Étude ultrastructurale et développementale du récepteur EphA4 dans l’hippocampe du rat

Afin de mieux comprendre l’évolution des fonctions du récepteur EphA4 pendant le développement du système nerveux central (SNC), nous avons étudié sa localisation cellulaire et subcellulaire dans l’hippocampe du rat, d’abord chez l’adulte, puis pendant le développement postnatal, ainsi que ses rôles potentiels dans la genèse, la migration ou la maturation des cellules granulaires dans l’hippocampe adulte. Pour ce faire, nous avons utilisé la méthode d’immunocytochimie en microscopie photonique, électronique et confocale. En microscopie photonique, une forte immunoréactivité (peroxydase/DAB) pour EphA4 est observée aux jours 1 et 7 suivant la naissance (P1 et P7) dans les couches de corps cellulaires, avec un marquage notamment associé à la surface des corps cellulaires des cellules granulaires et pyramidales, ainsi que dans les couches de neuropile du gyrus dentelé et des secteurs CA3 et CA1. L’intensité du marquage diminue progressivement dans les couches de corps cellulaires, entre P7 et P14, pour devenir faible à P21 et chez l’adulte, tandis qu’elle persiste dans les couches de neuropile, sauf celles qui reçoivent des afférences du cortex entorhinal. En microscopie électronique, après marquage à la peroxydase/DAB, EphA4 décore toute la surface des cellules pyramidales et granulaires, du corps cellulaire jusqu’aux extrémités distales, entre P1 et P14, pour devenir confiné aux extrémités synaptiques, c’est-à-dire les terminaisons axonales et les épines dendritiques, à P21 et chez l’adulte. À la membrane plasmique des astrocytes, EphA4 est redistribué comme dans les neurones, marquant le corps cellulaire et ses prolongements proximaux à distaux, à P1 et P7, pour devenir restreint aux prolongements périsynaptiques distaux, à partir de P14. D’autre part, des axones en cours de myélinisation présentent souvent une forte immunoréactivité punctiforme à leur membrane plasmique, à P14 et P21. En outre, dans les neurones et les astrocytes, le réticulum endoplasmique, l’appareil de Golgi et les vésicules de transport, organelles impliquées dans la synthèse, la modification posttraductionnelle et le transport des protéines glycosylées, sont aussi marqués, et plus intensément chez les jeunes animaux. Enfin, EphA4 est aussi localisé dans le corps cellulaire et les dendrites des cellules granulaires générées chez l’adulte, au stade de maturation où elles expriment la doublecortine (DCX). De plus, des souris adultes knockouts pour EphA4 présentent des cellules granulaires DCX-positives ectopiques, c’est-à-dire positionnées en dehors de la zone sous-granulaire, ce qui suggère un rôle d’EphA4 dans la régulation de leur migration. Ces travaux révèlent ainsi une redistribution d’EphA4 dans les cellules neuronales et gliales en maturation, suivant les sites cellulaires où un remodelage morphologique s’effectue : les corps cellulaires lorsqu’ils s’organisent en couches, les prolongements dendritiques et axonaux pendant leur croissance, guidage et maturation, puis les épines dendritiques, les terminaisons axonales et les prolongements astrocytaires distaux associés aux synapses excitatrices, jusque chez l’adulte, où la formation de nouvelles synapses et le renforcement des connexions synaptiques existantes sont exercés. Ces localisations pourraient ainsi correspondre à différents rôles d’EphA4, par lesquels il contribuerait à la régulation des capacités plastiques du SNC, selon le stade développemental, la région, l’état de santé, ou l’expérience comportementale de l’animal.To gain more insight into the various functions of EphA4 receptor during the development of the central nervous system (CNS), we have characterized its cellular and subcellular localization in the rat hippocampus, first in the adult, and second during the postnatal development. We have also examined its potential roles in the genesis, migration, or maturation of the granule cells in the adult hippocampus. For that purpose, we have used immunocytochemistry in light, electron, and confocal microscopy. At the light microsocpic level, a strong EphA4 immunoreactivity (peroxidase/DAB) is observed at postnatal days 1 and 7 (P1 and P7) in the cell body layers, with a labeling notably associated with the surface of pyramidal and granule cell bodies, as well as in the neuropil layers of CA3, CA1, and dentate gyrus regions. The intensity of the labeling diminishes progressively in the cell body layers, between P7 and P14, to become weak at P21 and in the adult, while it persists in the neuropil layers, except in those receiving inputs from the entorhinal cortex. At the electron microscopic level, after peroxidase/DAB labeling, EphA4 covers the entire surface of pyramidal and granule cells, from the cell body to the distal extremities, between P1 and P14, but becomes restricted to the synaptic extremities, i.e. the axon terminals and dendritic spines, at P21 and in the adult. At the plasma membrane of astrocytes, EphA4 is redistributed as in neurons, from the cell body and proximal to distal processes, at P1 and P7, to the distal perisynaptic processes, at P14 and older ages. In addition, axons in the process of myelination present strong punctiform immunoreactivity at their plasma membrane, at P14 and P21. Moreover, in neurons and astrocytes, the endoplamic reticulum, Golgi apparatus, and transport vesicles, organelles involved in the synthesis, post-translational modifications, and transport of glycosylated proteins, are also labeled, and also more intensely in younger animals. Lastly, EphA4 is located in the cell body and dendrites of adult-generated granule cells, at the stage of maturation where they express doublecortin (DCX). In addition, EphA4 adult knockout mice display DCX-positive granule cells in an ectopic position, outside of the subgranular zone, suggesting a role for EphA4 in the regulation of their migration. This work thus reveals a redistribution of EphA4 in neuronal and glial cells, in the cellular sites where cellular motility occurs during their maturation: the cell bodies when they position and organize themselves into layers, the dendritic and axonal processes during their growth, guidance, and maturation, and the dendritic spines, axon terminals, and distal astrocytic processes when synapses are formed or strengthened. These locations could thus reflect different roles for EphA4, similarly associated with the regulation of plasticity in the CNS, according to the stage of development, the region, the CNS integrity, or the behavioural experience of an animal

