A principal target of human immunity to malaria identified by molecular population genetic and immunological analyses

New strategies are required to identify the most important targets of protective immunity in complex eukaryotic pathogens. Natural selection maintains allelic variation in some antigens of the malaria parasite Plasmodium falciparum. Analysis of allele frequency distributions could identify the loci under most intense selection. The merozoite surface protein 1 (Msp1) is the most-abundant surface component on the erythrocyte-invading stage of P. falciparum. Immunization with whole Msp1 has protected monkeys completely against homologous and partially against non-homologous parasite strains. The single-copy msp1 gene, of about 5 kilobases, has highly divergent alleles with stable frequencies in endemic populations. To identify the region of msp1 under strongest selection to maintain alleles within populations, we studied multiple intragenic sequence loci in populations in different regions of Africa and Southeast Asia. On both continents, the locus with the lowest inter-population variance in allele frequencies was block 2, indicating selection in this part of the gene. To test the hypothesis of immune selection, we undertook a large prospective longitudinal cohort study. This demonstrated that serum IgG antibodies against each of the two most frequent allelic types of block 2 of the protein were strongly associated with protection from P. falciparum malaria.     

Expression of sclerostin in the developing zebrafish (Danio rerio) brain and skeleton

Sclerostin is a highly conserved, secreted, cystine-knot protein which regulates osteoblast function. Humans with mutations in the sclerostin gene (SOST), manifest increased axial and appendicular skeletal bone density with attendant complications. In adult bone, sclerostin is expressed in osteocytes and osteoblasts. Danio rerio sclerostin-like protein is closely related to sea bass sclerostin, and is related to chicken and mammalian sclerostins. Little is known about the expression of sclerostin in early developing skeletal or extra-skeletal tissues. We assessed sclerostin (sost) gene expression in developing zebrafish (D. rerio) embryos with whole mount is situ hybridization methods. The earliest expression of sost mRNA was noted during 12h post-fertilization (hpf). At 15hpf, sost mRNA was detected in the developing nervous system and in Kupffer's vesicle. At 18, 20 and 22hpf, expression in rhombic lip precursors was seen. By 24hpf, expression in the upper and lower rhombic lip and developing spinal cord was noted. Expression in the rhombic lip and spinal cord persisted through 28hpf and then diminished in intensity through 44hpf. At 28hpf, sost expression was noted in developing pharyngeal cartilage; expression in pharyngeal cartilage increased with time. By 48hpf, sost mRNA was clearly detected in the developing pharyngeal arch cartilage. Sost mRNA was abundantly expressed in the pharyngeal arch cartilage, and in developing pectoral fins, 72, 96 and 120hpf. Our study is the first detailed analysis of sost gene expression in early metazoan development.     

Taz1 enforces cell-cycle regulation of telomere synthesis

The dramatic telomerase-dependent overelongation of telomeres in cells lacking Taz1 (ortholog of human TRF1/TRF2) or Rap1 implicates these proteins in restraint of telomerase activity. However, the modes by which these proteins regulate telomerase remain mysterious. Here we show that the mechanisms underlying excessive telomerase activity differ markedly between taz1Δ and rap1Δ strains. Despite allowing elevated telomerase access, rap1Δ telomeres are processed and synthesized in a cell-cycle-constrained manner similar to that of wild-type cells. In contrast, taz1Δ telomeres are processed with little cell-cycle dependency and recruit telomerase over an abnormally wide range of cell-cycle stages. Furthermore, although taz1Δ telomeres experience transient attrition mediated by replication fork stalling, this is balanced not only by temporal expansion of the telomerase activity period, but also by markedly increased recruitment of telomerase and its accessory factor Est1, suggesting that stalled forks generate robust substrates for telomerase.     

Sex pheromone evolution is associated with differential regulation of the same desaturase gene in two genera of leafroller moths

Chemical signals are prevalent in sexual communication systems. Mate recognition has been extensively studied within the Lepidoptera, where the production and recognition of species-specific sex pheromone signals are typically the defining character. While the specific blend of compounds that makes up the sex pheromones of many species has been characterized, the molecular mechanisms underpinning the evolution of pheromone-based mate recognition systems remain largely unknown. We have focused on two sets of sibling species within the leafroller moth genera Ctenopseustis and Planotortrix that have rapidly evolved the use of distinct sex pheromone blends. The compounds within these blends differ almost exclusively in the relative position of double bonds that are introduced by desaturase enzymes. Of the six desaturase orthologs isolated from all four species, functional analyses in yeast and gene expression in pheromone glands implicate three in pheromone biosynthesis, two Δ9-desaturases, and a Δ10-desaturase, while the remaining three desaturases include a Δ6-desaturase, a terminal desaturase, and a non-functional desaturase. Comparative quantitative real-time PCR reveals that the Δ10-desaturase is differentially expressed in the pheromone glands of the two sets of sibling species, consistent with differences in the pheromone blend in both species pairs. In the pheromone glands of species that utilize (Z)-8-tetradecenyl acetate as sex pheromone component (Ctenopseustis obliquana and Planotortrix octo), the expression levels of the Δ10-desaturase are significantly higher than in the pheromone glands of their respective sibling species (C. herana and P. excessana). Our results demonstrate that interspecific sex pheromone differences are associated with differential regulation of the same desaturase gene in two genera of moths. We suggest that differential gene regulation among members of a multigene family may be an important mechanism of molecular innovation in sex pheromone evolution and speciation.     

