Clearance kinetics and matrix binding partners of the receptor for advanced glycation end products

Elucidating the sites and mechanisms of sRAGE action in the healthy state is vital to better understand the biological importance of the receptor for advanced glycation end products (RAGE). Previous studies in animal models of disease have demonstrated that exogenous sRAGE has an anti-inflammatory effect, which has been reasoned to arise from sequestration of pro-inflammatory ligands away from membrane-bound RAGE isoforms. We show here that sRAGE exhibits in vitro binding with high affinity and reversibly to extracellular matrix components collagen I, collagen IV, and laminin. Soluble RAGE administered intratracheally, intravenously, or intraperitoneally, does not distribute in a specific fashion to any healthy mouse tissue, suggesting against the existence of accessible sRAGE sinks and receptors in the healthy mouse. Intratracheal administration is the only effective means of delivering exogenous sRAGE to the lung, the organ in which RAGE is most highly expressed; clearance of sRAGE from lung does not differ appreciably from that of albumin. Copyright: © 2014 Milutinovic et al

The downward spiral of mental disorders and educational attainment: a systematic review on early school leaving.

BACKGROUND: Most psychiatric disorders present symptom patterns that cause severe impairment on the emotional, cognitive and social level. Thus, adolescents who suffer from a mental disorder risk finding themselves in a downward spiral caused by the reciprocal association of psychological symptoms and negative school experiences that may culminate in early school leaving. In addition to previous collective work that mainly focused on school refusing behaviour among children and was presented as an expert's opinion, the following systematic review fills the knowledge gap by providing a structured overview of the bidirectional association between mental health and secondary school dropout based on a sound methodology and with a particular focus on mediating factors. METHODS: Four electronic databases were searched from January 1990 until June 2014. Selected references were assessed for study details, main results, mediating factors and methodological limitations. Standardized risk of bias assessment was conducted. RESULTS: Mood and anxiety disorders seemed to have a less consequential direct effect on early school leaving than substance use and disruptive behaviour disorders. The association between externalizing disorders and educational attainment was even stronger when the disorder occurred early in life. On the other hand, internalizing disorders were reported to develop as a consequence of school dropout. Only few studies had addressed gender differences, with discrepant results. Socio-economic background, academic achievement and family support were identified as significant mediating factors of the association between mental disorders and subsequent educational attainment. CONCLUSIONS: Findings suggested a strong association between mental health and education, in both directions. However, most studies focused on mediating factors that could not be targeted by intervention programs

Dictyostelium Ric8 is a nonreceptor guanine exchange factor for heterotrimeric G proteins and is important for development and chemotaxis

Heterotrimeric G proteins couple external signals to the activation of intracellular signal transduction pathways. Agonist-stimulated guanine nucleotide exchange activity of G-protein-coupled receptors results in the exchange of G-protein-bound GDP to GTP and the dissociation and activation of the complex into Gα-GTP and a Gβγ dimer. In Dictyostelium, a basal chemotaxis pathway consisting of heterotrimeric and monomeric G proteins is sufficient for chemotaxis. Symmetry breaking and amplification of chemoattractant sensing occurs between heterotrimeric G protein signaling and Ras activation. In a pull-down screen coupled to mass spectrometry, with Gα proteins as bait, we have identified resistant to inhibitors of cholinesterase 8 (Ric8) as a nonreceptor guanine nucleotide exchange factor for Gα-protein. Ric8 is not essential for the initial activation of heterotrimeric G proteins or Ras by uniform chemoattractant; however, it amplifies Gα signaling, which is essential for Ras-mediated symmetry breaking during chemotaxis and development.