El desarrollo de la interacción oral en clase de ELE mediante las actividades lúdicas

Selon la conception de la langue comme moyen de communication, l’interaction orale est reconnue comme l’un des aspects les plus importants. Dans le cadre de ce présent travail, nous attribuons une importance particulière à son développement dans le processus d’enseignement-apprentissage de l’espagnol comme langue étrangère (ELE). Toutefois, les étudiants d’ELE en contexte non-hispanophone n’ayant pas les mêmes opportunités de mettre en pratique leurs habiletés orales que ceux qui apprennent la langue en situation d’immersion linguistique, soit en contexte socioculturelle hispanophone, leur motivation peut ainsi se voir affectée. En considérant ce qui précède, un des objectifs du professeur d’ELE serait de réussir à ce que les étudiants qui étudient en contextes non-hispanophones (tel est le cas de Montréal) puissent développer une interaction oral efficiente. Dans le but d’essayer d’offrir une solution partielle à cette problématique, nous positionnons, dans un premier temps, l’interaction oral dans la bibliographie spécialisée et analysons la théorie relative à son développement et à son évolution dans le temps, ce qui nous permet de mettre en lumière le facteur motivationnel comme l’un des éléments essentiels à l’apprentissage d’une langue étrangère et ainsi, proposer l’usage des activités ludiques comme potentielle solution motivatrice. En deuxième lieu, nous analysons les manuels et les plans des cours d’ELE offerts dans les universités de Montréal, pour ainsi pouvoir interpréter la situation actuelle tant de l’interaction oral que de l’usage des activités ludiques en classe d’ELE dans ce contexte géographique et éducatif. La description et l’analyse de ces données nous permettent d’établir un premier diagnostic et certains critères de base pour évaluer les activités nécessaires dans tel contexte. Finalement, nous proposons une série d’activités ludiques adaptées à chaque niveau (A1-B2), dont l’objectif principal est d’améliorer l’interaction oral et favoriser la motivation chez l’étudiant.In the conception of language as way of communication, oral interaction is recognized as one of the most important aspects and, in the frame of the present work, special importance is placed on its development in the teaching and learning process of Spanish as foreign language (SFL). Nevertheless, SFL students in non-Spanish-speaking contexts do not have the same opportunities to practice their orals skills as those who learn Spanish in experiences of immersion within a Hispanic sociocultural context. This can result in undermining their motivation. Considering the above, one of the aims of the SFL teacher would be to achieve that pupils studying in non-Spanish-speaking contexts (as is the case of Montreal) develop effective oral interaction skills. To try to offer a partial solution to this problem, firstly, we locate oral interaction in the specialized bibliography and analyze the theory regarding its development and evolution over time. This allows us to identify the factor of motivation as one of the essential elements in learning foreign languages and to propose the use of recreational activities as a potential solution for motivation. Secondly, we analyze the currently used SFL manuals and the SFL course programs offered at Montreal universities, in order to interpret the current state of both oral interaction and the use of recreational activities in SFL classes within this geographical and educational context. The description and analysis of this information allow us to establish a first diagnostic, and certain basic criteria to assess the necessary activities for the abovementioned context. Finally, we propose a series of recreational activities adapted to every level (A1-B2), of which the principal aim is to promote oral interaction and to foster motivation in the pupil

