Identification of small-molecule elastase inhibitors as antagonists of IL-36 cytokine activation.

IL-1 family cytokines act as apical initiators of inflammation in many settings and can promote the production of a battery of inflammatory cytokines, chemokines and other inflammatory mediators in diverse cell types. IL-36α, IL-36β and IL-36γ, which belong to the extended IL-1 family, have been implicated as key initiators of skin inflammation in psoriasis. IL-36γ is highly upregulated in lesional skin from psoriatic individuals, and heritable mutations in the natural IL-36 receptor antagonist result in a severe form of psoriasis.

Suppressing IL-36-driven inflammation using peptide pseudosubstrates for neutrophil proteases.

Sterile inflammation is initiated by molecules released from necrotic cells, called damage-associated molecular patterns (DAMPs). Members of the extended IL-1 cytokine family are important DAMPs, are typically only released through necrosis, and require limited proteolytic processing for activation. The IL-1 family cytokines, IL-36α, IL-36β, and IL-36γ, are expressed as inactive precursors and have been implicated as key initiators of psoriatic-type skin inflammation.

An unauthorized biography of the second heart field and a pioneer/scaffold model for cardiac development.

The identification of subpharyngeal cardiac precursors has had a strong influence on the way we think about early cardiac development. From this discovery was born the concept of multiple heart fields. Early support for the concept came from gene expression, genetic retrospective fate mapping, and gene targeting studies, which collectively suggested the existence of a second heart field (SHF) on the basis of specific Islet-1 (Isl-1) expression, presence of two cardiac ancestral lineages, and compatible cardiac knockout phenotypes, respectively.

Elevated expression of MeCP2 in cardiac and skeletal tissues is detrimental for normal development.

MeCP2 plays a critical role in interpreting epigenetic signatures that command chromatin conformation and regulation of gene transcription. In spite of MeCP2's ubiquitous expression, its functions have always been considered in the context of brain physiology. In this study, we demonstrate that alterations of the normal pattern of expression of MeCP2 in cardiac and skeletal tissues are detrimental for normal development.

Insights into the organization of dorsal spinal cord pathways from an evolutionarily conserved raldh2 intronic enhancer.

Comparative studies of the tetrapod raldh2 (aldh1a2) gene, which encodes a retinoic acid (RA) synthesis enzyme, have led to the identification of a dorsal spinal cord enhancer. Enhancer activity is directed dorsally to the roof plate and dorsal-most (dI1) interneurons through predicted Tcf- and Cdx-homeodomain binding sites and is repressed ventrally via predicted Tgif homeobox and ventral Lim-homeodomain binding sites. Raldh2 and Math1/Cath1 expression in mouse and chicken highlights a novel, transient, endogenous Raldh2 expression domain in dI1 interneurons, which give rise to ascending circuits and intraspinal commissural interneurons, suggesting roles for RA in the ontogeny of spinocerebellar and intraspinal proprioceptive circuits.

Five new TTF1/NKX2.1 mutations in brain-lung-thyroid syndrome: rescue by PAX8 synergism in one case.

Thyroid transcription factor 1 (NKX2-1/TITF1) mutations cause brain-lung-thyroid syndrome, characterized by congenital hypothyroidism (CH), infant respiratory distress syndrome (IRDS) and benign hereditary chorea (BHC). The objectives of the present study were (i) detection of NKX2-1 mutations in patients with CH associated with pneumopathy and/or BHC, (ii) functional analysis of new mutations in vitro and (iii) description of the phenotypic spectrum of brain-lung-thyroid syndrome. We identified three new heterozygous missense mutations (L176V, P202L, Q210P), a splice site mutation (376-2A-->G), and one deletion of NKX2-1 at 14q13.

An inactivating mutation within the first extracellular loop of the thyrotropin receptor impedes normal posttranslational maturation of the extracellular domain.

The TSH receptor (TSHR), a member of the large family of G protein-coupled receptors, controls both function and growth of thyroid cells; hence, mutations of this receptor result in thyroid dysfunction. Here, we took advantage of the description of a new inactivating TSHR mutation (Q489H) in two brothers with hypothyroidism, to precise maturation, intracellular trafficking, exporting pathways, and activation mechanisms of this receptor. Functional characterization of the Q489H-TSHR in transiently transfected HEK293 cells showed cell surface expression, normal TSH binding affinity, and its inability to generate intracellular cAMP in response to TSH stimulation.

Polymorphic length of FOXE1 alanine stretch: evidence for genetic susceptibility to thyroid dysgenesis.

Familial cases of congenital hypothyroidism from thyroid dysgenesis (TD) (OMIM 218700) occur with a frequency 15-fold higher than by chance, FOXE1 is one of the candidate genes for this genetic predisposition and contains an alanine tract. Our purpose is to assess the influence of length of the alanine tract of FOXE1 on genetic susceptibility to TD. A case-control association study (based on 115 patients affected by TD and 129 controls genotyped by direct sequencing) and transmission disequilibrium testing (TDT) analyses were performed.

Linkage and mutational analysis of familial thyroid dysgenesis demonstrate genetic heterogeneity implicating novel genes.

The pathophysiology of thyroid dysgenesis (TD) is not elucidated yet in the majority of cases. The unexpected familial clustering of congenital hypothyroidism due to TD suggests a genetically determined disorder. Four genes have been hitherto involved in thyroid development, including migration and growth.

Molecular mechanisms of thyroid dysgenesis.

Thyroid dysgenesis (TD) is the most prevalent form of congenital hypothyroidism. Ttf-1, Ttf-2, Pax8 and the Tshr are expressed at early stages of thyroid development and are implicated in thyroid ontogeny. Mutations in these genes have been found in some cases of TD.

PAX8, TITF1, and FOXE1 gene expression patterns during human development: new insights into human thyroid development and thyroid dysgenesis-associated malformations.

Thyroid dysgenesis (TD) is responsible for most cases of congenital hypothyroidism, a condition that affects about one in 4000 newborns. Mutations in PAX8, TITF1, or FOXE1 may account for congenital hypothyroidism in patients with either isolated TD or TD with associated malformations involving kidney, lung, forebrain, and palate. Pax8, titf1, and foxe1 are expressed in the mouse thyroid bud as soon as it differentiates on the pharyngeal floor.