Early onset preeclampsia is characterized by altered placental lipid metabolism and a premature increase in circulating FABP4

Preeclampsia is a pregnancy-associated disorder that manifests as a sudden increase in maternal blood pressure accompanied by proteinuria. Because the placenta is a key organ in preeclampsia, we used proteomic and lipidomic analyses to compare placentae from preeclamptic and gestational age matched control pregnancies. Fatty acid binding protein 4 (FABP4), enoyl-CoA dehydrogenase and delta-3,5-delta-2,4-dienoyl-CoA isomerase had altered abundance in preeclamptic placentae compared to controls. FABP4 placental protein and RNA and plasma levels were all increased in early-onset preeclampsia (prior to 28 weeks gestation) compared to controls (6-fold, 3.3-fold and 3.5-fold respectively). After 28 weeks, FABP4 protein in control placenta and plasma increased to the same concentrations as in preeclampsia. Total tetracosapentaenoic acid in preeclamptic placentae was decreased to 0.6 of control levels before 28 weeks. The data indicate a disruption of fatty acid transport and metabolism in the placenta in early onset preeclampsia that is reflected in the maternal plasma

Évolution d'une ville: Rouen 1962-82

Pour une comparaison rigoureuse de l’espace rouennais, les auteurs proposent, au lieu du maillage changeant des îlots ou quartiers, un maillage fixe de carrés de 250 m de côté où les données sont transférées par calcul. Cette procédure («grid map» des Britanniques) autorise des traitements statistiques moins biaisés

A Privacy Preserving Distributed Reputation Mechanism

International audienceReputation systems allow to estimate the trustworthiness of entities based on their past behavior. Electronic commerce, peer-to-peer routing and collaborative environments, just to cite a few, highly benefit from using reputation systems. To guarantee an accurate estimation, reputation systems typically rely on a central authority, on the identification and authentication of all the participants, or both. In this paper, we go a step further by presenting a distributed reputation mechanism which is robust against malicious behaviors and that preserves the privacy of its clients. Guaranteed error bounds on the estimation are provided

Proteomic characterisation reveals active Wnt-signalling by human multipotent stromal cells as a key regulator of beta cell survival and proliferation

Aims/hypothesis: Novel strategies to stimulate the expansion of beta cell mass in situ are warranted for diabetes therapy. The aim of this study was to elucidate the secretome of human bone marrow (BM)-derived multipotent stromal cells (MSCs) with documented islet regenerative paracrine function. We hypothesised that regenerative MSCs will secrete a unique combination of protein factors that augment islet regeneration. Methods: Human BM-derived MSCs were examined for glucose-lowering capacity after transplantation into streptozotocin-treated NOD/severe combined immunodeficiency (SCID) mice and segregated into samples with regenerative (MSCR) vs nonregenerative (MSCNR) capacity. Secreted proteins associated with islet regenerative function were identified using stable isotope labelling with amino acids in cell culture (SILAC)-based quantitative proteomics. To functionally validate the importance of active Wnt signalling, we stimulated the Wnt-signalling pathway in MSCNR samples during ex vivo expansion using glycogen synthase kinase 3 (GSK3) inhibition (CHIR99201), and the conditioned culture media (CM) generated was tested for the capacity to support cultured human islet cell survival and proliferation in vitro. Results: MSCR showed increased secretion of proteins associated with cell growth, matrix remodelling, immunosuppressive and proangiogenic properties. In contrast, MSCNR uniquely secreted proteins known to promote inflammation and negatively regulate angiogenesis. Most notably, MSCR maintained Wnt signalling via Wnt5A/B (~2.5-fold increase) autocrine activity during ex vivo culture, while MSCNR repressed Wnt signalling via Dickkopf-related protein (DKK)1 (~2.5-fold increase) and DKK3 secretion. Inhibition of GSK3 activity in MSCNR samples increased the accumulation of nuclear β-catenin and generated CM that augmented beta cell survival (13% increases) and proliferation when exposed to cultured human islets. Conclusions/interpretation: Maintenance of active Wnt signalling within human MSCs promotes the secretion of matricellular and proangiogenic proteins that formulate a niche for islet regeneration

Identification of a GTP-bound Rho specific scFv molecular sensor by phage display selection

