This study has two main objectives. The ® rst is to specify the nature of the mental representation and processes underlying spatial reasoning with diagrams and sentences. The second is to investigate whether mental representations reproduce geometrical relations relative to spatial reference frames. Forty participants solved 64 spatial reasoning problems that were displayed using diagrams or sentences. Problems varied with respect to their logical structure and geometrical content. We measured the premise's inspection times, the responses, and the response times. Problems were signi® cantly (p , .01) easier to represent and solve when displayed as diagrams than as sentences, indicating that participants constructed mental models. Mental representations and spatial deductions also varied consistently with the geometrical content, suggesting that mental models reproduced this content relative to a viewer-centred reference frame.Cette e tude avait deux objectifs principaux: (1) de terminer la nature de la repre  sentation mentale et des processus sousjacents au raisonnement spatial avec des phrases et des diagrammes; et (2) l'usage de re fe rences spatiales lors du raisonnement spatial. Quarante adultes ont re solu 64 proble Á mes de raisonnement spatial pre sente s aÁ l'aide de phrases ou de diagrammes. Ces proble Á mes variaient suivant leur structure logique et leur contenu ge ome trique. Nous avons mesure le temps d'inspection de chaque pre misse, les re ponses, et les temps de re ponses. Les proble Á mes e taient signi® cativement (p , .01) plus faciles aÁ re soudre lorsque pre sente s sous forme de diagrammes que de phrases; indiquant que les sujets construisaient des modeÁ les mentaux. L' effet du contenu ge ome trique suggeÁ re que les mode Á les mentaux reproduisent ce contenu relativement aÁ un systeÁ me de re fe rences spatiales.

BACKGROUND Following solid organ or hematopoietic cell transplantation, refractory opportunistic viral reactivations are a significant cause of morbidity and mortality but can effectively be controlled by virus‐specific T‐cell transfer. Among effective and safe strategies is the use of “third‐party” (neither from the transplant donor nor recipient) virus‐specific T cells that can be manufactured from healthy donors and used as “off‐the‐shelf” therapies. Leukoreduction system chambers (LRSCs), recovered after routine plateletpheresis, were evaluated as a potential source of peripheral blood mononuclear cells (PBMCs) for the manufacturing of clinical‐scale virus‐specific T cell. STUDY DESIGN AND METHODS PBMCs from the same donors obtained either from LRSCs or peripheral blood were compared, focusing on T‐cell function and phenotype as well as the potential to generate cytomegalovirus (CMV)‐specific T‐cell lines from both CMV seropositive and seronegative donors. RESULTS PBMCs from both sources were comparable except for a transient downregulation of CD62L expression on freshly extracted PBMCs from LRSCs. Both nonspecific stimulation using anti‐CD3/CD28 antibodies and CMV peptides revealed that LRSCs or blood T cells were equivalent in terms of expansion, differentiation, and function. Moreover, PBMCs from LRSCs can be used to generate autologous monocyte‐derived dendritic cells to prime and expand CMV‐specific T cells from seronegative donors. CONCLUSION LRSCs are a reliable source of PBMCs for the generation of virus‐specific T cells for immunotherapy. These findings have implications for the development of third‐party therapeutic T‐cell products from well‐characterized blood product donors.

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Background. The stimulation and expansion of antigen-specific T cells ex vivo enables the targeting of a multitude of cancer antigens. However, clinical scale T-cell expansion from rare precursors requires repeated stimulations ex vivo leading to T-cell terminal effector differentiation and exhaustion that adversely impact therapeutic potential. We leveraged immune checkpoint blockade relevant to antigen-specific CD8+ human T cells to improve the expansion and function of T cells targeting clinically relevant antigens. Methods. A clinically-compliant protocol relying on peptide-pulsed monocyte-derived dendritic cells and cytokines was used to expand antigen-specific CD8+ targeting the oncogenic Epstein-Barr virus (EBV) and the tumor associated antigen (TAA) Wilms Tumor 1 (WT1) protein. The effects of antibody-mediated blockade of immune checkpoints applied to the cultures (T-cell expansion, phenotypes and function) were assessed at various time points. Genomic studies including single cell RNA (scRNA) sequencing and T-cell receptor sequencing was performed on EBV-specific T cells to inform about the impact of immune checkpoint blockade on the clonal distribution and gene expression of the expanded T cells. Results. Several immune checkpoints were expressed early by ex vivo expanded antigen-specific CD8+ T cells, including PD-1 and TIM-3 with co-expression matching evidence of T-cell dysfunction as the cultures progressed. The introduction of anti-PD-L1 (expressed by the dendritic cells) and anti-TIM-3 antibodies in combination (but not individually) to the culture led to markedly improved antigen-specific T-cell expansion based on cell counts, fluorescent multimer staining and functional tests. This was not associated with evidence of T-cell dysfunction when compared to T cells expanded without immune checkpoint blockade. Genomic studies largely confirmed these results, showing that double blockade does not impart particular transcriptional programs or patterns on TCR repertoires. However, our data indicate that combined blockade may nonetheless alter gene expression in a minority of clonotypes and have donor-specific impacts. Conclusions. The manufacturing of antigen-specific CD8+ T cells can be improved in terms of yield and functionality using blockade of TIM-3 and the PD-L1/PD-1 axis in combination. Overcoming the deleterious effects of multiple antigenic stimulations through PD-L1/TIM-3 blockade is a readily applicable approach for several adoptive-immunotherapy strategies.

Cette etude vise a determiner, dans le domaine des surfaces, les relations entre la genese des invariants qualitatifs (identiti, transitivitt de I'identite) et celle des invariantd quantitatifs (identiti, transitivite de l'identite). Afin d'eliminer les effets possibles d'interaction dans la mesure de ces notions, un groupe 'A' (n = 56, dges moyens: 5;6 et 6;6 ans) subit les epreuves Identite Qualitative et Transitivite Qualitative alors qu'un autre groupe ' B (n = 82, lges moyens: 5;6, 6;6 et 7;6 ans) subit les tpreuves Identitt Quantitative et Transitivite Quantitative. L'analyse statistique nonparamktrique des resultats permet d'attester I'authenticitt des principaux stades obtenus pour les invariants qualitatifs et les invariants quantitatifs. Pour chaque type &invariants, le stade 3 marque le synchronisme d'acquisition des notions d'identite et de transitivite. En outre, l'tge d'acquisition des invariants qualitatifs (6;3 ans) et celui des invariants quantitatifs (7;2 ans) confirment l'anteriorite genktique des premiers.

Cette étude vise à déterminer, dans le domaine des surfaces, les relations entre la genèse des invariants qualitatifs (identité, transitivité de l'identité) et celle des invariants' quantitatifs (identité, transitivité de l'identité). Afin d'éliminer les effets possibles d'interaction dans la mesure de ces notions, un groupe ‘A’ (n = 56, âges moyens: 5;6 et 6;6 ans) subit les épreuves Identité Qualitative et Transitivité Qualitative alors qu'un autre groupe ‘B’ (n = 82, âges moyens: 5;6, 6;6 et 7;6 ans) subit les épreuves Identité Quantitative et Transitivité Quantitative. L'analyse statistique nonparamétrique des résultats permet d'attester l'authenticité des principaux stades obtenus pour les invariants qualitatifs et les invariants quantitatifs. Pour chaque type d'invariants, le stade 3 marque le synchronisme d'acquisition des notions d'identité et de transitivité. En outre, l'âge d'acquisition des invariants qualitatifs (6;3 ans) et celui des invariants quantitatifs (7;2 ans) confirment l'antériorité génétique des premiers.

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