Elimination of Schistosoma mansoni Adult Worms by Rhesus Macaques: Basis for a Therapeutic Vaccine?

Infection with blood-dwelling schistosome worms is a major cause of human disease in many tropical countries. Despite intensive efforts a vaccine has proved elusive, not least because the chronic nature of the infection provides few pointers for vaccine development. The rhesus macaque appears unique among animal models in that adult worms establish but are eventually lost. We investigated whether this was due to pathological or immunological causes by monitoring the fate of a schistosome infection, and were able to rule out escape of worms from the portal system as a result of egg-induced vascular shunts. A substantial worm population established in all animals but there was a wide variation in the numbers recovered at 18 weeks. We observed a strong inverse association between the rapidity and intensity of the IgG response and worm burden. Rather than an acute lethal attack, immune-mediated elimination of worms appeared to be a prolonged process directed against vital components of exposed surfaces, causing worms to starve to death. We suggest that if the mechanisms deployed by the rhesus macaque could be replicated in humans by administration of key recombinant antigens, they would form the basis for a vaccine with both prophylactic and therapeutic properties

Full-sky correlations of peaks in the microwave background

We compute precise predictions for the two-point correlation function of local maxima (or minima) in the temperature of the microwave background, under the assumption that it is a random gaussian field. For a given power spectrum and peak threshold there are no adjustable parameters, and since this analysis does not make the small-angle approximation of Heavens & Sheth (1999), it is essentially complete. We find oscillatory features which are absent in the temperature autocorrelation function, and we also find that the small-angle approximation to the peak-peak correlation function is accurate to better than 0.01 on all scales. These high-precision predictions can form the basis of a sensitive test of the gaussian hypothesis with upcoming all-sky microwave background experiments MAP and Planck, affording a thorough test of the inflationary theory of the early Universe. To illustrate the effectiveness of the technique, we apply it to simulated maps of the microwave sky arising from the cosmic string model of structure formation, and compare with the bispectrum as a non-gaussian discriminant. We also show how peak statistics can be a valuable tool in assessing and statistically removing contamination of the map by foreground point sources.Comment: submitted to MNRA

Do left atrial strain and strain rate reflect intrinsic atrial function, or are they determined by left ventricular function?

Background: Left atrial (LA) strain (S) and strain rate (SR) are reported as measures of intrinsic function. Aim: Since the LA and left ventricle (LV) are connected through the mitral annulus, we investigated: (1) if deformation indices in the LA are mostly predicted by deformation of the LV; (2) if timings of S and SR events are similar in both the LA and LV; and (3) if alteration of S and SR in patients with primarily LV dysfunction would be similar in the LA and LV. Methods: We retrospectively assessed 50 asymptomatic women (Group 1) and 20 patients with recent (< 96 h) acute pulmonary oedema (10 women) (Group 2). Using speckle tracking, the amplitude and timings of S and SR were averaged from three apical views, for one cardiac cycle, starting from the P-wave. Results: In Group 1, all deformation indices were higher in the LA compared with the LV (p < 0.001 for all). In Group 2, S and SR during LA contraction were higher in the LA vs. LV (p < 0.05 for both), but all other deformation indices were not different in the LA vs. LV. All timings of S and SR occurred simultaneously in LA and LV in both groups, except S during LA contraction in Group 1, which occurred slightly earlier in LA than in LV. By multiple regression analysis, the most important predictors of LA deformation indices were the corresponding LV deformation indices, especially in patients with LV dysfunction (Group 1: r = 0.35–0.52; Group 2: r = 0.76–0.85; p < 0.05 by Fisher r-to-z transform). Conclusions: LA deformation strongly reflects LV deformation both in asymptomatic subjects and in patients with LV dysfunction. With the possible exception of LA contraction in asymptomatic individuals, discriminating intrinsic LA function from LV influence is difficult using deformation analysis

Non-perturbative dynamics of hot non-Abelian gauge fields: beyond leading log approximation

