Contrôle de la compétence temporelle des cellules progénitrices de la rétine par Ikaros et rôle de la voie du CNTF/LIF dans la différenciation et l'apoptose des photorécepteurs bâtonnets

Tableau d’honneur de la Faculté des études supérieures et postdoctorales, 2007-2008.Facteur de transcription Ikaro

Comparability of Results from Pair and Classical Model Formulations for Different Sexually Transmitted Infections

The “classical model” for sexually transmitted infections treats partnerships as instantaneous events summarized by partner change rates, while individual-based and pair models explicitly account for time within partnerships and gaps between partnerships. We compared predictions from the classical and pair models over a range of partnership and gap combinations. While the former predicted similar or marginally higher prevalence at the shortest partnership lengths, the latter predicted self-sustaining transmission for gonorrhoea (GC) and Chlamydia (CT) over much broader partnership and gap combinations. Predictions on the critical level of condom use (Cc) required to prevent transmission also differed substantially when using the same parameters. When calibrated to give the same disease prevalence as the pair model by adjusting the infectious duration for GC and CT, and by adjusting transmission probabilities for HIV, the classical model then predicted much higher Cc values for GC and CT, while Cc predictions for HIV were fairly close. In conclusion, the two approaches give different predictions over potentially important combinations of partnership and gap lengths. Assuming that it is more correct to explicitly model partnerships and gaps, then pair or individual-based models may be needed for GC and CT since model calibration does not resolve the differences

CXCR4 Expression in Prostate Cancer Progenitor Cells

Tumor progenitor cells represent a population of drug-resistant cells that can survive conventional chemotherapy and lead to tumor relapse. However, little is known of the role of tumor progenitors in prostate cancer metastasis. The studies reported herein show that the CXCR4/CXCL12 axis, a key regulator of tumor dissemination, plays a role in the maintenance of prostate cancer stem-like cells. The CXCL4/CXCR12 pathway is activated in the CD44+/CD133+ prostate progenitor population and affects differentiation potential, cell adhesion, clonal growth and tumorigenicity. Furthermore, prostate tumor xenograft studies in mice showed that a combination of the CXCR4 receptor antagonist AMD3100, which targets prostate cancer stem-like cells, and the conventional chemotherapeutic drug Taxotere, which targets the bulk tumor, is significantly more effective in eradicating tumors as compared to monotherapy

Retinoic Acid Receptor (RAR) signaling preserves tendon stem cells characteristics and prevents spontaneous differentiation in vitro.

Introduction: Previous studies have reported that adult mesenchymal stem cells (MSCs) tend to gradually lose their stem cell characteristics in vitro when placed outside their niche environment. They subsequently undergo spontaneous differentiation towards mesenchymal lineages after only a few passages. We observed a similar phenomenon with adult tendon stem cells (TSCs) where expression of key tendon genes such as Scleraxis (Scx), are being repressed with time in culture. We hypothesized that an environment able to restore or maintain Scleraxis expression could be of therapeutic interest for in vitro use and tendon cell-based therapies. Methods: TSCs were isolated from human cadaveric Achilles tendon and expanded for 4 passages. A high content imaging assay that monitored the induction of Scx nuclear localization was used to screen ~1000 known drugs. Results: We identified RAR agonists as potent inducers of nuclear Scx in the small molecule screen. The upregulation correlated with improved maintenance of tendon stem cell properties through inhibition of spontaneous differentiation rather than the anticipated induction of tenogenic differentiation. Our results suggest that histone epigenetic modifications by RAR are driving this effect which is not likely only dependent on Scleraxis nuclear binding but also mediated through other key genes involved in stem cell self-renewal and differentiation. Furthermore, we demonstrate that the effect of RAR compounds on TSCs is reversible by revealing their multi-lineage differentiation ability upon withdrawal of the compound. Conclusion: Based on these findings, RAR agonists could provide a valid approach for maintaining TSC stemness during expansion in vitro, thus improving their regenerative potential for cell-based therapy

The effects of positioning of transcatheter aortic valves on fluid dynamics of the aortic root.

Transcatheter aortic valve implantation is a novel treatment for severe aortic valve stenosis. Due to the recent use of this technology and the procedural variability, there is very little data that quantify the hemodynamic consequences of variations in valve placement. Changes in aortic wall stresses and fluid retention in the sinuses of Valsalva can have a significant effect on the clinical response a patient has to the procedure. By comprehensively characterizing complex flow in the sinuses of Valsalva using digital particle image velocimetry and an advanced heart-flow simulator, various positions of a deployed transcatheter valve with respect to a bioprosthetic aortic valve (valve-in-valve) were tested in vitro. Displacements of the transcatheter valve were axial and directed below the simulated native valve annulus. It was determined that for both blood residence time and aortic Reynolds stresses, it is optimal to have the annulus of the transcatheter valve deployed as close to the aortic valve annulus as possible

The effects of positioning of transcatheter aortic valves on fluid dynamics of the aortic root.

Transcatheter aortic valve implantation is a novel treatment for severe aortic valve stenosis. Due to the recent use of this technology and the procedural variability, there is very little data that quantify the hemodynamic consequences of variations in valve placement. Changes in aortic wall stresses and fluid retention in the sinuses of Valsalva can have a significant effect on the clinical response a patient has to the procedure. By comprehensively characterizing complex flow in the sinuses of Valsalva using digital particle image velocimetry and an advanced heart-flow simulator, various positions of a deployed transcatheter valve with respect to a bioprosthetic aortic valve (valve-in-valve) were tested in vitro. Displacements of the transcatheter valve were axial and directed below the simulated native valve annulus. It was determined that for both blood residence time and aortic Reynolds stresses, it is optimal to have the annulus of the transcatheter valve deployed as close to the aortic valve annulus as possible

Article Synergistic Activation of Phospholipase C-b3 by Ga q and Gbg Describes a Simple Two-State Coincidence Detector

Summary Background: Receptors that couple to G i and G q often interact synergistically in cells to elicit cytosolic Ca 2+ transients that are several-fold higher than the sum of those driven by each receptor alone. Such synergism is commonly assumed to be complex, requiring regulatory interaction between components, multiple pathways, or multiple states of the target protein. Results: We show that cellular G i -G q synergism derives from direct supra-additive stimulation of phospholipase C-b3 (PLC-b3) by G protein subunits Gbg and Ga q , the relevant components of the G i and G q signaling pathways. No additional pathway or proteins are required. Synergism is quantitatively explained by the classical and simple two-state (inactive4active) allosteric mechanism. We show generally that synergistic activation of a two-state enzyme reflects enhanced conversion to the active state when both ligands are bound, not merely the enhancement of ligand affinity predicted by positive cooperativity. The two-state mechanism also explains why synergism is unique to PLC-b3 among the four PLC-b isoforms and, in general, why one enzyme may respond synergistically to two activators while another does not. Expression of synergism demands that an enzyme display low basal activity in the absence of ligand and becomes significant only when basal activity is % 0.1% of maximal. Conclusions: Synergism can be explained by a simple and general mechanism, and such a mechanism sets parameters for its occurrence. Any two-state enzyme is predicted to respond synergistically to multiple activating ligands if, but only if, its basal activity is strongly suppressed