Functional analysis of Ectodysplasin-A mutations causing selective tooth agenesis.

Mutations of the Ectodysplasin-A (EDA) gene are generally associated with the syndrome hypohidrotic ectodermal dysplasia (MIM 305100), but they can also manifest as selective, non-syndromic tooth agenesis (MIM300606). We have performed an in vitro functional analysis of six selective tooth agenesis-causing EDA mutations (one novel and five known) that are located in the C-terminal tumor necrosis factor homology domain of the protein. Our study reveals that expression, receptor binding or signaling capability of the mutant EDA1 proteins is only impaired in contrast to syndrome-causing mutations, which we have previously shown to abolish EDA1 expression, receptor binding or signaling. Our results support a model in which the development of the human dentition, especially of anterior teeth, requires the highest level of EDA-receptor signaling, whereas other ectodermal appendages, including posterior teeth, have less stringent requirements and form normally in response to EDA mutations with reduced activity

Population substructure in Finland and Sweden revealed by the use of spatial coordinates and a small number of unlinked autosomal SNPs

Abstract Background Despite several thousands of years of close contacts, there are genetic differences between the neighbouring countries of Finland and Sweden. Within Finland, signs of an east-west duality have been observed, whereas the population structure within Sweden has been suggested to be more subtle. With a fine-scale substructure like this, inferring the cluster membership of individuals requires a large number of markers. However, some studies have suggested that this number could be reduced if the individual spatial coordinates are taken into account in the analysis. Results We genotyped 34 unlinked autosomal single nucleotide polymorphisms (SNPs), originally designed for zygosity testing, from 2044 samples from Sweden and 657 samples from Finland, and 30 short tandem repeats (STRs) from 465 Finnish samples. We saw significant population structure within Finland but not between the countries or within Sweden, and isolation by distance within Finland and between the countries. In Sweden, we found a deficit of heterozygotes that we could explain by simulation studies to be due to both a small non-random genotyping error and hidden substructure caused by immigration. Geneland, a model-based Bayesian clustering algorithm, clustered the individuals into groups that corresponded to Sweden and Eastern and Western Finland when spatial coordinates were used, whereas in the absence of spatial information, only one cluster was inferred. Conclusion We show that the power to cluster individuals based on their genetic similarity is increased when including information about the spatial coordinates. We also demonstrate the importance of estimating the size and effect of genotyping error in population genetics in order to strengthen the validity of the results.</p

The African cholera surveillance network (Africhol) consortium meeting, 10–11 June 2015, Lomé, Togo

The fifth annual meeting of the African cholera surveillance network (Africhol) took place on 10–11 June 2015 in Lomé, Togo. Together with international partners, representatives from the 11 member countries -Cameroon, Côte d’Ivoire, Democratic Republic of Congo, Guinea, Kenya, Mozambique, Nigeria, Tanzania, Togo, Uganda, Zimbabwe- and an invited country (Malawi) shared their experience. The meeting featured three sessions: i) cholera surveillance, prevention and control in participating countries, ii) cholera surveillance methodology, such as cholera mapping, cost-effectiveness studies and the issue of overlapping epidemics from different diseases, iii) cholera laboratory diagnostics tools and capacity building. The meeting has greatly benefitted from the input of technical expertise from participating institutions and the observations emerging from the meeting should enable national teams to make recommendations to their respective governments on the most appropriate and effective measures to be taken for the prevention and control of cholera. Recommendations for future activities included collecting precise burden estimates in surveillance sites; modeling cholera burden for Africa; setting up cross-border collaborations; strengthening laboratory capacity for the confirmation of suspected cholera cases and for vaccine impact assessment in settings where oral cholera vaccine would be used; adapting cholera surveillance to concurrent issues (e.g., Ebola); and developing national cholera control plans including rationale vaccination strategies together with other preventive and control measures such as improvements in water, sanitation and hygiene (WASH). ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12919-016-0068-z) contains supplementary material, which is available to authorized users

Variants in the fetal genome near FLT1 are associated with risk of preeclampsia.

