Quinoline-resistance reversing agents for the malaria parasite Plasmodium falciparum

Resistance to quinoline antimalarials, especially to chloroquine and mefloquine has had a major impact on the treatment of malaria worldwide. In the period since 2000, significant progress has been made in understanding the origins of chloroquine resistance and to a lesser extent mefloquine resistance in Plasmodium falciparum. Chloroquine resistance correlates directly with mutations in the pfcrt gene of the parasite, while changes in another gene, pfmdr1, may also be related to chloroquine resistance in some strains. Mutations in pfcrt do not appear to correlate with mefloquine resistance, but some studies have implicated pfmdr1 in mefloquine resistance. Its involvement however, has not been definitively demonstrated. The protein products of these genes, PfCRT and Pgh-1 are both located in the food vacuole membrane of the parasite. Current evidence suggests that PfCRT is probably a transporter protein. Chloroquine appears to exit the food vacuole via this transporter in resistant PfCRT mutants. Pgh-1 on the other hand, resembles mammalian multi-drug resistance proteins and appears to be involved in expelling hydrophobic drugs from the food vacuole. Resistance reversing agents are believed to act by inhibiting these proteins. The currently known chloroquine- and mefloquine-resistance reversing agents are discussed in this review. This includes a discussion of structure-activity relationships in these compounds and hypotheses on their possible mechanisms of action. The status of current clinical applications is also briefly discussed

Study of relativistic bound state wave functions in quasielastic (e,e'p) reactions

The unpolarized response functions of the quasielastic $^{16}O(e,e^\prime p)^{15}N$ reaction are calculated for three different types of relativistic bound state wave functions. The wave functions are obtained from relativistic Hartree, relativistic Hartree-Fock and density dependent relativistic Hartree calculations that reproduce the experimental charge radius of $^{16}$O. The sensitivity of the unpolarized response functions to the single particle structure of the different models is investigated in the relativistic plane wave impulse approximation. Redistributions of the momentum dependence in the longitudinal and transverse response function can be related to the binding energy of the single particle states. The interference responses $R_{LT}$ and $R_{TT}$ reveal a strong sensitivity to the small component of the relativistic bound state wave function.Comment: 18 pages REVTEX, 5 figures include

Thermodynamical Properties of a Rotating Ideal Bose Gas

In a recent experiment, a Bose-Einstein condensate was trapped in an anharmonic potential which is well approximated by a harmonic and a quartic part. The condensate was set into such a fast rotation that the centrifugal force in the corotating frame overcompensates the harmonic part in the plane perpendicular to the rotation axis. Thus, the resulting trap potential became Mexican-hat shaped. We present an analysis for an ideal Bose gas which is confined in such an anharmonic rotating trap within a semiclassical approximation where we calculate the critical temperature, the condensate fraction, and the heat capacity. In particular, we examine in detail how these thermodynamical quantities depend on the rotation frequency.Comment: Author Information under http://www.theo-phys.uni-essen.de/tp/ags/pelster_dir

“Josef Albers en Amérique, Peintures sur papier”

Josef Albers, Color study for homage to the square, platinium, not dated, 29,5 X 29,6 cm © 2011 The Josef and Anni foundation / Artists rights society, New-York / Bild-Kunst, Germany. Rights reserved. “Josef Albers en Amérique”, which ran at the Centre Pompidou from February to April 2012, focused on the artist’s work following his 1933 emigration to the United States, where he lived until his death in 1976. Albers was 45 years old when he left Germany and had logged thirteen years at the Bau..

Modification of pfap2μ and pfubp1 Markedly Reduces Ring-Stage Susceptibility of Plasmodium falciparum to Artemisinin In Vitro.

Management of uncomplicated malaria worldwide is threatened by the emergence in Asia of Plasmodium falciparum carrying variants of the pfk13 locus and exhibiting reduced susceptibility to artemisinin. Mutations in two other genes, ubp1 and ap2μ, are associated with artemisinin resistance in rodent malaria and with clinical failure of combination therapy in African malaria patients. Transgenic P. falciparum clones, each carrying orthologues of mutations in pfap2μ and pfubp1 associated with artemisinin resistance in Plasmodium chabaudi, were derived by Cas9 gene editing. Susceptibility to artemisinin and other antimalarial drugs was determined. Following exposure to 700 nM dihydroartemisinin in the ring-stage survival assay, we found strong evidence that transgenic parasites expressing the I592T variant (11% survival), but not the S160N variant (1% survival), of the AP2μ adaptin subunit were significantly less susceptible than the parental wild-type parasite population. The V3275F variant of UBP1, but not the V3306F variant, also displayed reduced susceptibility to dihydroartemisinin (8.5% survival versus 0.5% survival). AP2μ and UBP1 variants did not elicit reduced susceptibility to 48 h of exposure to artemisinin or to other antimalarial drugs. Therefore, variants of the AP2 adaptor complex μ-subunit and of the ubiquitin hydrolase UBP1 reduce in vitro artemisinin susceptibility at the early ring stage in P. falciparum These findings confirm the existence of multiple pathways to perturbation of either the mode of action of artemisinin, the parasite's adaptive mechanisms of resistance, or both. The cellular role of UBP1 and AP2μ in Plasmodium parasites should now be elucidated

Metadata: A Case Study at Western Sydney University: Assessment of Metadata Schema for Active Research Data Management

