine (CQ), it may result in spread of higher level of mutations resulting in drug resistance and treatment failure in near future. Therefore, to avoid further higher mutations in the parasite, use of better treatment regimens such as artesunate combination therapy must be introduced against SP combination.

  4. Antibody responses to Plasmodium falciparum and Plasmodium vivax blood-stage and sporozoite antigens in the postpartum period.

    PubMed

    McLean, Alistair R D; Boel, Machteld E; McGready, Rose; Ataide, Ricardo; Drew, Damien; Tsuboi, Takafumi; Beeson, James G; Nosten, François; Simpson, Julie A; Fowkes, Freya J I

    2016-01-01

    During pregnancy a variety of immunological changes occur to accommodate the fetus. It is unknown whether these changes continue to affect humoral immunity postpartum or how quickly they resolve. IgG levels were measured to P. falciparum and P. vivax antigens in 201 postpartum and 201 controls over 12 weeks. Linear mixed-effects models assessed antibody maintenance over time and the effect of microscopically confirmed Plasmodium spp. infection on antibody levels, and whether this was different in postpartum women compared with control women. Postpartum women had reduced Plasmodium spp. antibody levels compared to controls at baseline. Over 12 weeks, mean antibody levels in postpartum women increased to levels observed in control women. Microscopically confirmed P. falciparum and P. vivax infections during follow-up were associated with an increase in species-specific antibodies with similar magnitudes of boosting observed in postpartum and control women. Antibodies specific for pregnancy-associated, VAR2CSA-expressing parasites did not rapidly decline postpartum and did not boost in response to infection in either postpartum or control women. After pregnancy, levels of malaria-specific antibodies were reduced, but recovered to levels seen in control women. There was no evidence of an impaired ability to mount a boosting response in postpartum women. PMID:27558000

  5. Expression and function of pvcrt-o, a Plasmodium vivax ortholog of pfcrt, in Plasmodium falciparum and Dictyostelium discoideum.

    PubMed

    Sá, Juliana Martha; Yamamoto, Marcio M; Fernandez-Becerra, Carmen; de Azevedo, Mauro Ferreira; Papakrivos, Janni; Naudé, Bronwen; Wellems, Thomas E; Del Portillo, Hernando A

    2006-12-01

    Chloroquine resistance in Plasmodium vivax threatens the use of this drug as first-line treatment for millions of people infected each year worldwide. Unlike Plasmodium falciparum, in which chloroquine resistance is associated with mutations in the pfcrt gene encoding a digestive vacuole transmembrane protein, no point mutations have been associated with chloroquine resistance in the P. vivax ortholog gene, pvcrt-o (also called pvcg10). However, the question remains whether pvcrt-o can affect chloroquine response independent of mutations. Since P. vivax cannot be cultured in vitro, we used two heterologous expression systems to address this question. Results from the first system, in which chloroquine sensitive P. falciparum parasites were transformed with pvcrt-o, showed a 2.2-fold increase in chloroquine tolerance with pvcrt-o expression under a strong promoter; this effect was reversed by verapamil. In the second system, wild type pvcrt-o or a mutated form of the gene was expressed in Dictyostelium discoideum. Forms of PvCRT-o engineered to express either lysine or threonine at position 76 produced a verapamil-reversible reduction of chloroquine accumulation in this system to approximately 60% of that in control cells. Our data support an effect of PvCRT-o on chloroquine transport and/or accumulation by P. vivax, independent of the K76T amino acid substitution.

  6. 75 FR 41233 - Issuance of Permits

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-07-15

    ... Lemur Conservation 75 FR 62586; November April 12, 2010 Foundation. 30, 2009. 231677 Terrance David... Permit number Applicant Federal Register notice Permit issuance date 00568A Bryce Carlson/Emory 75 FR 22162; April 27, June 24, 2010 University. 2010. 02299A John Turner 75 FR 27814; May 18, June 30,...

  7. 40 CFR 35.925-6 - Permits.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 1 2012-07-01 2012-07-01 false Permits. 35.925-6 Section 35.925-6 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY GRANTS AND OTHER FEDERAL ASSISTANCE STATE AND LOCAL ASSISTANCE Grants for Construction of Treatment Works-Clean Water Act § 35.925-6 Permits. That the...