Many aspects of high-temperature gauge theories, such as the electroweak baryon number violation rate, color conductivity, and the hard gluon damping rate, have previously been understood only at leading logarithmic order (that is, neglecting effects suppressed only by an inverse logarithm of the gauge coupling). We discuss how to systematically go beyond leading logarithmic order in the analysis of physical quantities. Specifically, we extend to next-to-leading-log order (NLLO) the simple leading-log effective theory due to Bodeker that describes non-perturbative color physics in hot non-Abelian plasmas. A suitable scaling analysis is used to show that no new operators enter the effective theory at next-to-leading-log order. However, a NLLO calculation of the color conductivity is required, and we report the resulting value. Our NLLO result for the color conductivity can be trivially combined with previous numerical work by G. Moore to yield a NLLO result for the hot electroweak baryon number violation rate.Comment: 20 pages, 1 figur

Schistosoma mansoni Stomatin Like Protein-2 Is Located in the Tegument and Induces Partial Protection against Challenge Infection

Schistosomiasis is a parasitic disease causing serious chronic morbidity in tropical countries. Together with the publication of the transcriptome database, a series of new vaccine candidates were proposed based on their functional classification. However, the prediction of vaccine candidates from sequence information or even by proteomics or microarrays data is somewhat speculative and there remains the considerable task of functional analysis of each new gene/protein. In this study, we present the characterization of one of these molecules, a stomatin like protein 2 (SmStoLP-2). Sequence analysis predicts signals that could contribute to protein membrane association and mitochondrial targeting, which was confirmed by differential extractions of schistosome tegument membranes and mitochondria. Additionally, confocal microscope analysis showed SmStoLP-2 present in the tegument of 7-day-old schistosomula and adult worms. Studies in patients living in endemic areas for schistosomiasis revealed high levels of IgG1, IgG2, IgG3 and IgA anti-SmStoLP-2 antibodies in individuals resistant to reinfection. Recombinant SmStoLP-2 protein, when used as vaccine, induced significant levels of protection in mice. This reduction in worm burden was associated with a typical Th1-type immune response. These results indicate that SmStoLP-2 could be useful in association with other antigens for the composition of a vaccine against schistosomiasis

Altered Patterns of Gene Expression Underlying the Enhanced Immunogenicity of Radiation-Attenuated Schistosomes

Schistosoma mansoni is a blood-dwelling parasitic worm that causes schistosomiasis in humans throughout Africa and parts of South America. A vaccine would enhance attempts to control and eradicate the disease that currently relies on treatment with a single drug. Although a manufactured vaccine has yet to generate high levels of protection, this can be achieved with infective parasite larvae that have been disabled by exposure to radiation. How these weakened parasites are able to induce protective immunity when normal parasites do not, is the question addressed by our experiments. We have used a technique of gene expression profiling to compare the patterns in normal and disabled parasites, over the period when they would trigger an immune response in the host. We found that only a handful of genes were differentially expressed, all of them diminished in the disabled parasite. However, a more sensitive technique to examine groups of genes revealed that those involved in nervous system and muscle function were depressed in the disabled parasites. We suggest that reduced mobility of these larvae permits them longer contact with the immune system, thus enabling a strong protective immune response to develop

Enzymatic Shaving of the Tegument Surface of Live Schistosomes for Proteomic Analysis: A Rational Approach to Select Vaccine Candidates

Adult schistosome parasites can reside in the host bloodstream for decades surrounded by components of the immune system. It was originally proposed that their survival depended on the secretion of an inert bilayer, the membranocalyx, to protect the underlying plasma membrane from attack. We have investigated whether any proteins were exposed on the surface of live worms using incubation with selected hydrolases, in combination with mass spectrometry to identify released proteins. We show that a small number of parasite proteins are accessible to the enzymes and so could represent constituents of the membranocalyx. We also identified several proteins acquired by the parasite on contact with host cells. In addition, components of the cytolytic complement pathway were detected, but these appeared not to harm the worm, indicating that some of its own surface proteins could inhibit the lytic pathway. We suggest that, collectively, the ‘superficial’ parasite proteins may provide good candidates for a schistosome vaccine

Plasma markers of oxidative stress are uncorrelated in a wild mammal.