Western Sydney University has engaged Cloud Services provider Intersect to provide access to Mediaflux on an Intersect research data management platform called Idea . Idea has been designed with the intention of managing research data throughout the full data lifecycle from collection to archiving. WSU-derived research data are currently stored across many different silos and there is consideration of management of data through research data management plans. However, the use of metadata is not consistent. As part of the Australian Research Data Commons (ARDC) National Data Assets Initiative, the ARDC funded a collaborative multi-university Institutional Underpinnings project to develop a national Institutional Research Data Management Framework (the Framework). Several essential Elements to the Framework were developed, one of which is the Active Research Data Management Element . The intention of this Element is to provide “institutions with guidance to ensure that research practice is efficient and impactful, and that research data is managed according to requirements such as those outlined in The Australian Code for the Responsible Conduct of Research”. Our approach at Western Sydney University in implementation of the Active Research Data Management Element of the Framework was to take the turnkey Idea platform, configure using a default metadata schema and engage with researchers in ingesting live research project datasets. This case study evaluates the metadata schema to reflect active research datasets uploaded directly from a data source to the Idea research data repository. The Idea platform provides the ability for researchers to curate, manage, protect and disseminate research data. It will also provide the capacity for handling data from research instrument platforms as increasingly, the University’s research infrastructure requires a component that automates metadata creation and storage for aspects of the research cycle

Towards a Step Change in Managing Research Data at Western Sydney University: Assessment of the Active Data Management Ecosystem

This paper describes the approach taken by Western Sydney University in the assessment of a turnkey research data management platform. Key recommendations from the Active Research Data Management Element of the Research Data Management Framework developed by the Australian Research Data Commons were implemented. WSU-derived research data are currently stored across many different silos and there is consideration of management of data through research data management plans. However, the use of metadata is not consistent and often non-existent. WSU trialled the use of the Idea package provided by Cloud Services provider Intersect, which is based on Mediaflux, for the management of research data throughout the full data lifecycle from collection to archiving. The Active Research Data Management Element provided useful insights into the assessment of Idea in the areas of data management, use of metadata, automated data workflows, research data governance and the criteria for platform selection

Pedagógusképzés a befogadó oktatásért Európában

A tanulmány információkat tartalmaz az Európai Uniónak azokról az oktatási irányelveiről, amelyek valamennyi európai pedagógus képzését érintik, foglalkozik az Európai Ügynökség a Sajátos Nevelési Igényű Tanulók Oktatásának Fejlesztéséért (az Ügynökség) projektjével, amelynek központi témája a „Pedagógusképzés a befogadó oktatásért” (TE41). Bemutatja a projekt célját, s ennek kapcsán rávilágít az egyes országok előtt álló lehetőségekre és kihívásokra, felhívja a figyelmet az Ügynökség TE41 projektjének részeként kialakított befogadó tanári profil sajátosságaira

A New Advanced Backcross Tomato Population Enables High Resolution Leaf QTL Mapping and Gene Identification.

Quantitative Trait Loci (QTL) mapping is a powerful technique for dissecting the genetic basis of traits and species differences. Established tomato mapping populations between domesticated tomato (Solanum lycopersicum) and its more distant interfertile relatives typically follow a near isogenic line (NIL) design, such as the S. pennellii Introgression Line (IL) population, with a single wild introgression per line in an otherwise domesticated genetic background. Here, we report on a new advanced backcross QTL mapping resource for tomato, derived from a cross between the M82 tomato cultivar and S. pennellii This so-called Backcrossed Inbred Line (BIL) population is comprised of a mix of BC2 and BC3 lines, with domesticated tomato as the recurrent parent. The BIL population is complementary to the existing S. pennellii IL population, with which it shares parents. Using the BILs, we mapped traits for leaf complexity, leaflet shape, and flowering time. We demonstrate the utility of the BILs for fine-mapping QTL, particularly QTL initially mapped in the ILs, by fine-mapping several QTL to single or few candidate genes. Moreover, we confirm the value of a backcrossed population with multiple introgressions per line, such as the BILs, for epistatic QTL mapping. Our work was further enabled by the development of our own statistical inference and visualization tools, namely a heterogeneous hidden Markov model for genotyping the lines, and by using state-of-the-art sparse regression techniques for QTL mapping

Comparison of the susceptibility of Plasmodium knowlesi and Plasmodium falciparum to antimalarial agents.

BACKGROUND: The simian malaria parasite Plasmodium knowlesi is now a well-recognized pathogen of humans in South-East Asia. Clinical infections appear adequately treated with existing drug regimens, but the evidence base for this practice remains weak. The availability of P. knowlesi cultures adapted to continuous propagation in human erythrocytes enables specific studies of in vitro susceptibility of the species to antimalarial agents, and could provide a surrogate system for testing investigational compounds against Plasmodium vivax and other non-Plasmodium falciparum infections that cannot currently be propagated in vitro. OBJECTIVES: We sought to optimize protocols for in vitro susceptibility testing of P. knowlesi and to contrast outputs with those obtained for P. falciparum under comparable test conditions. METHODS: Growth monitoring of P. knowlesi in vitro was by DNA quantification using a SYBR Green fluorescent assay or by colorimetric detection of the lactate dehydrogenase enzyme. For comparison, P. falciparum was tested under conditions identical to those used for P. knowlesi. RESULTS: The SYBR Green I assay proved the most robust format over one (27 h) or two (54 h) P. knowlesi life cycles. Unexpectedly, P. knowlesi displays significantly greater susceptibility to the dihydrofolate reductase inhibitors pyrimethamine, cycloguanil and trimethoprim than does P. falciparum, but is less susceptible to the selective agents blasticidin and DSM1 used in parasite transfections. Inhibitors of dihydroorotate dehydrogenase also demonstrate lower activity against P. knowlesi. CONCLUSIONS: The fluorescent assay system validated here identified species-specific P. knowlesi drug susceptibility profiles and can be used for testing investigational compounds for activity against non-P. falciparum malaria