Structural and Functional Insights into Endoglin Ligand Recognition and Binding

Endoglin, a type I membrane glycoprotein expressed as a disulfide-linked homodimer on human vascular endothelial cells, is a component of the transforming growth factor (TGF)-β receptor complex and is implicated in a dominant vascular dysplasia known as hereditary hemorrhagic telangiectasia as well as in preeclampsia. It interacts with the type I TGF-β signaling receptor activin receptor-like kinase (ALK)1 and modulates cellular responses to Bone Morphogenetic Protein (BMP)-9 and BMP-10. Structurally, besides carrying a zona pellucida (ZP) domain, endoglin contains at its N-terminal extracellular region a domain of unknown function and without homology to any other known protein, therefore called the orphan domain (OD). In this study, we have determined the recognition and binding ability of full length ALK1, endoglin and constructs encompassing the OD to BMP-9 using combined methods, consisting of surface plasmon resonance and cellular assays. ALK1 and endoglin ectodomains bind, independently of their glycosylation state and without cooperativity, to different sites of BMP-9. The OD comprising residues 22 to 337 was identified among the present constructs as the minimal active endoglin domain needed for partner recognition. These studies also pinpointed to Cys350 as being responsible for the dimerization of endoglin. In contrast to the complete endoglin ectodomain, the OD is a monomer and its small angle X-ray scattering characterization revealed a compact conformation in solution into which a de novo model was fitted

Probiotics, gut microbiota and their influence on host health and disease

The gastrointestinal tract (GIT) of mammals hosts a high and diverse number of different microorganisms, known as intestinal microbiota. Many probiotics were originally isolated from the GIT, and they were defined by the FAO/WHO as live microorganisms which when administered in adequate amounts confer a health benefit on the host. Probiotics exert their beneficial effects on the host through four main mechanisms: interference with potential pathogens, improvement of barrier function, immunomodulation and production of neurotransmitters, and their host targets vary from the resident microbiota to cellular components of the gut-brain axis. However, in spite of the wide array of beneficial mechanisms deployed by probiotic bacteria, relatively few effects have been supported by clinical data. In this regard, different probiotic strains have been effective in Antibiotic-Associated Diarrhea or Inflammatory Bowel Disease for instance. The aim of this review was to compile the molecular mechanisms underlying the beneficial effects of probiotics, mainly through their interaction with the intestinal microbiota and with the intestinal mucosa. The specific benefits discuss in this paper include among others those elicited directly through dietary modulation of the human gut microbiota.This article is protected by copyright. All rights reservedResearch in our lab is funded by Grants AGL2013-44039R and AGL2013-44761-P from the Spanish “Plan Estatal de I+D+I.” Part of the authors is also partially funded by the [15VI013] Contract-Programme from the University of Vigo and the Agrupamento INBIOMED from DXPCTSUG-FEDER unha maneira de facer Europa (2012/273). B. S. was recipient of a Ramón y Cajal postdoctoral contract from the Spanish Ministry of Economy and Competitiveness

From Christian Social Order to Humane Democracy Three Itineraries Leading to the MRP 1936-1948

The career of three leaders for the MRP from their training in the movements of catholic youth shows their implanting in the social action. It is during the war that they converted it into political action, convinced that it is a means to facilitate a more just social order. But they are rather quickly reticent in front of the functioning of the parties and the necessities of the political life, preferring a mass movement able to transform the society

The Activity of Crizotinib in Chemo-Refractory MET-Amplified Esophageal and Gastric Adenocarcinomas: Results from the AcSé-Crizotinib Program

International audienceBackground: The AcSé-crizotinib program provides extensive screening of crizotinib-targeted genomic alteration in several malignancies. We here report the results in patients with esogastric MET-amplified adenocarcinomas.Objective: The objective of the study was to evaluate the efficacy and tolerability of crizotinib in patients with pretreated esogastric MET-amplified adenocarcinoma who have no alternative treatment options.Patients and methods: MET expression was evaluated by fluorescence in situ hybridization in tumor samples with immunohistochemistry scores ≥ 2+. Patients with chemo-refractory tumors showing ≥ 6 MET copies were eligible for crizotinib 250 mg twice daily. The primary efficacy outcome was the objective response rate after two cycles of crizotinib.Results: MET was prospectively analyzed in 570 esogastric adenocarcinomas. Amplifications were found in 35/570 adenocarcinomas (29/523 gastric and 6/47 esophageal). Nine patients were treated with crizotinib. The objective response rate after two cycles was 33.3% (95% CI 7.5-70), the best overall response rate was 55.6% (95% CI 21.2-86.3), with median progression-free survival of 3.2 months (95% CI 1.0-5.4), and overall survival of 8.1 months (95% CI 1.7-24.6). Safety was consistent with that previously reported for crizotinib.Conclusions: Large-scale screening for MET-amplified esogastric adenocarcinomas is feasible. MET amplification was observed in 5.5% of gastric and 12.8% of esophageal adenocarcinomas. Crizotinib shows encouraging results in selected patients. Thus, c-MET inhibition for MET-amplified tumors deserves further evaluation