Dancing with the Tides: Fluctuations of Coastal Phytoplankton Orchestrated by Different Oscillatory Modes of the Tidal Cycle

Population fluctuations are often driven by an interplay between intrinsic population processes and extrinsic environmental forcing. To investigate this interplay, we analyzed fluctuations in coastal phytoplankton concentration in relation to the tidal cycle. Time series of chlorophyll fluorescence, suspended particulate matter (SPM), salinity and temperature were obtained from an automated measuring platform in the southern North Sea, covering 9 years of data at a resolution of 12 to 30 minutes. Wavelet analysis showed that chlorophyll fluctuations were dominated by periodicities of 6 hours 12 min, 12 hours 25 min, 24 hours and 15 days, which correspond to the typical periodicities of tidal current speeds, the semidiurnal tidal cycle, the day-night cycle, and the spring-neap tidal cycle, respectively. During most of the year, chlorophyll and SPM fluctuated in phase with tidal current speed, indicative of alternating periods of sinking and vertical mixing of algal cells and SPM driven by the tidal cycle. Spring blooms slowly built up over several spring-neap tidal cycles, and subsequently expanded in late spring when a strong decline of the SPM concentration during neap tide enabled a temporary “escape” of the chlorophyll concentration from the tidal mixing regime. Our results demonstrate that the tidal cycle is a major determinant of phytoplankton fluctuations at several different time scales. These findings imply that high-resolution monitoring programs are essential to capture the natural variability of phytoplankton in coastal waters.     

Proline isomer-specific antibodies reveal the early pathogenic tau conformation in Alzheimer's disease

cis-trans isomerization of proteins phosphorylated by proline-directed kinases is proposed to control numerous signaling molecules and is implicated in the pathogenesis of Alzheimer's and other diseases. However, there is no direct evidence for the existence of cis-trans protein isomers in?vivo or for their conformation-specific function or regulation. Here we develop peptide chemistries that allow the generation of cis- and trans-specific antibodies and use them to raise antibodies specific for isomers of phosphorylated tau. cis, but not trans, p-tau appears early?in the brains of humans with mild cognitive impairment, accumulates exclusively in degenerated neurons, and localizes to dystrophic neurites during Alzheimer's progression. Unlike trans p-tau, the cis isomer cannot promote microtubule assembly, is more resistant to dephosphorylation and degradation, and is more prone to aggregation. Pin1 converts cis to trans p-tau to prevent Alzheimer's tau pathology. Isomer-specific antibodies and vaccines may therefore have value for the early diagnosis and treatment of Alzheimer's disease.     

Malaria and helminth co-infections in children living in endemic countries: A systematic review with meta-analysis

BackgroundCurrent knowledge on the burden of, and interactions between malaria and helminth co-infections, as well as the impact of the dual infections on anaemia, remains inconclusive. We have conducted a systematic review with meta-analysis to update current knowledge as a first step towards developing and deploying coordinated approaches to the control and, ultimately, elimination of malaria-helminth co-infections among children living in endemic countries.Methodology/Principal findingsWe searched Medline, Embase, Global Health and Web of Science from each database inception until 16 March 2020, for peer-reviewed articles reporting malaria-helminth co-infections in children living in endemic countries. No language restriction was applied. Following removal of duplicates, two reviewers independently screened the studies for eligibility. We used the summary odds ratio (OR) and 95% confidence intervals (CI) as a measure of association (random-effects model). We also performed Chi-square heterogeneity test based on Cochrane’s Q and evaluated the severity of heterogeneity using I² statistics. The included studies were examined for publication bias using a funnel plot and statistical significance was assessed using Egger’s test (bias if p<0.1).Fifty-five of the 3,507 citations screened were eligible, 28 of which had sufficient data for meta-analysis. The 28 studies enrolled 22, 114 children in 13 countries across sub-Saharan Africa, Southeast Asia and South America. Overall, the pooled estimates showed a prevalence of Plasmodium-helminth co-infections of 17.7% (95% CI 12.7–23.2%). Summary estimates from 14 studies showed a lower odds of P. falciparum infection in children co-infected with Schistosoma spp (OR: 0.65; 95%CI: 0.37–1.16). Similar lower odds of P. falciparum infection were observed from the summary estimates of 24 studies in children co-infected with soil transmitted helminths (STH) (OR: 0.42; 95%CI: 0.28–0.64).When adjusted for age, gender, socio-economic status, nutritional status and geographic location of the children, the risk of P. falciparum infection in children co-infected with STH was higher compared with children who did not have STH infection (OR = 1.3; 95% CI 1.03–1.65).A subset of 16 studies showed that the odds of anaemia were higher in children co-infected with Plasmodium and STH than in children with Plasmodium infection alone (OR = 1.20; 95% CI: 0.59–2.45), and were almost equal in children co-infected with Plasmodium-Schistosoma spp or Plasmodium infection alone (OR = 0.97, 95% CI: 0.30–3.14).Conclusions/SignificanceThe current review suggests that prevalence of malaria-helminth co-infection is high in children living in endemic countries. The nature of the interactions between malaria and helminth infection and the impact of the co-infection on anaemia remain inconclusive and may be modulated by the immune responses of the affected children.     

Functional normalization of 450k methylation array data improves replication in large cancer studies

We propose an extension to quantile normalization that removes unwanted technical variation using control probes. We adapt our algorithm, functional normalization, to the Illumina 450k methylation array and address the open problem of normalizing methylation data with global epigenetic changes, such as human cancers. Using data sets from The Cancer Genome Atlas and a large case–control study, we show that our algorithm outperforms all existing normalization methods with respect to replication of results between experiments, and yields robust results even in the presence of batch effects. Functional normalization can be applied to any microarray platform, provided suitable control probes are available.

Electronic supplementary material

The online version of this article (doi:10.1186/s13059-014-0503-2) contains supplementary material, which is available to authorized users.