TGFβ1 single-nucleotide polymorphism C-509T alters mucosal cell function in pediatric eosinophilic esophagitis.

Eosinophilic esophagitis (EoE) is a chronic Th2 antigen-driven disorder associated with tissue remodeling. Inflammation and remodeling lead to esophageal rigidity, strictures, and dysphagia. TGFβ1 drives esophageal remodeling including epithelial barrier dysfunction and subepithelial fibrosis. A functional SNP in the TGFβ1 gene that increases its transcription (C-509T) is associated with elevated numbers of esophageal TGFβ1-expressing cells. We utilized esophageal biopsies and fibroblasts from TT-genotype EoE children to understand if TGFβ1 influenced fibroblast and epithelial cell function in vivo. Genotype TT EoE esophageal fibroblasts had higher baseline TGFβ1, collagen1α1, periostin, and MMP2 (p < 0.05) gene expression and distinct contractile properties compared with CC genotype (n = 6 subjects per genotype). In vitro TGFβ1 exposure caused greater induction of target gene expression in genotype CC fibroblasts (p < 0.05). Esophageal biopsies from TT-genotype subjects had significantly less epithelial membrane-bound E-cadherin (p < 0.01) and wider cluster distribution at nanometer resolution. TGFβ1 treatment of stratified primary human esophageal epithelial cells and spheroids disrupted transepithelial resistance (p < 0.001) and E-cadherin localization (p < 0.0001). A TGFβ1-receptor-I inhibitor improved TGFβ1-mediated E-cadherin mislocalization. These data suggest that EoE severity can depend on genotypic differences that increase in vivo exposure to TGFβ1. TGFβ1 inhibition may be a useful therapy in subsets of EoE patients

Molecular mediators of the association between child obesity and mental health

Biological mechanisms underlying the association between obesity and depression remain unclear. We investigated the role of metabolites and DNA methylation as mediators of the relationship between childhood obesity and subsequent poor mental health in the English Avon Longitudinal Study of Parents and Children. Obesity was defined according to United Kingdom Growth charts at age 7 years and mental health through the Short Mood and Feelings Questionnaire (SMFQ) completed at age 11 years. Metabolites and DNA methylation were measured by nuclear magnetic resonance spectroscopy and Illumina array in blood at the age of 7 years. The associations between obesity and SMFQ score, as continuous count data or using cut-offs to define depressive symptoms (SMFQ >7) or depression (SMFQ >11), were tested using adjusted Poisson and logistic regression. Candidate metabolite mediators were identified through metabolome-wide association scans for obesity and SMFQ score, correcting for false-discovery rate. Candidate DNA methylation mediators were identified through testing the association of putative BMI-associated CpG sites with SMFQ scores, correcting for look-up false-discovery rate. Mediation by candidate molecular markers was tested. Two-sample Mendelian randomization (MR) analyses were additionally applied to test causal associations of metabolites with depression in independent adult samples. 4,018 and 768 children were included for metabolomics and epigenetics analyses, respectively. Obesity at 7 years was associated with a 14% increase in SMFQ score (95% CI: 1.04, 1.25) and greater odds of depression (OR: 1.46 (95% CI: 0.78, 2.38) at 11 years. Natural indirect effects (mediating pathways) between obesity and depression for tyrosine, leucine and conjugated linoleic acid were 1.06 (95% CI: 1.00, 1.13, proportion mediated (PM): 15%), 1.04 (95% CI: 0.99, 1.10, PM: 9.6%) and 1.06 (95% CI: 1.00, 1.12, PM: 13.9%) respectively. In MR analysis, one unit increase in tyrosine was associated with 0.13 higher log odds of depression (p = 0.1). Methylation at cg17128312, located in the FBXW9 gene, had a natural indirect effect of 1.05 (95% CI: 1.01,1.13, PM: 27%) as a mediator of obesity and SMFQ score. Potential biologically plausible mechanisms involving these identified molecular features include neurotransmitter regulation, inflammation, and gut microbiome modulation. These results require replication in further observational and mechanistic studies

