Dysregulation of allergic airway inflammation in the absence of microbial colonization.

RATIONALE: The incidence of allergic disorders is increasing in developed countries and has been associated with reduced exposure to microbes and alterations in the commensal bacterial flora. OBJECTIVES: To ascertain the relevance of commensal bacteria upon the development of an allergic response, we utilized a model of allergic airway inflammation in germ-free (GF) mice that lack any exposure to pathogenic or non-pathogenic microorganisms. METHODS: Allergic airway inflammation was induced in GF, specific pathogen free (SPF) or recolonized mice by sensitization and challenge with ovalbumin (OVA). The resulting cellular infiltrate and cytokine production were measured. MEASUREMENTS AND MAIN RESULTS: Our results show that the total number of infiltrating lymphocytes and eosinophils were elevated in the airways of allergic GF mice as compared to control SPF mice, and that this increase could be reversed by re-colonization of GF mice with the complex commensal flora of SPF mice. Exaggerated airway eosinophilia correlated with increased local production of Th2 associated cytokines, elevated IgE production and an altered number and phenotype of conventional dendritic cells (cDC). Regulatory T cell populations and regulatory cytokine levels were unaltered but GF mice exhibited an increased number of basophils and decreased numbers of alveolar macrophages (AM) and plasmacytoid dendritic cells (pDC). CONCLUSIONS: These data demonstrate that the presence of commensal bacteria is critical for ensuring normal cellular maturation, recruitment and control of allergic airway inflammation

Sexual polyploidization in red clover Poliploidização sexual em trevo vermelho

Because sexual polyploidization broadens genetic basis and supply plant breeders with more variability for the selection process, it can be useful in red clover breeding. This paper reports results of three crossing cycles, starting from a parental generation of tetraploid red clover plants (female parent), and diploids from the Quiñiqueli cultivar, selected for production of more than 1% of giant pollen grains (male parent) aiming to obtain tetraploid plants to be used in red clover breeding programs. Crosses in the next generations were performed by mutual cross-pollinations. Chromosome number chimerism and high pollen sterility were detected in F1, F2 and F3, but there was a trend towards increasing seed production and seed viability along the generations, probably due to successful competition between fertile and sterile gametes. The identification of fertile triploids, as well as their recurrent formation along the generations, indicates that triploid block is not complete in red clover, and that triploids may be successfully used as a bridge for the production of sexual polyploids.<br>Porque a poliploidização sexual amplia a base genética e proporciona aos melhoristas maior variabilidade para o processo de seleção, ela pode ser uma ferramenta útil ao melhoramento de trevo vermelho. Com o objetivo de obter plantas tetraplóides que possam ser utilizadas em programas de melhoramento de trevo vermelho, este trabalho relata resultados de três ciclos de cruzamentos, partindo de uma população parental de plantas tetraplóides de trevo vermelho, como genitores femininos, e de diplóides da cultivar Quiñiqueli, selecionados para produção de mais de 1% de grãos de pólen gigantes, como genitores masculinos. Nas outras gerações, os cruzamentos foram realizados por polinizações cruzadas mútuas. Quimerismo para número cromossômico e alta esterilidade de pólen foram detectados em F1 , F2 e F3, mas houve uma tendência para aumento da produção e viabilidade das sementes ao longo das gerações, provavelmente devido à competição bem sucedida entre gametas férteis e estéreis. A identificação de triplóides férteis, assim como sua formação recorrente ao longo das gerações, indica que o bloco triplóide não é completo em trevo vermelho e que triplóides podem ser utilizados com sucesso para a produção de poliplóides sexuais

Small intestinal resident eosinophils maintain gut homeostasis following microbial colonization.

The intestine harbors a large population of resident eosinophils, yet the function of intestinal eosinophils has not been explored. Flow cytometry and whole-mount imaging identified eosinophils residing in the lamina propria along the length of the intestine prior to postnatal microbial colonization. Microscopy, transcriptomic analysis, and mass spectrometry of intestinal tissue revealed villus blunting, altered extracellular matrix, decreased epithelial cell turnover, increased gastrointestinal motility, and decreased lipid absorption in eosinophil-deficient mice. Mechanistically, intestinal epithelial cells released IL-33 in a microbiota-dependent manner, which led to eosinophil activation. The colonization of germ-free mice demonstrated that eosinophil activation in response to microbes regulated villous size alterations, macrophage maturation, epithelial barrier integrity, and intestinal transit. Collectively, our findings demonstrate a critical role for eosinophils in facilitating the mutualistic interactions between the host and microbiota and provide a rationale for the functional significance of their early life recruitment in the small intestine

Mutations in GDF11 and the extracellular antagonist, Follistatin, as a likely cause of Mendelian forms of orofacial clefting in humans

Contains fulltext : 208676.pdf (publisher's version ) (Closed access)Cleft lip with or without cleft palate (CL/P) is generally viewed as a complex trait with multiple genetic and environmental contributions. In 70% of cases, CL/P presents as an isolated feature and/or deemed nonsyndromic. In the remaining 30%, CL/P is associated with multisystem phenotypes or clinically recognizable syndromes, many with a monogenic basis. Here we report the identification, via exome sequencing, of likely pathogenic variants in two genes that encode interacting proteins previously only linked to orofacial clefting in mouse models. A variant in GDF11 (encoding growth differentiation factor 11), predicting a p.(Arg298Gln) substitution at the Furin protease cleavage site, was identified in one family that segregated with CL/P and both rib and vertebral hypersegmentation, mirroring that seen in Gdf11 knockout mice. In the second family in which CL/P was the only phenotype, a mutation in FST (encoding the GDF11 antagonist, Follistatin) was identified that is predicted to result in a p.(Cys56Tyr) substitution in the region that binds GDF11. Functional assays demonstrated a significant impact of the specific mutated amino acids on FST and GDF11 function and, together with embryonic expression data, provide strong evidence for the importance of GDF11 and Follistatin in the regulation of human orofacial development