Comment l'évaluation peut-elle aider l'élève à progresser ?

Dès les premières années de scolarité, les écarts entre les élèves s'élargissent et les dispositifs de remédiation ne suffisent pas toujours à aider les élèves à dépasser leurs difficultés. En effet, agir ainsi ne permet pas de remédier aux difficultés à long terme, il s'agit d'apprendre aux élèves à être acteurs de leurs apprentissages et à analyser leurs stratégies et leurs productions avant, pendant et après. Les évaluations formatrices sont des outils efficaces qui permettent de développer les compétences métacognitives. La question qui se pose ainsi est donc : comment l'évaluation peut-elle aider l'élève à progresser ? Par une observation des élèves avant d'être évalués puis par des échanges construits avec eux au sujet de l'activité en cours et des stratégies utilisées, nous tenterons de vérifier si l'évaluation peut permettre d'aider les élèves à progresser en leur faisant notamment prendre conscience des apprentissages, de leurs difficultés et erreurs et en les aidant à modifier leurs stratégies

Synthesis and biological activities of new di- and trimeric quinoline derivatives

International audienceThe synthesis of non-peptidic helix mimetics based on a trimeric quinoline scaffold is described. The ability of these new compounds, as well as their synthetic dimeric intermediates, to bind to various members of the Bcl-2 protein anti-apoptotic group is also evaluated. The most interesting derivative of this new series (compound A) inhibited Bcl-xL/Bak, Bcl-xL/Bax and Bcl-xL/Bid interactions with IC50 values around 25 μM

NOD1 Cooperates with TLR2 to Enhance T Cell Receptor-Mediated Activation in CD8 T Cells

<div><p>Pattern recognition receptors (PRR), like Toll-like receptors (TLR) and NOD-like receptors (NLR), are involved in the detection of microbial infections and tissue damage by cells of the innate immune system. Recently, we and others have demonstrated that TLR2 can additionally function as a costimulatory receptor on CD8 T cells. Here, we establish that the intracytosolic receptor NOD1 is expressed and functional in CD8 T cells. We show that C12-iEDAP, a synthetic ligand for NOD1, has a direct impact on both murine and human CD8 T cells, increasing proliferation and effector functions of cells activated via their T cell receptor (TCR). This effect is dependent on the adaptor molecule RIP2 and is associated with an increased activation of the NF-κB, JNK and p38 signaling pathways. Furthermore, we demonstrate that NOD1 stimulation can cooperate with TLR2 engagement on CD8 T cells to enhance TCR-mediated activation. Altogether our results indicate that NOD1 might function as an alternative costimulatory receptor in CD8 T cells. Our study provides new insights into the function of NLR in T cells and extends to NOD1 the recent concept that PRR stimulation can directly control T cell functions.</p> </div

NOD1 is expressed by CD8 T cells.

<p>NLR mRNA expression assessed by quantitative RT-PCR in murine CD8 T cells (black bars), macrophages (white bars) and splenocytes (grey bars) (nd: not detected). Results are the mean expression of NLR relative to HPRT ± SD of 3 independent experiments.</p

NOD1 cooperates with TLR2 to enhance TCR-mediated activation in human CD8 T cells.

<p>Flow cytometry assessment of the (A) proliferation (the percentage of proliferating cells is indicated), (B) CD25 expression (the mean fluorescence intensity of CD8 T cells is indicated) and (C) cell numbers of CFSE stained human CD8 T cells activated for 72 h with anti-CD3 in the absence or presence of C12, Pam, or both C12 and Pam. Results are representative of 3 independent experiments. CD8 T cell numbers are the mean cell number ± SD of triplicates.</p

NOD1 cooperates with TLR2 to enhance TCR-mediated CD8 T cell activation.

<p>(A–C) Flow cytometry assessment of the proliferation (the percentage of proliferating cells is indicated within the histograms) (A), cell numbers (B) and CD25 expression (the mean fluorescence intensity of CD8 T cells is indicated within the histograms) (C) of CFSE stained murine CD8 T cells cultured for 48 h with anti-CD3, in the absence or presence of C12, Pam, or both C12 and Pam. (D–F) Determination of IL-2 (D), IFN-γ (E) and TNF-α (F) concentrations in the supernatants of CD8 T cells cultured for 48 h with anti-CD3, in the absence or presence of C12, Pam, or both C12 and Pam. (G) Determination by western blotting of IκBα, β-actin, Phospho-ERK (P-ERK), total ERK, Phospho-JNK (P-JNK), total JNK, Phospho-p38 (P-p38) and total p38 protein levels in F5 CD8 lymphoblasts cultured for 30 minutes in medium alone or with 1 nM of NP68, in the absence or presence of C12, Pam, or both C12 and Pam. (B) Cell number values are the mean fold increases of anti-CD3 stimulated CD8 T cell numbers in the different conditions, in comparison to the control condition anti-CD3 alone, ± SD from 4 independent experiments (** = p<0.01; Student <i>t</i> test). The other results are representative of 4 (A and C) or 3 (D, E, F and G) independent experiments.</p

NOD1 ligand directly increases TCR-activated CD8 T cell proliferation and effector functions.