  8. 40 CFR 35.925-6 - Permits.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 1 2013-07-01 2013-07-01 false Permits. 35.925-6 Section 35.925-6 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY GRANTS AND OTHER FEDERAL ASSISTANCE STATE AND LOCAL ASSISTANCE Grants for Construction of Treatment Works-Clean Water Act § 35.925-6 Permits. That the...

  9. 40 CFR 35.925-6 - Permits.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 1 2011-07-01 2011-07-01 false Permits. 35.925-6 Section 35.925-6 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY GRANTS AND OTHER FEDERAL ASSISTANCE STATE AND LOCAL ASSISTANCE Grants for Construction of Treatment Works-Clean Water Act § 35.925-6 Permits. That the...

  10. 40 CFR 35.925-6 - Permits.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 1 2014-07-01 2014-07-01 false Permits. 35.925-6 Section 35.925-6 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY GRANTS AND OTHER FEDERAL ASSISTANCE STATE AND LOCAL ASSISTANCE Grants for Construction of Treatment Works-Clean Water Act § 35.925-6 Permits. That the...

  11. 30 CFR 778.17 - Permit term.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 3 2010-07-01 2010-07-01 false Permit term. 778.17 Section 778.17 Mineral... term. (a) Each application shall state the anticipated or actual starting and termination date of each... an initial permit term in excess of 5 years in order to obtain necessary financing for equipment...

  12. 46 CFR 176.113 - Passengers permitted.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... passengers permitted on any vessel may be the greatest number permitted by the length of rail criterion, deck area criterion, or fixed seating criterion described in this paragraph or a combination of these criteria as allowed by paragraph (c) of this section. (1) Length of rail criterion. One passenger may...

  13. 50 CFR 216.35 - Permit restrictions.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... parts is subject to the provisions of 50 CFR part 14. (d) The permit holder shall not take from the wild... ADMINISTRATION, DEPARTMENT OF COMMERCE MARINE MAMMALS REGULATIONS GOVERNING THE TAKING AND IMPORTING OF MARINE MAMMALS Special Exceptions § 216.35 Permit restrictions. The following restrictions shall apply to...

  14. 50 CFR 216.35 - Permit restrictions.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... parts is subject to the provisions of 50 CFR part 14. (d) The permit holder shall not take from the wild... ADMINISTRATION, DEPARTMENT OF COMMERCE MARINE MAMMALS REGULATIONS GOVERNING THE TAKING AND IMPORTING OF MARINE MAMMALS Special Exceptions § 216.35 Permit restrictions. The following restrictions shall apply to...

  15. 33 CFR 107.220 - Permits.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... shall make a written certification to that effect identifying which OFAC general license applies or... Waters § 107.220 Permits. (a) Applications for a permit may be obtained by writing or calling the Chief... applications must be written in English and legible. (c) The information and documentation in this...

  16. 50 CFR 600.501 - Vessel permits.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... are contained in 50 CFR part 229 of this title. (b) Responsibility of owners and operators. The owners... additional permit restrictions on the permit under 15 CFR part 904, if the vessel is involved in the... authorize FFV's or persons to harass, capture, or kill marine mammals. No marine mammals may be taken in...

  17. 9 CFR 122.2 - Permits required.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ..., SERUMS, TOXINS, AND ANALOGOUS PRODUCTS; ORGANISMS AND VECTORS ORGANISMS AND VECTORS § 122.2 Permits required. No organisms or vectors shall be imported into the United States or transported from one State or... be required under this section for importation of organisms for which an import permit has...

  18. 9 CFR 122.2 - Permits required.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ..., SERUMS, TOXINS, AND ANALOGOUS PRODUCTS; ORGANISMS AND VECTORS ORGANISMS AND VECTORS § 122.2 Permits required. No organisms or vectors shall be imported into the United States or transported from one State or... be required under this section for importation of organisms for which an import permit has...

