Incidence and mechanism of the pivot shift. An in vitro study.

Accepted versio

Two Naegele Pelves.*

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Sympatric Plasmodium falciparum isolates from Venezuela have structured var gene repertoires

BACKGROUND: The human malaria parasite Plasmodium falciparum expresses adhesins belonging to the erythrocyte membrane protein 1 (PfEMP1) family on the surface of the infected host erythrocyte. These antigens elicit a strain-specific antibody response that is associated with protection from disease. During clonal expansion of blood-stage parasites, the surface phenotype of the infected erythrocyte changes because of transcriptional switching among the 40 to 50 members of the highly polymorphic var multi-gene family which encode PfEMP1 variants. Studies to date have compared var repertoires of natural isolates from various geographical locations but have not addressed any within-population structure that may exist among repertoires. METHODS: Distinct parasite genotypes from a single population co-circulating among a defined group of hosts were selected. PCR products encoding the DBL-α domain of PfEMP-1 were cloned and sequenced from each of three isolates. Repertoire similarity was statistically evaluated using combinatorial analysis. The chromosomal location of shared sequences was inferred from similarity to dbl-α of known location in the 3D7 genome. RESULTS: Sympatric parasites were found to share few var gene sequences, even when alleles at other polymorphic loci were shared. A number of the sequences shared by at least two of the isolates studied were found to be related to 3D7 genomic sequences with non-telomeric chromosomal locations, or atypical domain structures, which may represent globally conserved loci. CONCLUSION: The parasite population studied is structured, with minimal overlap in PfEMP1 repertoires. The var gene family accumulates diversity more rapidly than other antigen genes examined. This may be facilitated by ectopic recombination among the sub-telomeric regions of P. falciparum chromosomes

Artesunate reduces but does not prevent posttreatment transmission of Plasmodium falciparum to Anopheles gambiae.

Combination therapy that includes artemisinin derivatives cures most falciparum malaria infections. Lowering transmission by reducing gametocyte infectivity would be an additional benefit. To examine the effect of such therapy on transmission, Gambian children with Plasmodium falciparum malaria were treated with standard regimens of chloroquine or pyrimethamine-sulfadoxine alone or in combination with 1 or 3 doses of artesunate. The infectivity to mosquitoes of gametocytes in peripheral blood was determined 4 or 7 days after treatment. Infection of mosquitoes was observed in all treatment groups and was positively associated with gametocyte density. The probability of transmission was lowest in those who received pyrimethamine-sulfadoxine and 3 doses of artesunate, and it was 8-fold higher in the group that received pyrimethamine-sulfadoxine alone. Artesunate reduced posttreatment infectivity dramatically but did not abolish it completely. The study raises questions about any policy to use pyrimethamine-sulfadoxine alone as the first-line treatment for malaria

Plasmodium falciparum Antigens on the Surface of the Gametocyte-Infected Erythrocyte

BACKGROUND: The asexual blood stages of the human malaria parasite Plasmodium falciparum produce highly immunogenic polymorphic antigens that are expressed on the surface of the host cell. In contrast, few studies have examined the surface of the gametocyte-infected erythrocyte. METHODOLOGY/PRINCIPAL FINDINGS: We used flow cytometry to detect antibodies recognising the surface of live cultured erythrocytes infected with gametocytes of P. falciparum strain 3D7 in the plasma of 200 Gambian children. The majority of children had been identified as carrying gametocytes after treatment for malaria, and each donated blood for mosquito-feeding experiments. None of the plasma recognised the surface of erythrocytes infected with developmental stages of gametocytes (I-IV), but 66 of 194 (34.0%) plasma contained IgG that recognised the surface of erythrocytes infected with mature (stage V) gametocytes. Thirty-four (17.0%) of 200 plasma tested recognised erythrocytes infected with trophozoites and schizonts, but there was no association with recognition of the surface of gametocyte-infected erythrocytes (odds ratio 1.08, 95% C.I. 0.434-2.57; P = 0.851). Plasma antibodies with the ability to recognise gametocyte surface antigens (GSA) were associated with the presence of antibodies that recognise the gamete antigen Pfs 230, but not Pfs48/45. Antibodies recognising GSA were associated with donors having lower gametocyte densities 4 weeks after antimalarial treatment. CONCLUSIONS/SIGNIFICANCE: We provide evidence that GSA are distinct from antigens detected on the surface of asexual 3D7 parasites. Our findings suggest a novel strategy for the development of transmission-blocking vaccines

The addition of artesunate to chloroquine for treatment of Plasmodium falciparum malaria in Gambian children delays, but does not prevent treatment failure.