Parental Misperception of Their Child's Body Weight Status Impedes the Assessment of the Child's Lifestyle Behaviors

Objectives. To examine if distinct characteristics are associated with parental misclassification of underweight (UW), normal weight (NW), and overweight or obese (OWOB) children and the implications of misclassification on the parental evaluation of the child's lifestyle habits. Methods. Cross-sectional analysis (2004 sample) of the Quebec Longitudinal Study of Child Development (1998–2010) (n = 1,125). Results. 16%, 55%, and 77% of NW, UW and OWOB children were perceived inaccurately, respectively. Misperception was significantly higher in nonimmigrant parents of UW children, in highly educated parents of NW children and in NW and OWOB children with lower BMI percentiles. Erroneous body weight status identification impedes the evaluation of eating habits of all children as well as physical activity and fitness levels of UW and OWOB children. Conclusion. Parental misclassification of the child's body weight status and lifestyle habits constitutes an unfavorable context for healthy body weight management

The resilience of verbal sequence learning:Evidence from the Hebb repetition effect

In a single large-scale study, we demonstrate that verbal sequence learning as studied using the classic Hebb repetition effect (Hebb, 1961)—the improvement in the serial recall of a repeating sequence compared to non-repeated sequences—is resilient to both wide and irregular spacing between sequence repetitions. Learning of a repeated sequence of letters was evident to a comparable degree with three, five, and eight intervening non-repeated sequences and regardless of whether the spacing between repetitions was regular or irregular. Importantly, this resilience of verbal sequence learning was observed despite the fact that there was complete item-set overlap between repeated and non-repeated sequences. The findings are consistent with the conceptualization of the Hebb repetition effect as a laboratory analogue of natural phonological word-form learning. The results also have implications for the two leading models of Hebb sequence learning: Whereas the results are incompatible with the model of Page and Norris (2009), they can be handled readily by the model of Burgess and Hitch (2006) through the abandonment of its assumption of long-term (across-trial level) decay

Role Allocation and Team Structure in Command and Control Teams Topic 4 (Primary) Experimentation, Metrics, and Analysis Topic 2 Organizational Concepts and Approaches

Defence and security organizations are increasingly faced with uncertain and dynamic global security environments. Often highly structured in nature, command and control (C2) in these organizations may not traditionally allow for the adaptability and flexibility required in these complex situations. In response, models of more agile, decentralized organizations -such as Edge organizations -have been proposed. To further the understanding of these organizations and their potential benefits and limitations, we sought to examine how edge-like teams spontaneously adopt and organize roles when engaging in complex, collaborative activities in the context of crisis management situations. A forest firefighting simulation was used to compare functional (explicitly assigned roles) to edge-like (no assigned roles) organizations. Four-person teams completed scenarios characterized by the occurrence of sudden and critical events. Behavioural indicators associated with various roles in the simulation (e.g., operations, resources management, search and rescue) were measured, and we assessed the extent to which these indicators matched when comparing functional teams to edge-like teams. A behavioural indicator matching across the two conditions would indicate that edge-like teams adopted a similar structure as functional teams. The results suggest edge-like teams allocate role differently from functional teams, but for a given team that allocation remain relatively stable once established. The findings are discussed with regards to team effectiveness and agility in complex C2 environments

