Une intervention cognitive clinique auprès d'enfants ayant subi un traumatisme crânien cérébral

Une intervention cognitive clinique auprès d'enfants ayant subi un traumatisme crânien cérébral La présente étude pilote vise à étudier l'implantation d'un protocole à cas unique de type A-B-A, c'est-à-dire avec d'abord la prise de mesures de base (A) suivi de l'insertion du traitement (B) avec reprise à la toute fin des premières mesures (A), en entraînement cognitif clinique auprès de deux garçons de 9 et 12 ans ayant subi un traumatisme crânien cérébral (TCC) sévère et se situant en phase quatre de la réadaptation. Ce type de protocole s'inscrit dans un plan d'entraînement cognitif avec le logiciel informatisé RÉÉDUC 4.0 (Pépin & Loranger, 1996), permettant de travailler sur des habiletés cognitives de base, dont certaines en lien avec la lecture. Les liens entre la compétence en lecture et les habiletés cognitives du logiciel RÉÉDUC sont documentés dans une étude préliminaire qui est rapportée dans ces pages. Cette étude a recours aux activités de RÉÉDUC 4.0 et de l'Épreuve de Performance Fonctionnelle en Lecture (Ruel & Collard, 1976). L'étude principale propose, suite à un entraînement cognitif de 15 heures sur RÉÉDUC 4.0, de bonnes possibilités d'implantation d'un protocole à cas unique pour ce type d'intervention clinique. De plus, les données suggèrent une amélioration de la vitesse du traitement de l'information ainsi que de certaines habiletés cognitives, mais peu de changements au niveau des habiletés de lecture telles que mesurées par l'EPFL

Vitesse des opérations mentales et mémoire de travail comme facteurs prédictifs des aptitudes intellectuelles et des habiletés en lecture des enfants de 3 à 9 ans

Les effets positifs de la prévention des difficultés d’apprentissage chez les enfants n'ont plus à être démontrés. Il demeure cependant primordial de prévenir ces difficultés avant l’entrée à l’école. Les habiletés en lecture sont des mesures représentatives et reconnues des apprentissages scolaires. Cependant, peu de recherches existent sur la contribution de variables générales comme les aptitudes intellectuelles et de variables plus spécifiques comme la vitesse des opérations mentales (VOM) et la mémoire de travail(MT) à la prédiction des habiletés en lecture des jeunes d ’âge préscolaire, aussi jeunes que de 3 à 5 ans et d ’âge scolaire de 5 à 8 ans. Dans un premier temps, cette thèse vise à documenter les liens entre la VOM, la MT et les aptitudes intellectuelles chez 68enfants d’âge préscolaire de 3 à 5 ans et 163 enfants d ’âge scolaire de 5 à 8 ans. Elle vise ensuite à prédire, par ces mesures de VOM, de MT et d ’aptitudes intellectuelles prises au temps un, les habiletés en lecture 18 mois plus tard chez ces mêmes groupes. En regard au premier objectif, les résultats suggèrent que les variables d’aptitudes intellectuelles, de VOM et de MT sont significativement reliées entre elles, et ce, dès 3ans. Lorsque la variable de l’âge est contrôlée, la MT chez le groupe préscolaire ainsi que la MT et la VOM chez le groupe scolaire contribuent à la prédiction des aptitudes intellectuelles mesurées par un test psychométrique. La VOM est la variable ayant la plus forte contribution unique à un concept général d’intelligence chez les deux groupes. En regard au deuxième objectif, lorsqu’on contrôle la variable de l’âge, les résultats suggèrent que la MT chez le groupe préscolaire ainsi que la VOM, la MT et les aptitudes intellectuelles prédisent significativement les habiletés en lecture. Pour le groupe scolaire, la VOM en tâches de temps de réaction est cependant la variable la plus indépendante de l’âge et des aptitudes intellectuelles offrant une contribution unique aux habiletés en lecture

Fn3 Proteins Engineered to Recognize Tumor Biomarker Mesothelin Internalize Upon Binding

