Comparative Gene Expression Analysis throughout the Life Cycle of Leishmania braziliensis: Diversity of Expression Profiles among Clinical Isolates

Leishmania is a group of parasites (Protozoa, Trypanosomatidae) responsible for a wide spectrum of clinical forms. Among the factors explaining this phenotypic polymorphism, parasite features are important contributors. One approach to identify them consists in characterizing the gene expression profiles throughout the life cycle. In a recent study, the transcriptome of 3 Leishmania species was compared and this revealed species-specific differences, albeit in a low number. A key issue, however, is to ensure that the observed differences are indeed species-specific and not specific of the strains selected for representing the species. In order to illustrate the relevance of this concern, we analyzed here the gene expression profiles of 5 clinical isolates of L. braziliensis at seven time points of the life cycle. Our results clearly illustrate the unique character of each isolate in terms of gene expression dynamics: one Leishmania strain is not necessarily representative of a given species

Paternal and maternal influences on differences in birth weight between Europeans and Indians born in the UK.

BACKGROUND: Ethnic groups differ significantly in adult physique and birth weight. We aimed to improve understanding of maternal versus paternal contributions to ethnic differences in birth weight, by comparing the offspring of same-ethnic versus mixed-ethnic unions amongst Europeans and South Asian Indians in the UK. METHODOLOGY AND PRINCIPAL FINDINGS: We used data from the UK Office for National Statistics Longitudinal Study (LS) and the Chelsea and Westminster Hospital (CWH), London. In the combined sample at all gestational ages, average birth weight of offspring with two European parents was significantly greater than that of offspring with two Indian parents [Δ = 344 (95% CI 329, 360) g]. Compared to offspring of European mothers, the offspring of Indian mothers had lower birth weight, whether the father was European [Δ = -152 (95% CI -92, -212) g] or Indian [Δ = -254 (95% -315, -192) g]. After adjustment for various confounding factors, average birth weight of offspring with European father and Indian mother was greater than that of offspring with two Indian parents [LS: Δ = 249 (95% CI 143, 354) g; CWH: Δ = 236 (95% CI 62, 411) g]. Average birth weight of offspring with Indian father and European mother was significantly less than that of offspring with two European parents [LS: Δ = -117 (95% CI -207, -26) g; CWH: Δ = -83 (-206, 40) g]. CONCLUSIONS/SIGNIFICANCE: Birth weight of offspring with mixed-ethnic parentage was intermediate between that of offspring with two European or two Indian parents, demonstrating a paternal as well as a maternal contribution to ethnic differences in fetal growth. This can be interpreted as demonstrating paternal modulation of maternal investment in offspring. We suggest long-term nutritional experience over generations may drive such ethnic differences through parental co-adaptation

Metabolic Network for the Biosynthesis of Intra- and Extracellular alpha-Glucans Required for Virulence of Mycobacterium tuberculosis

Mycobacterium tuberculosis synthesizes intra- and extracellular alpha-glucans that were believed to originate from separate pathways. The extracellular glucose polymer is the main constituent of the mycobacterial capsule that is thought to be involved in immune evasion and virulence. However, the role of the alpha-glucan capsule in pathogenesis has remained enigmatic due to an incomplete understanding of alpha-glucan biosynthetic pathways preventing the generation of capsule-deficient mutants. Three separate and potentially redundant pathways had been implicated in alpha-glucan biosynthesis in mycobacteria: the GlgC-GlgA, the Rv3032 and the TreS-Pep2-GlgE pathways. We now show that alpha-glucan in mycobacteria is exclusively assembled intracellularly utilizing the building block alpha-maltose-1-phosphate as the substrate for the maltosyltransferase GlgE, with subsequent branching of the polymer by the branching enzyme GlgB. Some alpha-glucan is exported to form the alpha-glucan capsule. There is an unexpected convergence of the TreS-Pep2 and GlgC-GlgA pathways that both generate alpha-maltose-1-phosphate. While the TreS-Pep2 route from trehalose was already known, we have now established that GlgA forms this phosphosugar from ADP-glucose and glucose 1-phosphate 1000-fold more efficiently than its hitherto described glycogen synthase activity. The two routes are connected by the common precursor ADPglucose, allowing compensatory flux from one route to the other. Having elucidated this unexpected configuration of the metabolic pathways underlying alpha-glucan biosynthesis in mycobacteria, an M. tuberculosis double mutant devoid of alpha-glucan could be constructed, showing a direct link between the GlgE pathway, alpha-glucan biosynthesis and virulence in a mouse infection model

Hypermethylation of the DLC1 CpG island does not alter gene expression in canine lymphoma