Symmetries of Snyder--de Sitter space and relativistic particle dynamics

We study the deformed conformal-Poincare symmetries consistent with the Snyder--de Sitter space. A relativistic particle model invariant under these deformed symmetries is given. This model is used to provide a gauge independent derivation of the Snyder--de Sitter algebra. Our results are valid in the leading order in the parameters appearing in the model.Comment: 12 pages, LaTeX, version appearing in JHEP, minor changes to match published versio

Genetic divergence among African and American cotton (Gossypium hirsutum L. race latifolium H.) cultivars and inbred lines through random amplification of polymorphic DNA (RAPD) markers.

Cotton (Gossypium spp.) is an important cash crop and the second largest source of textile fiber and edible oil throughout the world. This study was conducted to investigate the genetic divergence through random amplified polymorphism (RAPD) molecular markers among the introduced African and American cultivars and inbred lines of cotton (Gossypium hirsutum L. raça latifolium H.) in Mozambique. We used 24 RAPD primers that amplified a total of 166 bands, identifying 90.96% ofpolymorphism. The intra and inter group genetic variability quantification evidenced significant variability of 16.30% between the African and American groups. The highest genetic similarity was observed among the African commercial cotton cultivars, whereas American cultivars and inbred lines were considered the most dissimilar ones. The arithmetic complement of Jaccard, obtained with 151 RAPD molecular markers showed that African cultivars Albar BC853 and STAM 42 were the most similar, while the most dissimilar combinations were TAMCOT Sphinx and ISA 205 followed by TAMCOT Sphinx vs ALBAR BC853 and TAMCOT Sphinx vs REMU 40 combinations.Keywords: Molecular variance analysis, decamer primers, dissimilarity, Gossypium hirsutum, molecular markers

Distinct Binding and Immunogenic Properties of the Gonococcal Homologue of Meningococcal Factor H Binding Protein

Neisseria meningitidis is a leading cause of sepsis and meningitis. The bacterium recruits factor H (fH), a negative regulator of the complement system, to its surface via fH binding protein (fHbp), providing a mechanism to avoid complement-mediated killing. fHbp is an important antigen that elicits protective immunity against the meningococcus and has been divided into three different variant groups, V1, V2 and V3, or families A and B. However, immunisation with fHbp V1 does not result in cross-protection against V2 and V3 and vice versa. Furthermore, high affinity binding of fH could impair immune responses against fHbp. Here, we investigate a homologue of fHbp in Neisseria gonorrhoeae, designated as Gonococcal homologue of fHbp (Ghfp) which we show is a promising vaccine candidate for N. meningitidis. We demonstrate that Gfhp is not expressed on the surface of the gonococcus and, despite its high level of identity with fHbp, does not bind fH. Substitution of only two amino acids in Ghfp is sufficient to confer fH binding, while the corresponding residues in V3 fHbp are essential for high affinity fH binding. Furthermore, immune responses against Ghfp recognise V1, V2 and V3 fHbps expressed by a range of clinical isolates, and have serum bactericidal activity against N. meningitidis expressing fHbps from all variant groups

Deciphering interplay between Salmonella invasion effectors

Bacterial pathogens have evolved a specialized type III secretion system (T3SS) to translocate virulence effector proteins directly into eukaryotic target cells. Salmonellae deploy effectors that trigger localized actin reorganization to force their own entry into non-phagocytic host cells. Six effectors (SipC, SipA, SopE/2, SopB, SptP) can individually manipulate actin dynamics at the plasma membrane, which acts as a ‘signaling hub’ during Salmonella invasion. The extent of crosstalk between these spatially coincident effectors remains unknown. Here we describe trans and cis binary entry effector interplay (BENEFIT) screens that systematically examine functional associations between effectors following their delivery into the host cell. The results reveal extensive ordered synergistic and antagonistic relationships and their relative potency, and illuminate an unexpectedly sophisticated signaling network evolved through longstanding pathogen–host interaction