Mesothelin is a cell surface protein that is overexpressed in numerous cancers, including breast, ovarian, lung, liver, and pancreatic tumors. Aberrant expression of mesothelin has been shown to promote tumor progression and metastasis through interaction with established tumor biomarker CA125. Therefore, molecules that specifically bind to mesothelin have potential therapeutic and diagnostic applications. However, no mesothelin-targeting molecules are currently approved for routine clinical use. While antibodies that target mesothelin are in development, some clinical applications may require a targeting molecule with an alternative protein fold. For example, non-antibody proteins are more suitable for molecular imaging and may facilitate diverse chemical conjugation strategies to create drug delivery complexes. In this work, we engineered variants of the fibronectin type III domain (Fn3) non-antibody protein scaffold to bind to mesothelin with high affinity, using directed evolution and yeast surface display. Lead engineered Fn3 variants were solubly produced and purified from bacterial culture at high yield. Upon specific binding to mesothelin on human cancer cell lines, the engineered Fn3 proteins internalized and co-localized to early endosomes. To our knowledge, this is the first report of non-antibody proteins engineered to bind mesothelin. The results validate that non-antibody proteins can be engineered to bind to tumor biomarker mesothelin, and encourage the continued development of engineered variants for applications such as targeted diagnostics and therapeutics

Fn3 Proteins Engineered to Recognize Tumor Biomarker Mesothelin Internalize Upon Binding

Mesothelin is a cell surface protein that is overexpressed in numerous cancers, including breast, ovarian, lung, liver, and pancreatic tumors. Aberrant expression of mesothelin has been shown to promote tumor progression and metastasis through interaction with established tumor biomarker CA125. Therefore, molecules that specifically bind to mesothelin have potential therapeutic and diagnostic applications. However, no mesothelin-targeting molecules are currently approved for routine clinical use. While antibodies that target mesothelin are in development, some clinical applications may require a targeting molecule with an alternative protein fold. For example, non-antibody proteins are more suitable for molecular imaging and may facilitate diverse chemical conjugation strategies to create drug delivery complexes. In this work, we engineered variants of the fibronectin type III domain (Fn3) non-antibody protein scaffold to bind to mesothelin with high affinity, using directed evolution and yeast surface display. Lead engineered Fn3 variants were solubly produced and purified from bacterial culture at high yield. Upon specific binding to mesothelin on human cancer cell lines, the engineered Fn3 proteins internalized and co-localized to early endosomes. To our knowledge, this is the first report of non-antibody proteins engineered to bind mesothelin. The results validate that non-antibody proteins can be engineered to bind to tumor biomarker mesothelin, and encourage the continued development of engineered variants for applications such as targeted diagnostics and therapeutics

Difference in neural response to social exclusion observation and subsequent altruism between adolescents and adults

Empathy and prosocial behaviors toward peers promote successful social development and creation of significant long-term relationships, but surprisingly little is known about the maturation of these skills during the period of adolescence. As the majority of studies have used questionnaires or pain observation paradigms, it remains unknown whether the empathic response of adolescents differs from that of adults in a paradigm that is closer to everyday life. In the current study, fMRI was used to examine the neural correlates of social exclusion observation and subsequent prosocial behavior in 20 adolescents (aged 12–17 years) and 20 adults (aged 22–30 years) while playing a ball-tossing game with what they believed to be real individuals. Observing someone being excluded compared to observing equal inclusion of all players elicited a significantly higher activation of the IFG (pars triangularis) in adults compared to adolescents. When given the opportunity to directly help the excluded player during the game, adolescents showed significantly less prosocial behavior than adults, which was underpinned by a significantly lower activity in the right temporoparietal junction, medial/dorsomedial prefrontal cortex and fusiform face area. These findings might indicate that adolescents have a lower propensity to take the victim's perspective and share his or her distress when witnessing social exclusion, which leads to a lower altruistic motivation to help. The factors that could generate what can be interpreted as a downward modulation of empathy during adolescence are discussed