  19. 9 CFR 122.2 - Permits required.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ..., SERUMS, TOXINS, AND ANALOGOUS PRODUCTS; ORGANISMS AND VECTORS ORGANISMS AND VECTORS § 122.2 Permits required. No organisms or vectors shall be imported into the United States or transported from one State or... be required under this section for importation of organisms for which an import permit has...

  20. 9 CFR 122.2 - Permits required.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ..., SERUMS, TOXINS, AND ANALOGOUS PRODUCTS; ORGANISMS AND VECTORS ORGANISMS AND VECTORS § 122.2 Permits required. No organisms or vectors shall be imported into the United States or transported from one State or... be required under this section for importation of organisms for which an import permit has...

  1. Major developments in section 404-permitting

    SciTech Connect

    Ahrens, M.; Orr, S.

    2009-06-15

    Mountain coal mining in the Central Appalachians faces increased challenge under the Clean Water Act (CWA). These challenges have included the US Environmental Protection Agency's (EPA) increased involvement in permitting under Section 404 of the CWA; active opposition by environmental groups to Section 404 permits; and proposed federal legislation to reduce the availability of these permits. These recent challenges culminated in a June 11, 2009, Memorandum of Understanding (MoU) between the PEA, the Department of Interior (DoI) and the Army Corps of Engineers (Corps) that will limit the use of general permits for mountaintop coal mining and increase the scrutiny applied to individual permits, while also providing a coordinated approach for reviewing the backlog of pending permit application. By entering into the MoU, the federal agencies aim to reduce the environmental impacts of mountaintop coal mining while increasing certainty and transparency for permit applications. Challenges to Section 404 permitting for mountaintop coal mining are dynamic and new developments occur almost daily. This article provides a snapshot of the current climate.

  2. 46 CFR 176.110 - Routes permitted.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 46 Shipping 7 2012-10-01 2012-10-01 false Routes permitted. 176.110 Section 176.110 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) SMALL PASSENGER VESSELS (UNDER 100 GROSS TONS) INSPECTION AND CERTIFICATION General Provisions; Certificate of Inspection § 176.110 Routes permitted....

  3. 46 CFR 176.110 - Routes permitted.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 46 Shipping 7 2010-10-01 2010-10-01 false Routes permitted. 176.110 Section 176.110 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) SMALL PASSENGER VESSELS (UNDER 100 GROSS TONS) INSPECTION AND CERTIFICATION Certificate of Inspection § 176.110 Routes permitted. (a) The area of...

  4. 46 CFR 176.110 - Routes permitted.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 46 Shipping 7 2014-10-01 2014-10-01 false Routes permitted. 176.110 Section 176.110 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) SMALL PASSENGER VESSELS (UNDER 100 GROSS TONS) INSPECTION AND CERTIFICATION General Provisions; Certificate of Inspection § 176.110 Routes permitted....

  5. 46 CFR 176.110 - Routes permitted.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 46 Shipping 7 2013-10-01 2013-10-01 false Routes permitted. 176.110 Section 176.110 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) SMALL PASSENGER VESSELS (UNDER 100 GROSS TONS) INSPECTION AND CERTIFICATION General Provisions; Certificate of Inspection § 176.110 Routes permitted....

  6. 46 CFR 176.110 - Routes permitted.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 46 Shipping 7 2011-10-01 2011-10-01 false Routes permitted. 176.110 Section 176.110 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) SMALL PASSENGER VESSELS (UNDER 100 GROSS TONS) INSPECTION AND CERTIFICATION Certificate of Inspection § 176.110 Routes permitted. (a) The area of...

  7. 50 CFR 648.4 - Vessel permits.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ...) (5) Mackerel, squid, and butterfish vessels. Any vessel of the United States, including party and... land Atlantic mackerel, squid, or butterfish in or from the EEZ. (i) Loligo squid/butterfish and Illex squid moratorium permits. (A) Eligibility. To be eligible to apply for a moratorium permit to fish...

  8. 50 CFR 648.4 - Vessel permits.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ...) (5) Mackerel, squid, and butterfish vessels. Any vessel of the United States, including party and... land Atlantic mackerel, squid, or butterfish in or from the EEZ. (i) Loligo squid/butterfish and Illex squid moratorium permits. (A) Eligibility. To be eligible to apply for a moratorium permit to fish...