<p>Abstract</p> <p>Background</p> <p>This study is a comparative epigenetic evaluation of the methylation status of the <it>DLC1 </it>tumor suppressor gene in naturally-occurring canine lymphoma. Canine non-Hodgkin's lymphoma (NHL) has been proposed to be a relevant preclinical model that occurs spontaneously and may share causative factors with human NHL due to a shared home environment. The canine <it>DLC1 </it>mRNA sequence was derived from normal tissue. Using lymphoid samples from 21 dogs with NHL and 7 normal dogs, the methylation status of the promoter CpG island of the gene was defined for each sample using combined bisulfite restriction analysis (COBRA), methylation-specific PCR (MSP), and bisulfite sequencing methods. Relative gene expression was determined using real-time PCR.</p> <p>Results</p> <p>The mRNA sequence of canine <it>DLC1 </it>is highly similar to the human orthologue and contains all protein functional groups, with 97% or greater similarity in functional regions. Hypermethylation of the 5' and 3' flanking regions of the promoter was statistically significantly associated with the NHL phenotype, but was not associated with silencing of expression or differences in survival.</p> <p>Conclusion</p> <p>The canine <it>DLC1 </it>is constructed highly similarly to the human gene, which has been shown to be an important tumor suppressor in many forms of cancer. As in human NHL, the promoter CpG island of <it>DLC1 </it>in canine NHL samples is abnormally hypermethylated, relative to normal lymphoid tissue. This study confirms that hypermethylation occurs in canine cancers, further supporting the use of companion dogs as comparative models of disease for evaluation of carcinogenesis, biomarker diagnosis, and therapy.</p

Human IgG1 Responses to Surface Localised Schistosoma mansoni Ly6 Family Members Drop following Praziquantel Treatment

The heptalaminate-covered, syncytial tegument is an important anatomical adaptation that enables schistosome parasites to maintain long-term, intravascular residence in definitive hosts. Investigation of the proteins present in this surface layer and the immune responses elicited by them during infection is crucial to our understanding of host/parasite interactions. Recent studies have revealed a number of novel tegumental surface proteins including three (SmCD59a, SmCD59b and Sm29) containing uPAR/Ly6 domains (renamed SmLy6A SmLy6B and SmLy6D in this study). While vaccination with SmLy6A (SmCD59a) and SmLy6D (Sm29) induces protective immunity in experimental models, human immunoglobulin responses to representative SmLy6 family members have yet to be thoroughly explored.Using a PSI-BLAST-based search, we present a comprehensive reanalysis of the Schistosoma mansoni Ly6 family (SmLy6A-K). Our examination extends the number of members to eleven (including three novel proteins) and provides strong evidence that the previously identified vaccine candidate Sm29 (renamed SmLy6D) is a unique double uPAR/Ly6 domain-containing representative. Presence of canonical cysteine residues, signal peptides and GPI-anchor sites strongly suggest that all SmLy6 proteins are cell surface-bound. To provide evidence that SmLy6 members are immunogenic in human populations, we report IgG1 (as well as IgG4 and IgE) responses against two surface-bound representatives (SmLy6A and SmLy6B) within a cohort of S. mansoni-infected Ugandan males before and after praziquantel treatment. While pre-treatment IgG1 prevalence for SmLy6A and SmLy6B differs amongst the studied population (7.4% and 25.3% of the cohort, respectively), these values are both higher than IgG1 prevalence (2.7%) for a sub-surface tegumental antigen, SmTAL1. Further, post-treatment IgG1 levels against surface-associated SmLy6A and SmLy6B significantly drop (p = 0.020 and p < 0.001, respectively) when compared to rising IgG1 levels against sub-surface SmTAL1.Collectively, these results expand the number of SmLy6 proteins found within S. mansoni and specifically demonstrate that surface-associated SmLy6A and SmLy6B elicit immunological responses during infection in endemic communities

Evolutionary diversity in tropical tree communities peaks at intermediate precipitation

