Reduced in vitro susceptibility to artemisinin derivatives associated with multi-resistance in a traveller returning from South-East Asia

Decreased in vitro susceptibility to dihydroartemisinin (21.2 nM) and artesunate (16.3 nM) associated with decreased susceptibility or resistance to quinine (1131 nM), mefloquine (166 nM), lumefantrine (114 nM), pyronaridine (70.5 nM) and piperaquine (91.1 nM) is reported in a patient returning from South-East Asia after trekking along the Mekong from the south of Laos to the north of Thailand. Decreased in vitro susceptibility to artemisinin derivatives did not appear to be mediated by the number of copies of pfmdr1 or pfATPase6, pfcrt, pfmdr1 or pfmrp polymorphism. The high IC50 to mefloquine of this Asian isolate was not associated with pfmdr1 copy number. Pfnhe-1 microsatellite ms4760 showed a profile 7 (ms4760-7) with three repeats of DNNND and one repeat of DDDNHNDNHNN, which is associated with high quinine reduced susceptibility. The patient recovered in three days without relapse after treatment with the association of quinine and doxycycline. Decreased in vitro susceptibility to quinine and the delayed effect of doxycycline may both have contributed to the delayed parasite clearance time, D4 (0.5%) and D7 (0.004%). The in vitro data, with IC50 for dihydroartemisinin and artesunate were up to ten times those of the reference clone W2, which suggests that this isolate may be resistant to artemisinin derivatives, associated with a decreased susceptibility to quinine

Optical imaging of luminescence for in vivo quantification of gene electrotransfer in mouse muscle and knee

BACKGROUND: Optical imaging is an attractive non-invasive way to evaluate the expression of a transferred DNA, mainly thanks to its lower cost and ease of realization. In this study optical imaging was evaluated for monitoring and quantification of the mouse knee joint and tibial cranial muscle electrotransfer of a luciferase encoding plasmid. Optical imaging was applied to study the kinetics of luciferase expression in both tissues. RESULTS: The substrate of luciferase (luciferin) was injected either intraperitonealy (i.p.) or in situ into the muscle or the knee joint. Luminescence resulting from the luciferase-luciferin reaction was measured in vivo with a cooled CCD camera and/or in vitro on tissue lysate. Maximal luminescence of the knee joint and muscle after i.p. (2.5 mg) or local injection of luciferin (50 μg in the knee joint, 100 μg in the muscle) were highly correlated. With the local injection procedure adopted, in vivo and in vitro luminescences measured on the same muscles significantly correlated. Luminescence measurements were reproducible and the signal level was proportional to the amount of plasmid injected. In vivo luciferase activity in the electrotransfered knee joint was detected for two weeks. Intramuscular electrotransfer of 0.3 or 3 μg of plasmid led to stable luciferase expression for 62 days, whereas injecting 30 μg of plasmid resulted in a drop of luminescence three weeks after electrotransfer. These decreases were partially associated with the development of an immune response. CONCLUSION: A particular advantage of the i.p. injection of substrate is a widespread distribution at luciferase production sites. We have also highlighted advantages of local injection as a more sensitive detection method with reduced substrate consumption. Besides, this route of injection is relatively free of uncontrolled parameters, such as diffusion to the target organ, crossing of biological barriers and evidencing variations in local enzymatic kinetics, probably related to the reaction medium in the targeted organ. Optical imaging was shown to be a sensitive and relevant technique to quantify variations of luciferase activity in vivo. Further evaluation of the effective amount of luciferase in a given tissue by in vivo optical imaging relies on conditions of the enzymatic reaction and light absorption and presently requires in vitro calibration for each targeted organ

A heterotic sigma model with novel target geometry

We construct a (1,2) heterotic sigma model whose target space geometry consists of a transitive Lie algebroid with complex structure on a Kaehler manifold. We show that, under certain geometrical and topological conditions, there are two distinguished topological half--twists of the heterotic sigma model leading to A and B type half--topological models. Each of these models is characterized by the usual topological BRST operator, stemming from the heterotic (0,2) supersymmetry, and a second BRST operator anticommuting with the former, originating from the (1,0) supersymmetry. These BRST operators combined in a certain way provide each half--topological model with two inequivalent BRST structures and, correspondingly, two distinct perturbative chiral algebras and chiral rings. The latter are studied in detail and characterized geometrically in terms of Lie algebroid cohomology in the quasiclassical limit.Comment: 83 pages, no figures, 2 references adde