  9. 40 CFR 72.81 - Permit modifications.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... projects under § 72.44(g)(1)(i) and (2) of this part. (b) The following permit revisions shall follow, at... modification procedures or the fast-track modification procedures under § 72.82 of this part: (1) Consistent...: (i) Subparts E, F, and G of this part, where the Administrator is the permitting authority; or...

  10. 40 CFR 72.81 - Permit modifications.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... projects under § 72.44(g)(1)(i) and (2) of this part. (b) The following permit revisions shall follow, at... modification procedures or the fast-track modification procedures under § 72.82 of this part: (1) Consistent...: (i) Subparts E, F, and G of this part, where the Administrator is the permitting authority; or...

  11. 40 CFR 72.81 - Permit modifications.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... projects under § 72.44(g)(1)(i) and (2) of this part. (b) The following permit revisions shall follow, at... modification procedures or the fast-track modification procedures under § 72.82 of this part: (1) Consistent...: (i) Subparts E, F, and G of this part, where the Administrator is the permitting authority; or...

  12. 40 CFR 72.81 - Permit modifications.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... projects under § 72.44(g)(1)(i) and (2) of this part. (b) The following permit revisions shall follow, at... modification procedures or the fast-track modification procedures under § 72.82 of this part: (1) Consistent...: (i) Subparts E, F, and G of this part, where the Administrator is the permitting authority; or...

  13. 50 CFR 660.707 - Permits.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... applying for a permit under the authority of the High Seas Fishing Compliance Act, the Tuna Conventions Act... California, Oregon, and Washington. (1) A commercial fishing vessel of the United States must be registered... Tropical Tuna Commission. (2) All permits issued by NMFS in accordance with paragraph (b)(1) of...

  14. 27 CFR 25.232 - Basic permit.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 1 2014-04-01 2014-04-01 false Basic permit. 25.232 Section 25.232 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND TRADE BUREAU, DEPARTMENT OF THE TREASURY ALCOHOL BEER Beer Purchased From Another Brewer § 25.232 Basic permit. A brewer...

  15. 27 CFR 25.232 - Basic permit.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 1 2013-04-01 2013-04-01 false Basic permit. 25.232 Section 25.232 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND TRADE BUREAU, DEPARTMENT OF THE TREASURY ALCOHOL BEER Beer Purchased From Another Brewer § 25.232 Basic permit. A brewer...

  16. 27 CFR 25.232 - Basic permit.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 27 Alcohol, Tobacco Products and Firearms 1 2012-04-01 2012-04-01 false Basic permit. 25.232 Section 25.232 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND TRADE BUREAU, DEPARTMENT OF THE TREASURY LIQUORS BEER Beer Purchased From Another Brewer § 25.232 Basic permit. A brewer...

  17. 40 CFR 144.33 - Area permits.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 23 2014-07-01 2014-07-01 false Area permits. 144.33 Section 144.33 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) WATER PROGRAMS (CONTINUED) UNDERGROUND... permittee to construct and operate, convert, or plug and abandon wells within the permit area provided:...

  18. 40 CFR 52.151 - Operating permits.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 3 2011-07-01 2011-07-01 false Operating permits. 52.151 Section 52.151 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) APPROVAL AND PROMULGATION OF IMPLEMENTATION PLANS Arizona § 52.151 Operating permits. Insofar as...

  19. 40 CFR 52.151 - Operating permits.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 3 2012-07-01 2012-07-01 false Operating permits. 52.151 Section 52.151 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) APPROVAL AND PROMULGATION OF IMPLEMENTATION PLANS Arizona § 52.151 Operating permits. Insofar as...

  20. 50 CFR 665.242 - Permits.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... in Crustacean Permit Areas 1 or 2 must have a permit issued for that vessel. (4) Harvest of Hawaii crustacean MUS within the Northwestern Hawaiian Islands Marine National Monument is subject to the requirements of 50 CFR part 404. (b) General requirements. General requirements governing...