This is the final version. Available from Nature Research via the DOI in this record. Time-calibrated molecular phylogenies are deposited at the Dryad Digital Repository (https://doi.org/10.5061/dryad.gf1vhhmk0). A full description with details of data accessibility for Neo-TropTree can be found at http://www.neotroptree.info/.Global patterns of species and evolutionary diversity in plants are primarily determined by a temperature gradient, but precipitation gradients may be more important within the tropics, where plant species richness is positively associated with the amount of rainfall. The impact of precipitation on the distribution of evolutionary diversity, however, is largely unexplored. Here we detail how evolutionary diversity varies along precipitation gradients by bringing together a comprehensive database on the composition of angiosperm tree communities across lowland tropical South America (2,025 inventories from wet to arid biomes), and a new, large-scale phylogenetic hypothesis for the genera that occur in these ecosystems. We find a marked reduction in the evolutionary diversity of communities at low precipitation. However, unlike species richness, evolutionary diversity does not continually increase with rainfall. Rather, our results show that the greatest evolutionary diversity is found in intermediate precipitation regimes, and that there is a decline in evolutionary diversity above 1,490 mm of mean annual rainfall. If conservation is to prioritise evolutionary diversity, areas of intermediate precipitation that are found in the South American ‘arc of deforestation’, but which have been neglected in the design of protected area networks in the tropics, merit increased conservation attention.Natural Environment Research Council (NERC)Conselho Nacional de Desenvolvimento Científico e TecnológicoConselho Nacional de Desenvolvimento Científico e TecnológicoConselho Nacional de Desenvolvimento Científico e TecnológicoNational Science Foundation (NSF)Mohamed bin Zayed Species Conservation FundLeverhulme TrustCoordenação de Aperfeiçoamento de Pessoal de Nível Superio

Geographic variation in breeding system and environment predicts melanin-based plumage ornamentation of male and female Kentish plovers

Sexual selection determines the elaboration of morphological and behavioural traits and thus drives the evolution of phenotypes. Sexual selection on males and females can differ between populations, especially when populations exhibit different breeding systems. A substantial body of literature describes how breeding systems shape ornamentation across species, with a strong emphasis on male ornamentation and female preference. However, whether breeding system predicts ornamentation within species and whether similar mechanisms as in males also shape the phenotype of females remains unclear. Here, we investigate how different breeding systems are associated with male and female ornamentation in five geographically distinct populations of Kentish plovers Charadrius alexandrinus. We predicted that polygamous populations would exhibit more elaborate ornaments and stronger sexual dimorphism than monogamous populations. By estimating the size and intensity of male (n = 162) and female (n = 174) melanin-based plumage ornaments, i.e. breast bands and ear coverts, we show that plumage ornamentation is predicted by breeding system in both sexes. A difference in especially male ornamentation between polygamous (darker and smaller ornaments) and monogamous (lighter and larger) populations causes the greatest sexual dimorphism to be associated with polygamy. The non-social environment, however, may also influence the degree of ornamentation, for instance through availability of food. We found that, in addition to breeding system, a key environmental parameter, rainfall, predicted a seasonal change of ornamentation in a sex-specific manner. Our results emphasise that to understand the phenotype of animals, it is important to consider both natural and sexual selection acting on both males and females

The Causal Cascade to Multiple Sclerosis: A Model for MS Pathogenesis

BACKGROUND: MS pathogenesis seems to involve both genetic susceptibility and environmental risk factors. Three sequential factors are implicated in the environmental risk. The first acts near birth, the second acts during childhood, and the third acts long thereafter. Two candidate factors (vitamin D deficiency and Epstein-Barr viral infection) seem well suited to the first two environmental events. METHODOLOGY/PRINCIPAL FINDINGS: A mathematical Model for MS pathogenesis is developed, incorporating these environmental and genetic factors into a causal scheme that can explain some of the recent changes in MS-epidemiology (e.g., increasing disease prevalence, a changing sex-ratio, and regional variations in monozygotic twin concordance rates). CONCLUSIONS/SIGNIFICANCE: This Model suggests that genetic susceptibility is overwhelmingly the most important determinant of MS pathogenesis. Indeed, over 99% of individuals seem genetically incapable of developing MS, regardless of what environmental exposures they experience. Nevertheless, the contribution of specific genes to MS-susceptibility seems only modest. Thus, despite HLA DRB1*1501 being the most consistently identified genetic marker of MS-susceptibility (being present in over 50% of northern MS patient populations), only about 1% of individuals with this allele are even genetically susceptible to getting MS. Moreover, because genetic susceptibility seems so similar throughout North America and Europe, environmental differences principally determine the regional variations in disease characteristics. Additionally, despite 75% of MS-patients being women, men are 60% more likely to be genetically-susceptible than women. Also, men develop MS at lower levels of environmental exposure than women. Nevertheless, women are more responsive to the recent changes in environmental-exposure (whatever these have been). This explains both the changing sex-ratio and the increasing disease prevalence (which has increased by a minimum of 32% in Canada over the past 35 years). As noted, environmental risk seems to result from three sequential components of environmental exposure. The potential importance of this Model for MS pathogenesis is that, if correct, a therapeutic strategy, designed to interrupt one or more of these sequential factors, has the potential to markedly reduce or eliminate disease prevalence in the future