<p>(A) Flow cytometry assessment of the proliferation of CFSE stained murine CD8 T cells cultured for 72 h with or without anti-CD3 antibody, in the absence or presence of a dose range of C12, anti-CD28 or TLR2 ligand Pam. The percentage of proliferating cells is indicated within the histograms. The column graph represents the mean fold increase of anti-CD3 stimulated CD8 T cell proliferation in the different conditions, in comparison to the control condition anti-CD3 alone, ± SD from 5 independent experiments. (B–E) Flow cytometry assessment of CD69 (B) expression by CD8 T cell after 20 h of culture and of CD25 (C), CD44 (D) and CD62L (E) expression after 48 h of culture in medium containing or not anti-CD3 antibody, in the absence (solid grey) or presence of C12, anti-CD28 or Pam (black lines). The column graphs represent the mean fold increase of anti-CD3 stimulated CD8 T cell expression level of the different activation markers in the different conditions, in comparison to the control condition anti-CD3 alone, ± SD from 3 independent experiments. (F–H) Determination of IL-2, IFN-γ and TNF-α concentrations in CD8 T cells supernatants following 48 h of activation with anti-CD3, in the absence or presence of C12, anti-CD28 or Pam. Results are the mean concentrations of cytokines determined ± SD from 3 independent experiments. (I) Flow cytometry assessment of the surface expression of CD107a by CD8 T cells activated for 72 h with anti-CD3 in the absence or presence of C12, anti-CD28 or Pam, and restimulated for 4 h with anti-CD3. The column graph represents the mean fold increase of CD8 T cell surface expression level of CD107a in the different conditions, in comparison to the control condition anti-CD3 alone, ± SD from 3 independent experiments. (* = p<0.05 and ** = p<0.01; Student <i>t</i> test).</p

C12 effect on activated CD8 T cells is NOD1- and RIP2- dependent, and is associated with activation of the NF-κB, JNK and p38 signaling pathways.

<p>(A–B) Flow cytometry assessment of the proliferation of CFSE stained WT, NOD1^−/−, RIP2^−/−, MyD88^−/− and TRIF^−/− CD8 T cells activated for 72 h with anti-CD3, in the absence or presence of C12 or Pam. (A) The percentage of proliferating cells is indicated within the histograms. (B) The column graph represents the mean fold increase of anti-CD3 stimulated CD8 T cell proliferation in the different conditions, in comparison to the control condition anti-CD3 alone, ± SD from 3 independent experiments. (C) Determination by western blotting of IκBα, β-actin, Phospho-ERK (P-ERK), total ERK, Phospho-JNK (P-JNK), total JNK, Phospho-p38 (P-p38) and total p38 protein levels in F5 CD8 lymphoblasts cultured for 30 minutes in medium alone or with 1 nM of their specific antigenic peptide, NP68, in the absence or presence of C12, anti-CD28 or Pam. Results are representative of 3 independent experiments.</p

Identification of Small Inhibitory Molecules Targeting the Bfl-1 Anti-Apoptotic Protein That Alleviates Resistance to ABT-737

International audienceOne approach currently being developed in anticancer drug discovery is to search for small compounds capable of occupying and blocking the hydrophobic pocket of anti-apoptotic Bcl-2 family members necessary for interacting with pro-apoptotic proteins. Such an approach led to the discovery of several compounds, such as ABT-737 (which interacts with Bcl-2, Bcl-xl, and Bcl-w) or the latest one, ABT-199, that selectively targets Bcl-2 protein. The efficacy of those compounds is, however, limited by the expression of two other anti-apoptotic Bcl-2 members, Mcl-1 and Bfl-1. Based on the role of Bfl-1 in cancer, especially in chemoresistance associated with its overexpression in B-cell malignancies, we searched for modulators of protein-protein interaction through a high-throughput screening of a designed chemical library with relaxed drug-like properties to identify small molecules targeting Bfl-1 anti-apoptotic protein. We found two compounds that display electrophilic functions, interact with Bfl-1, inhibit Bfl-1 protective activity, and promote cell death of malignant B cells. Of particular interest, we observed a synergistic effect of those compounds with ABT-737 in Bfl-1 overexpressing lymphoma cell lines. Our results provide the basis for the development of Bfl-1 specific antagonists for antitumor therapies