<p>Abstract</p> <p>Background</p> <p>The Rho GTPases A, B and C proteins, members of the Rho family whose activity is regulated by GDP/GTP cycling, function in many cellular pathways controlling proliferation and have recently been implicated in tumorigenesis. Although overexpression of Rho GTPases has been correlated with tumorigenesis, only their GTP-bound forms are able to activate the signalling pathways implicated in tumorigenesis. Thus, the focus of much recent research has been to identify biological tools capable of quantifying the level of cellular GTP-bound Rho, or determining the subcellular location of activation. However useful, these tools used to study the mechanism of Rho activation still have limitations. The aim of the present work was to employ phage display to identify a conformationally-specific single chain fragment variable (scFv) that recognizes the active, GTP-bound, form of Rho GTPases and is able to discriminate it from the inactive, GDP-bound, Rho in endogenous settings.</p> <p>Results</p> <p>After five rounds of phage selection using a constitutively activated mutant of RhoB (RhoBQ63L), three scFvs (A8, C1 and D11) were selected for subsequent analysis. Further biochemical characterization was pursued for the single clone, C1, exhibiting an scFv structure. C1 was selective for the GTP-bound form of RhoA, RhoB, as well as RhoC, and failed to recognize GTP-loaded Rac1 or Cdc42, two other members of the Rho family. To enhance its production, soluble C1 was expressed in fusion with the N-terminal domain of phage protein pIII (scFv C1-N1N2), it appeared specifically associated with GTP-loaded recombinant RhoA and RhoB via immunoprecipitation, and endogenous activated Rho in HeLa cells as determined by immunofluorescence.</p> <p>Conclusion</p> <p>We identified an antibody, C1-N1N2, specific for the GTP-bound form of RhoB from a phage library, and confirmed its specificity towards GTP-bound RhoA and RhoC, as well as RhoB. The success of C1-N1N2 in discriminating activated Rho in immunofluorescence studies implies that this new tool, in collaboration with currently used RhoA and B antibodies, has the potential to analyze Rho activation in cell function and tumor development.</p

Human Multipotent Stromal Cell Secreted Effectors Accelerate Islet Regeneration

Human multipotent stromal cells (hMSC) can induce islet regeneration after transplantation via the secretion of proteins that establish an islet regenerative niche. However, the identity of hMSC-secreted signals and the mechanisms by which pancreatic islet regeneration is induced remain unknown. Recently, mammalian pancreatic α-cells have been shown to possess considerable plasticity, and differentiate into β-like cells after near complete β-cell loss or overexpression of key transcriptional regulators. These studies have generated new excitement that islet regeneration during diabetes may be possible if we can identify clinically applicable stimuli to modulate these key regulatory pathways. Herein, we demonstrate that intrapancreatic-injection of concentrated hMSC-conditioned media (CM) stimulated islet regeneration without requiring cell transfer. hMSC CM-injection significantly reduced hyperglycemia, increased circulating serum insulin concentration, and improved glucose tolerance in streptozotocin-treated mice. The rate and extent of endogenous β-cell mass recovery was dependent on total protein dose administered and was further augmented by the activation of Wnt-signaling using GSK3-inhibition during CM generation. Intrapancreatic hMSC CM-injection immediately set in motion a cascade of regenerative events that included the emergence of proliferating insulin + clusters adjacent to ducts, NKX6.1 expression in glucagon + cells at days 1–4 suggesting the acquisition of β-cell phenotype by α-cells, and accelerated β-cell maturation with increased MAFA-expression for \u3e1 month postinjection. Discovery and validation of islet regenerative hMSC-secreted protein may lead to the development of cell-free regenerative therapies able to tip the balance in favor of β-cell regeneration versus destruction during diabetes. Stem Cells 2019;37:516–528

DIFFICULTÉS DE LA PARTICIPATION EN RECHERCHE- ACTION : retour d'expériences de modélisation d'accompagnement en appui à l'aménagement du territoire au Sénégal et à la Réunion

International audienceComment aider les institutions et acteurs locaux à investir davantage les processus d'affectation des terres pour aménager leur territoire ? La décentralisation de l'aménagement du territoire engagée à la Réunion et au Sénégal est inachevée. Malgré l'arsenal législatif, les populations locales semblent peu impliquées dans les décisions les concernant en raison notamment de la difficulté à appréhender la complexité des systèmes d'interactions entre dynamiques sociales et environnementales. Le projet Domino vise à accompagner les processus de décision en proposant aux acteurs de construire et d'explorer des scenarii prospectifs d'affectation des terres. Cette expérience de modélisation participative repose sur une dynamique partenariale complexe sur chaque terrain, source de difficultés. Conscients des dérives potentielles, nous discutons la nécessité de construire une démarche qualité de notre recherche-action. Mots clés : montage de partenariat, démarche qualité, modèle, changement social, ComMod, interdisciplinarité, décentralisation, foncier, Sénégal, Réunio