Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Unfreezing school Reputations: The Role of Social Cognitive Flexibility

The school often generates different kinds of reputations. These reputations can have negative consequences on pupils’ learning process. Bad reputations make pupils’ efforts invisible, whereas good reputations restrict teachers’ perception of pupils’ desinvestment in learning. Although individualization seems to be an ideal alternative to thwarting reputation creation, it cannot be permanently applied in teachers' practice because of time pressures, cognitive overload, and other facilitators of the automatisms emergence. Hence, the aim is not to banish stereotypical reasoning, but rather to keep a balance between automaticity and reflection through a social cognitive flexibility approach (SCF). The current study tests the impact of a social cognitive flexibility approach on teachers’ thinking about pupils. Social cognitive flexibility seems to help teachers suspend hasty judgments of pupils’ attitudes and behaviors. The study considers the implications of social cognitive flexibility on teachers’ practice in terms of better perception of pupils’ learning potential

Du rapport à l'information au processus de la flexibilité sociocognitive chez l'enseignant: approche psychosociale

L'analyse de situations éducatives transversales selon une approche psychosociale et à partir de la méthode de la théorisation enracinée a permis, à l'issue de quatre études, de faire émerger l'importance pour les enseignants de développer une flexibilité sociocongitive (FSC) et une capacité d'observation réceptive pour contrer les biais et raccourcis de pensée issus de multiples sources (media, collègues, etc.). La FSC a été conceptualisée comme l'aptitude à suspendre le jugement, à recueillir des informations nouvelles et à les confronter aux informations reçues, afin de corriger/réajuster les jugements et attentes initiaux. Les résultats suggèrent que la FSC a pour corollaires le sentiment d'être concerné, la curiosité factuelle et l'investissement par l'enseignant d'une large zone d'action. Les implications de cette recherche pour la formation des futurs enseignants sont discutées à la lumière des données et de différentes perspectives théoriques

Alternatywny sposób rozwijania zdolności artystycznych uczniów: rola giętkości społeczno-poznawczej An alternative method to develop students' artistic abilities: the role of social cognitive flexibility

Social cognitive flexibility, or specific cognitive fluidity closely related to the situation in which it occurs, helps teachers to look at studentsin a different way than through a program, conventions and common teaching patterns only and let themselves be surprised by the students' potential. The method described in the paper allows not only to have an impact on the discipline of students, but also to reise their interest in the art and, consequently, to develop their abilities

Bystander in the classroom? The role of feeling-of-being-concerned in the perception of the possibility to help unruly behaving pupils and its relation with social cognitive flexibility

With the aim of dealing with educational cross-domain problems that are likely to appear in each course regardless of the teaching domain, the teachers can either take the initiative to help or they can choose not to intervene. Despite the helpful recommendations to make all pupils participate (UNESCO) or no child left behind (NCLB in the United States), most teachers are unaware of their differential helping behavior when they are faced with an ambiguous or problematic educational situation. In line with the bystander effect literature and stereotype content model, the mechanism that underlies the decision of not helping is identified as the feeling that drives an individual to get into the given situation: the feeling of being concerned (FBC). FBC is supposed to redirect individuals away from hasty, biased conclusions and lead them to some distance from any information (i.e., social cognitive flexibility). It is hypothesized that the more one feels concerned by the situation, the more distance he or she tends to take based on the available information. In a current online survey, the participating teachers in training first gave their opinions about the proposed statements (i.e., the social cognitive flexibility measures), then they read one standardized scenario of the educational situation, and finally they responded to questions related to the perceived possibility of helping the pupils in the scenario. The quantitative results (according to ANOVA) show that the teachers with a high FBC report a higher perceived possibility to help and show a higher level of social cognitive flexibility compared to those with a low FBC. These results are supported by significant correlations and are discussed in terms of their implications for the teachers’ practice

Who strives and who gives up? The role of social comparison distance and achievement goals on students’ learning investment

The current survey tests the effects of social comparison distance on investment in learning. The social comparison is known to have two directions: upward and downward. It is hypothesized that, apart from these two directions, there are two distances: moderate and extreme. These distances are supposed to have an impact on the learning investment (when students will strive) or the disinvestment (when they will not make a great effort). Globally, students seem to put more effort in the case of moderate-distance conditions than in the case of extreme-distance conditions. However, the effect of distance is different according to the achievement goals reported by participants (interaction between comparison distance and achievement goals): the participants with performance goals strive more in the moderate-distance condition, whereas those with mastery goals seem to put a quite stable effort regardless of the distance. Implications in educational settings are discussed

Face à la discrimination en contexte scolaire : former les enseignants à la flexibilité sociocognitive

La formation des enseignants à la lutte contre la discrimination est complexe, celle-ci s’exerçant souvent de manière indirecte et inconsciente. À partir d’une approche psychosociale, cet article présente un dispositif de formation déplaçant le focus souvent opéré sur l’individu et son appartenance vers la situation éducative et la possibilité de la modifier. Il rend compte d’une étude, menée dans le milieu naturel (lors d’un cours semestriel), analysant des récits de futurs praticiens rédigés en début et en fin de formation (2 × N = 64), à partir d’une séquence de film. Une analyse de contenu montre que, d’une manière générale, si dans les récits du début de la formation l’attention de futurs enseignants est focalisée sur l’élève et son milieu d’origine comme sources du problème, dans ceux de la fin de la formation émergent des éléments liés aux circonstances et à la pratique pédagogique et leur rôle dans la réaction de l’élève

Face à la discrimination en contexte scolaire : former les enseignants à la flexibilité sociocognitive

La formation des enseignants à la lutte contre la discrimination est complexe, celle-ci s’exerçant souvent de manière indirecte et inconsciente. À partir d’une approche psychosociale, cet article présente un dispositif de formation déplaçant le focus souvent opéré sur l’individu et son appartenance vers la situation éducative et la possibilité de la modifier. Il rend compte d’une étude, menée dans le milieu naturel (lors d’un cours semestriel), analysant des récits de futurs praticiens rédigés en début et en fin de formation (2 × N = 64), à partir d’une séquence de film. Une analyse de contenu montre que, d’une manière générale, si dans les récits du début de la formation l’attention de futurs enseignants est focalisée sur l’élève et son milieu d’origine comme sources du problème, dans ceux de la fin de la formation émergent des éléments liés aux circonstances et à la pratique pédagogique et leur rôle dans la réaction de l’élève.As people are frequently unaware of their discriminatory behaviour, designing training to counter these implicit mechanisms appears complex. We propose focusing on the situation rather than seeing the pupil as the problem because this situation-based approach not only helps better understand the challenges but also highlights several alternative solutions. The study was conducted during an introductory course for trainee teachers where we gathered two sets of their written observations of a 2-minute movie clip (2 × N = 64) at the beginning and end of the semester). Content analysis showed that the first set of comments mostly focused on the pupils and their social-cultural classes as the cause of the problem, while the second set of comments reflected more the role of the circumstances and the learning method to explain the pupils’ reactions