The Tulczyjew triple for classical fields

The geometrical structure known as the Tulczyjew triple has proved to be very useful in describing mechanical systems, even those with singular Lagrangians or subject to constraints. Starting from basic concepts of variational calculus, we construct the Tulczyjew triple for first-order Field Theory. The important feature of our approach is that we do not postulate {\it ad hoc} the ingredients of the theory, but obtain them as unavoidable consequences of the variational calculus. This picture of Field Theory is covariant and complete, containing not only the Lagrangian formalism and Euler-Lagrange equations but also the phase space, the phase dynamics and the Hamiltonian formalism. Since the configuration space turns out to be an affine bundle, we have to use affine geometry, in particular the notion of the affine duality. In our formulation, the two maps $\alpha$ and $\beta$ which constitute the Tulczyjew triple are morphisms of double structures of affine-vector bundles. We discuss also the Legendre transformation, i.e. the transition between the Lagrangian and the Hamiltonian formulation of the first-order field theor

Jacobi structures revisited

Jacobi algebroids, that is graded Lie brackets on the Grassmann algebra associated with a vector bundle which satisfy a property similar to that of the Jacobi brackets, are introduced. They turn out to be equivalent to generalized Lie algebroids in the sense of Iglesias and Marrero and can be viewed also as odd Jacobi brackets on the supermanifolds associated with the vector bundles. Jacobi bialgebroids are defined in the same manner. A lifting procedure of elements of this Grassmann algebra to multivector fields on the total space of the vector bundle which preserves the corresponding brackets is developed. This gives the possibility of associating canonically a Lie algebroid with any local Lie algebra in the sense of Kirillov.Comment: 20 page

Hamiltonian dynamics and constrained variational calculus: continuous and discrete settings

The aim of this paper is to study the relationship between Hamiltonian dynamics and constrained variational calculus. We describe both using the notion of Lagrangian submanifolds of convenient symplectic manifolds and using the so-called Tulczyjew's triples. The results are also extended to the case of discrete dynamics and nonholonomic mechanics. Interesting applications to geometrical integration of Hamiltonian systems are obtained.Comment: 33 page

Assessment of exposure to Plasmodium falciparum transmission in a low endemicity area by using multiplex fluorescent microsphere-based serological assays

Background: The evaluation of malaria transmission intensity is a crucial indicator for estimating the burden of malarial disease. In this respect, entomological and parasitological methods present limitations, especially in low transmission areas. The present study used a sensitive multiplex assay to assess the exposure to Plasmodium falciparum infection in children living in an area of low endemicity. In three Senegalese villages, specific antibody (IgG) responses to 13 pre-erythrocytic P. falciparum peptides derived from Lsa1, Lsa3, Glurp, Salsa, Trap, Starp, Csp and Pf11.1 proteins were simultaneously evaluated before (June), at the peak (September) and after (December) the period of malaria transmission, in children aged from 1 to 8 years. Results: Compared to other antigens, a high percentage of seropositivity and specific antibody levels were detected with Glurp, Salsa1, Lsa3NR2, and Lsa1J antigens. The seropositivity increased with age for all tested antigens. Specific IgG levels to Glurp, Salsa1, Lsa3NR2, and Lsa1J were significantly higher in P. falciparum infected children compared to non-infected and this increase is significantly correlated with parasite density. Conclusion: The multiplex assay represents a useful technology for a serological assessment of rapid variations in malaria transmission intensity, especially in a context of low parasite rates. The use of such combined serological markers (i.e. Glurp, Lsa1, Lsa3, and Salsa) could offer the opportunity to examine these variations over time, and to evaluate the efficacy of integrated malaria control strategies

Relationship between Exposure to Vector Bites and Antibody Responses to Mosquito Salivary Gland Extracts