A comprehensive assessment of social cognition from adolescence to adulthood

While it is well accepted that the social brain undergoes prolonged development throughout the teenage years, behavioral evidence of this development from adolescence to adulthood are lacking. The current study thus investigated multiple aspects of social cognition in 30 adolescents of 12–17 years, 32 young adults of 18–21 years, and 27 adults of 22–30 years. The Integrated Social Cognition Battery (mentalizing, social knowledge, emotion recognition) and a self-reported empathy questionnaire were administered, along with non-social cognition tests (selective attention, working memory, executive functions). Adolescents’ scores were significantly lower on the cognitive empathy subscale and emotion recognition task, even while taking into account other developing non-social cognitive functions. No difference was found regarding mentalizing, social knowledge, and other aspects of empathy. The results suggest a protracted development of some components of social cognition across adolescence, while others seem to be already developed. A nuanced understanding of social cognition development is discussed

Impact of traumatic brain injury on social cognition in adolescents and contribution of other higher order cognitive functions

Social cognition impairments can contribute to social participation difficulties following traumatic brain injury (TBI). However, little attention has been given to these impairments during adolescence, a period of life when peer relationships are central. The aim of the current study was to examine the impact of a moderate to severe TBI sustained in adolescence on multiple facets of social cognition. Twenty-three adolescents who had sustained a moderate-to-severe TBI were compared with a group of 23 typically developing peers. The Integrated Social Cognition Battery (mentalising, social knowledge, emotion recognition) and the Interpersonal Reactivity Index were administered, along with non-social cognition tests (selective attention, working memory, executive functions), IQ estimation, and a socio-demographic questionnaire. Adolescents with TBI reported having a significantly lower ability to take other people's perspectives versus controls. They also presented significantly lower levels of mentalising. After controlling for non-social higher-order cognitive variables, the group effect on mentalising remained marginally significant, whereas the effect on perspective taking remained significant. Our findings suggest the presence of primary deficits in social cognition following TBI in adolescence. These deficits could partially underlie the social reintegration difficulties encountered following TBI. A systematic assessment of social cognition in clinical practice is necessary

Directed evolution of a naïve yeast surface display library yielded Fn3 variants that bind soluble MSLN.

<p>We started with a naïve yeast surface display library with 2.8 x 10⁹ variants of the Fn3 non-antibody scaffold. The library was sorted for full-length protein expression, detected by an antibody to a terminal c-myc epitope tag, and binding to MSLN using MACS and FACS. Red polygon indicates example cell population collected for further enrichment and analysis. Additional diversity was introduced into the enriched library through a single round of mutagenic PCR and sorting of this second generation library resulted in further enrichment for MSLN binding variants. A double-negative population of yeast cells is characteristic of yeast surface display.</p

Engineered Fn3 protein variants 1.4.1 and 2.4.1 localized to early endosomes upon binding MSLN.

<p>Analysis by (A) flow cytometry and (B) imaging flow cytometry confirms MSLN presence on the surface of KB-3-1 cells compared to the MSLN-negative MCF-7 cells, as detected by an anti-MSLN antibody. (C, D) KB-3-1 cells (<i>top</i>) internalize AF488-labeled 1.4.1 (C) and AF488-labeled 2.4.1 (D), while MCF-7 cells show no specific binding or internalization (C <i>bottom</i>, D <i>bottom</i>). Endosomes are detected by an AF647-conjuated antibody recognizing the EAA1 early endosomal marker. Yellow in the merged images indicate co-localization between AF488-1.4.1 or AF488-2.4.1 anti-MSLN engineered proteins (green) and EEA1 (red). Original magnification 40X. Co-localization is quantified by the Bright Detail Similarity (BDS) metric, with values near 1 indicating co-localization. KB-3-1 BDS = 1.31 and 0.919 for AF488-1.4.1 and AF488-2.4.1, respectively. BDS values are not quantifiable for the negative control cell line, due to insufficient fraction of negative control cell population staining for binding or internalization of engineered protein variants.</p