: Preeclampsia, which affects approximately 5% of pregnancies, is a leading cause of maternal and perinatal death. The causes of preeclampsia remain unclear, but there is evidence for inherited susceptibility. Genome-wide association studies (GWAS) have not identified maternal sequence variants of genome-wide significance that replicate in independent data sets. We report the first GWAS of offspring from preeclamptic pregnancies and discovery of the first genome-wide significant susceptibility locus (rs4769613; P = 5.4 × 10(-11)) in 4,380 cases and 310,238 controls. This locus is near the FLT1 gene encoding Fms-like tyrosine kinase 1, providing biological support, as a placental isoform of this protein (sFlt-1) is implicated in the pathology of preeclampsia. The association was strongest in offspring from pregnancies in which preeclampsia developed during late gestation and offspring birth weights exceeded the tenth centile. An additional nearby variant, rs12050029, associated with preeclampsia independently of rs4769613. The newly discovered locus may enhance understanding of the pathophysiology of preeclampsia and its subtypes.<br/

Epigenetic alterations in skin homing CD4+CLA+ T cells of atopic dermatitis patients

T cells expressing the cutaneous lymphocyte antigen (CLA) mediate pathogenic inflammation in atopic dermatitis (AD). The molecular alterations contributing to their dysregulation remain unclear. With the aim to elucidate putative altered pathways in AD we profiled DNA methylation levels and miRNA expression in sorted T cell populations (CD4+, CD4+CD45RA+ naïve, CD4+CLA+, and CD8+) from adult AD patients and healthy controls (HC). Skin homing CD4+CLA+ T cells from AD patients showed significant differences in DNA methylation in 40 genes compared to HC (p < 0.05). Reduced DNA methylation levels in the upstream region of the interleukin-13 gene (IL13) in CD4+CLA+ T cells from AD patients correlated with increased IL13 mRNA expression in these cells. Sixteen miRNAs showed differential expression in CD4+CLA+ T cells from AD patients targeting genes in 202 biological processes (p < 0.05). An integrated network analysis of miRNAs and CpG sites identified two communities of strongly interconnected regulatory elements with strong antagonistic behaviours that recapitulated the differences between AD patients and HC. Functional analysis of the genes linked to these communities revealed their association with key cytokine signaling pathways, MAP kinase signaling and protein ubiquitination. Our findings support that epigenetic mechanisms play a role in the pathogenesis of AD by affecting inflammatory signaling molecules in skin homing CD4+CLA+ T cells and uncover putative molecules participating in AD pathways. © 2020, The Author(s).Peer reviewe

Epitopic Specificity of the Human Immune Response to the Invariant Region of a Polymorphic Plasmodium faciparum Merozoite Surface Antigen

application/pdfMerozoite surface antigen 2 (MSA2) is a Plasmodium falciparum vaccine candidate. Antibody responses to MSA2 in Melanesians naturally exposed to P. falciparum were investigated by ELISA using the recombinant MSA2 protein known as Ag 1609 and 65 overlapping synthetic peptides spanning predominantly the conserved N and C terminal regions of MSA2. Significant differences were obtained between control and malaria exposed subjects in the ability of sera to bind to Ag 1609. The median absorbance obtained with control sera was 0.36 whereas that obtained with sera from malaria exposed subjects was 1.8. The sera of ninety-five percent of malaria exposed subjects reacted significantly with Ag 1609. The percentage reactivity of the control sera with Ag 1609 was 39%. Overall the serological responses to the synthetic peptides were low and well defined B epitope regions were not delineated. The median absorbances were in general higher for the malaria exposed group than the controls with these differences being significant for five N terminal peptides and 14 C terminal peptides. One peptide (KECTDGNK) at the conserved C terminal end was identified for further investigation as a possible immunodiagnostic epitope. Immunisation of mice with an allelic form of Ag 1609 (namely Ag 1615) produced antibodies to the conserved C terminal of MSA2 but not to the N terminal.journal articl

Toxicogenomic Profiling of 28 Nanomaterials in Mouse Airways

Toxicogenomics opens novel opportunities for hazard assessment by utilizing computational methods to map molecular events and biological processes. In this study, the transcriptomic and immunopathological changes associated with airway exposure to a total of 28 engineered nanomaterials (ENM) are investigated. The ENM are selected to have different core (Ag, Au, TiO2, CuO, nanodiamond, and multiwalled carbon nanotubes) and surface chemistries (COOH, NH2, or polyethylene glycosylation (PEG)). Additionally, ENM with variations in either size (Au) or shape (TiO2) are included. Mice are exposed to 10 mu g of ENM by oropharyngeal aspiration for 4 consecutive days, followed by extensive histological/cytological analyses and transcriptomic characterization of lung tissue. The results demonstrate that transcriptomic alterations are correlated with the inflammatory cell infiltrate in the lungs. Surface modification has varying effects on the airways with amination rendering the strongest inflammatory response, while PEGylation suppresses toxicity. However, toxicological responses are also dependent on ENM core chemistry. In addition to ENM-specific transcriptional changes, a subset of 50 shared differentially expressed genes is also highlighted that cluster these ENM according to their toxicity. This study provides the largest in vivo data set currently available and as such provides valuable information to be utilized in developing predictive models for ENM toxicity.Peer reviewe