This is the final version of the article. Available from Wiley via the DOI in this record.Oxidative stress, which results from an imbalance between the production of potentially damaging reactive oxygen species versus antioxidant defenses and repair mechanisms, has been proposed as an important mediator of life-history trade-offs. A plethora of biomarkers associated with oxidative stress exist, but few ecological studies have examined the relationships among different markers in organisms experiencing natural conditions or tested whether those relationships are stable across different environments and demographic groups. It is therefore not clear to what extent studies of different markers can be compared, or whether studies that focus on a single marker can draw general conclusions regarding oxidative stress. We measured widely used markers of oxidative damage (protein carbonyls and malondialdehyde) and antioxidant defense (superoxide dismutase and total antioxidant capacity) from 706 plasma samples collected over a 4-year period in a wild population of Soay sheep on St Kilda. We quantified the correlation structure among these four markers across the entire sample set and also within separate years, age groups (lambs and adults), and sexes. We found some moderately strong correlations between some pairs of markers when data from all 4 years were pooled. However, these correlations were caused by considerable among-year variation in mean marker values; correlation coefficients were small and not significantly different from zero after accounting for among-year variation. Furthermore, within each year, age, and sex subgroup, the pairwise correlation coefficients among the four markers were weak, nonsignificant, and distributed around zero. In addition, principal component analysis confirmed that the four markers represented four independent axes of variation. Our results suggest that plasma markers of oxidative stress may vary dramatically among years, presumably due to environmental conditions, and that this variation can induce population-level correlations among markers even in the absence of any correlations within contemporaneous subgroups. The absence of any consistent correlations within years or demographic subgroups implies that care must be taken when generalizing from observed relationships with oxidative stress markers, as each marker may reflect different and potentially uncoupled biochemical processes.We would like to thank Melissa M. Page, Ruth Banks, Christopher Mitchell and Sharon Mitchell for technical assistance and the St Kilda summer field teams of 2010-2013. In addition, we are very grateful to the National Trust for Scotland for permission to carry out fieldwork on St Kilda, and QinetiQ, Angus Campbell and Kilda Cruises for logistic support. LLC was supported by a BBSRC EASTBIO Doctoral Training Partnership Studentship and DHN by a BBSRC David Phillips Fellowship. The Soay sheep project was supported by a NERC responsive mode grant to JMP over the course of our four-year study

The Genome Sequence of Caenorhabditis briggsae: A Platform for Comparative Genomics

The soil nematodes Caenorhabditis briggsae and Caenorhabditis elegans diverged from a common ancestor roughly 100 million years ago and yet are almost indistinguishable by eye. They have the same chromosome number and genome sizes, and they occupy the same ecological niche. To explore the basis for this striking conservation of structure and function, we have sequenced the C. briggsae genome to a high-quality draft stage and compared it to the finished C. elegans sequence. We predict approximately 19,500 protein-coding genes in the C. briggsae genome, roughly the same as in C. elegans. Of these, 12,200 have clear C. elegans orthologs, a further 6,500 have one or more clearly detectable C. elegans homologs, and approximately 800 C. briggsae genes have no detectable matches in C. elegans. Almost all of the noncoding RNAs (ncRNAs) known are shared between the two species. The two genomes exhibit extensive colinearity, and the rate of divergence appears to be higher in the chromosomal arms than in the centers. Operons, a distinctive feature of C. elegans, are highly conserved in C. briggsae, with the arrangement of genes being preserved in 96% of cases. The difference in size between the C. briggsae (estimated at approximately 104 Mbp) and C. elegans (100.3 Mbp) genomes is almost entirely due to repetitive sequence, which accounts for 22.4% of the C. briggsae genome in contrast to 16.5% of the C. elegans genome. Few, if any, repeat families are shared, suggesting that most were acquired after the two species diverged or are undergoing rapid evolution. Coclustering the C. elegans and C. briggsae proteins reveals 2,169 protein families of two or more members. Most of these are shared between the two species, but some appear to be expanding or contracting, and there seem to be as many as several hundred novel C. briggsae gene families. The C. briggsae draft sequence will greatly improve the annotation of the C. elegans genome. Based on similarity to C. briggsae, we found strong evidence for 1,300 new C. elegans genes. In addition, comparisons of the two genomes will help to understand the evolutionary forces that mold nematode genomes