Mosquito-borne diseases are major health problems worldwide. Serological responses to mosquito saliva proteins may be useful in estimating individual exposure to bites from mosquitoes transmitting these diseases. However, the relationships between the levels of these IgG responses and mosquito density as well as IgG response specificity at the genus and/or species level need to be clarified prior to develop new immunological markers to assess human/vector contact. To this end, a kinetic study of antibody levels against several mosquito salivary gland extracts from southeastern French individuals living in three areas with distinct ecological environments and, by implication, distinct Aedes caspius mosquito densities were compared using ELISA. A positive association was observed between the average levels of IgG responses against Ae. caspius salivary gland extracts and spatial Ae. caspius densities. Additionally, the average level of IgG responses increased significantly during the peak exposure to Ae. caspius at each site and returned to baseline four months later, suggesting short-lived IgG responses. The species-specificity of IgG antibody responses was determined by testing antibody responses to salivary gland extracts from Cx. pipiens, a mosquito that is present at these three sites at different density levels, and from two other Aedes species not present in the study area (Ae. aegypti and Ae. albopictus). The IgG responses observed against these mosquito salivary gland extracts contrasted with those observed against Ae. caspius salivary gland extracts, supporting the existence of species-specific serological responses. By considering different populations and densities of mosquitoes linked to environmental factors, this study shows, for the first time, that specific IgG antibody responses against Ae. caspius salivary gland extracts may be related to the seasonal and geographical variations in Ae. caspius density. Characterisation of such immunological-markers may allow the evaluation of the effectiveness of vector-control strategies or estimation of the risk of vector-borne disease transmission

Transiting exoplanets from the CoRoT space mission VIII. CoRoT-7b: the first Super-Earth with measured radius

We report the discovery of very shallow (DF/F = 3.4 10-4), periodic dips in the light curve of an active V = 11.7 G9V star observed by the CoRoT satellite, which we interpret as due to the presence of a transiting companion. We describe the 3-colour CoRoT data and complementary ground-based observations that support the planetary nature of the companion. Methods. We use CoRoT color information, good angular resolution ground-based photometric observations in- and out- of transit, adaptive optics imaging, near-infrared spectroscopy and preliminary results from Radial Velocity measurements, to test the diluted eclipsing binary scenarios. The parameters of the host star are derived from optical spectra, which were then combined with the CoRoT light curve to derive parameters of the companion. We examine carefully all conceivable cases of false positives, and all tests performed support the planetary hypothesis. Blends with separation larger than 0.40 arcsec or triple systems are almost excluded with a 8 10-4 risk left. We conclude that, as far as we have been exhaustive, we have discovered a planetary companion, named CoRoT-7b, for which we derive a period of 0.853 59 +/- 3 10-5 day and a radius of Rp = 1.68 +/- 0.09 REarth. Analysis of preliminary radial velocity data yields an upper limit of 21 MEarth for the companion mass, supporting the finding. CoRoT-7b is very likely the first Super-Earth with a measured radius.Comment: Accepted in Astronomy and Astrophysics; typos and language corrections; version sent to the printer w few upgrade

The Cellular Prion Protein Interacts with the Tissue Non-Specific Alkaline Phosphatase in Membrane Microdomains of Bioaminergic Neuronal Cells

BACKGROUND: The cellular prion protein, PrP(C), is GPI anchored and abundant in lipid rafts. The absolute requirement of PrP(C) in neurodegeneration associated to prion diseases is well established. However, the function of this ubiquitous protein is still puzzling. Our previous work using the 1C11 neuronal model, provided evidence that PrP(C) acts as a cell surface receptor. Besides a ubiquitous signaling function of PrP(C), we have described a neuronal specificity pointing to a role of PrP(C) in neuronal homeostasis. 1C11 cells, upon appropriate induction, engage into neuronal differentiation programs, giving rise either to serotonergic (1C11(5-HT)) or noradrenergic (1C11(NE)) derivatives. METHODOLOGY/PRINCIPAL FINDINGS: The neuronal specificity of PrP(C) signaling prompted us to search for PrP(C) partners in 1C11-derived bioaminergic neuronal cells. We show here by immunoprecipitation an association of PrP(C) with an 80 kDa protein identified by mass spectrometry as the tissue non-specific alkaline phosphatase (TNAP). This interaction occurs in lipid rafts and is restricted to 1C11-derived neuronal progenies. Our data indicate that TNAP is implemented during the differentiation programs of 1C11(5-HT) and 1C11(NE) cells and is active at their cell surface. Noteworthy, TNAP may contribute to the regulation of serotonin or catecholamine synthesis in 1C11(5-HT) and 1C11(NE) bioaminergic cells by controlling pyridoxal phosphate levels. Finally, TNAP activity is shown to modulate the phosphorylation status of laminin and thereby its interaction with PrP. CONCLUSION/SIGNIFICANCE: The identification of a novel PrP(C) partner in lipid rafts of neuronal cells favors the idea of a role of PrP in multiple functions. Because PrP(C) and laminin functionally interact to support neuronal differentiation and memory consolidation, our findings introduce TNAP as a functional protagonist in the PrP(C)-laminin interplay. The partnership between TNAP and PrP(C) in neuronal cells may provide new clues as to the neurospecificity of PrP(C) function