In a randomized controlled trial, chloroquine monotherapy was compared with the combination of artesunate and chloroquine for treating uncomplicated Plasmodium falciparum malaria in 536 Gambian children. Chloroquine-treated children exhibited a 28-day clinical failure rate of 15% (95% confidence interval [CI] = 9.2-22%) compared with 11% (7.8-15%) among children receiving the combination (P = 0.08, by Wilcoxon test). Seventy-three percent of chloroquine-treated children exhibited parasitemia during follow-up compared with 49% of children receiving the combination (relative risk = 1.5, 95% CI = 1.3-1.7; chi2 = 21.18, P < 0.001). A significant reduction in clinical and parasitologic treatment failure in the combination group occurred in the first two weeks following treatment, but this was eroded over weeks three and four of follow-up. The impact of combination therapy on the transmission of chloroquine-resistant parasites is discussed. Chloroquine plus artesunate is not sufficiently efficacious to justify its introduction as a replacement for chloroquine monotherapy in The Gambia

A mass threshold in the number density of passive galaxies at z∼\sim2

The process that quenched star formation in galaxies at intermediate and high redshift is still the subject of considerable debate. One way to investigate this puzzling issue is to study the number density of quiescent galaxies at z~2, and its dependence on mass. Here we present the results of a new study based on very deep Ks-band imaging (with the HAWK-I instrument on the VLT) of two HST CANDELS fields (the UKIDSS Ultra-deep survey (UDS) field and GOODS-South). The new HAWK-I data (taken as part of the HUGS VLT Large Program) reach detection limits of Ks>26 (AB mag). We select a sample of passively-evolving galaxies in the redshift range 1.4<z<2.5. Thanks to the depth and large area coverage of our imaging, we have been able to extend the selection of quiescent galaxies a magnitude fainter than previous analyses. Through extensive simulations we demonstrate, for the first time, that the observed turn-over in the number of quiescent galaxies at K>22 is real. This has enabled us to establish unambiguously that the number counts of quiescent galaxies at z~2 flatten and slightly decline at magnitudes fainter than Ks~22(AB mag.). We show that this trend corresponds to a stellar mass threshold $M_*10^{10.8}\,{\rm M_{\odot}}$ below which the mechanism that halts the star formation in high-redshift galaxies seems to be inefficient. Finally we compare the observed pBzK number counts with those of quiescent galaxies extracted from four different semi-analytic models. We find that none of the models provides a statistically acceptable description of the number density of quiescent galaxies at these redshifts. We conclude that the mass function of quiescent galaxies as a function of redshift continues to present a key and demanding challenge for proposed models of galaxy formation and evolution.Comment: Accepted for publication on Astronomy and Astrophysic

Non-parametric analysis of the rest-frame UV sizes and morphological disturbance amongst L* galaxies at 4<z<8

We present the results of a study investigating the sizes and morphologies of redshift 4 < z < 8 galaxies in the CANDELS GOODS-S, HUDF and HUDF parallel fields. Based on non-parametric measurements and incorporating a careful treatment of measurement biases, we quantify the typical size of galaxies at each redshift as the peak of the log-normal size distribution, rather than the arithmetic mean size. Parameterizing the evolution of galaxy half-light radius as $r_{50} \propto (1+z)^n$, we find $n = -0.20 \pm 0.26$ at bright UV-luminosities ($0.3L_{*(z=3)} < L < L_*$) and $n = -0.47 \pm 0.62$ at faint luminosities ($0.12L_* < L < 0.3L_*$). Furthermore, simulations based on artificially redshifting our z~4 galaxy sample show that we cannot reject the null hypothesis of no size evolution. We show that this result is caused by a combination of the size-dependent completeness of high-redshift galaxy samples and the underestimation of the sizes of the largest galaxies at a given epoch. To explore the evolution of galaxy morphology we first compare asymmetry measurements to those from a large sample of simulated single S\'ersic profiles, in order to robustly categorise galaxies as either `smooth' or `disturbed'. Comparing the disturbed fraction amongst bright ($M_{UV} \leq -20$) galaxies at each redshift to that obtained by artificially redshifting our z~4 galaxy sample, while carefully matching the size and UV-luminosity distributions, we find no clear evidence for evolution in galaxy morphology over the redshift interval 4 < z < 8. Therefore, based on our results, a bright ($M_{UV} \leq -20$) galaxy at z~6 is no more likely to be measured as `disturbed' than a comparable galaxy at z~4, given the current observational constraints.Comment: 29 pages, 25 figures, 4 tables, published in MNRA