Microglia contribute to social behavioral adaptation to chronic stress

Microglial activation has been regarded mainly as an exacerbator of stress response, a common symptom in psychiatric disorders. This study aimed to determine whether microglia contribute to adaptive response of the brain and behavior toward stress using a mild and adaptive stress model - chronic restraint stress (CRS) - with wild type (WT) and CX3CR1-GFP (CX3CR1[G]) mice and human schizophrenia patients' data. Our results revealed that CRS did not exacerbate anxiety and depressive-like behaviors, but instead strengthened social dominance and short-term spatial learning in WT mice. Compared to WT and CX3CR1(+/G) heterozygous mice, CX3CR1(G/G) homozygotes were subordinate in social interaction before and after CRS. Microglia in WT mice underwent a series of region-specific changes involving their phagocytosis of presynaptic vesicular glutamate transporter 2 protein, contacts with synaptic elements, CD206(+)microglial proportion, and gene expressions such as Cx3cr1. By contrast, CX3CR1-deficient microglia showed decreased CD206(+) while increased MHCII+ subpopulations and hypo-ramification in the hippocampus, as well as sensitized polarization and morphological change in response to CRS. Furthermore, CD206(+) microglial abundancy was positively correlated with social dominancy and microglial ramification in CX3CR1-GFP mice. Moreover, CX3CR1 mRNA level was reduced in CRS-treated mouse brains and showed a smaller interactome with other brain genes in the dorsal-lateral prefrontal cortices of patients with schizophrenia. Our findings overall highlight microglia and its receptor CX3CR1 as key contributors in regulation of social behavioral adaptation to chronic stress.Peer reviewe

Engaging family supporters of adult patients with diabetes to improve clinical and patient-centered outcomes: study protocol for a randomized controlled trial

Abstract Background Most adults with diabetes who are at high risk for complications have family or friends who are involved in their medical and self-care (“family supporters”). These family supporters are an important resource who could be leveraged to improve patients’ engagement in their care and patient health outcomes. However, healthcare teams lack structured and feasible approaches to effectively engage family supporters in patient self-management support. This trial tests a strategy to strengthen the capacity of family supporters to help adults with high-risk diabetes engage in healthcare, successfully enact care plans, and lower risk of diabetes complications. Methods/design We will conduct a randomized trial evaluating the CO-IMPACT (Caring Others Increasing EnageMent in Patient Aligned Care Teams) intervention. Two hunded forty adults with diabetes who are at high risk for diabetes complications due to poor glycemic control or high blood pressure will be randomized, along with a family supporter (living either with the patient or remotely), to CO-IMPACT or enhanced usual primary care for 12 months. CO-IMPACT provides patient-supporter dyads: it provides one coaching session addressing supporter techniques for helping patients with behavior change motivation, action planning, and proactive communication with healthcare providers; biweekly automated phone calls to prompt dyad action on new patient health concerns; phone calls to prompt preparation for patients’ primary care visits; and primary care visit summaries sent to both patient and supporter. Primary outcomes are changes in patient activation, as measured by the Patient Activation Measure-13, and change in 5-year cardiac event risk, as measured by the United Kingdom Prospective Diabetes Study cardiac risk score for people with diabetes. Secondary outcomes include patients’ diabetes self-management behaviors, diabetes distress, and glycemic and blood pressure control. Measures among supporters will include use of effective support techniques, burden, and distress about patient’s diabetes care. Discussion If effective in improving patient activation and diabetes management, CO-IMPACT will provide healthcare teams with evidence-based tools and techniques to engage patients’ available family or friends in supporting patient self-management, even if they live remotely. The core skills addressed by CO-IMPACT can be used by patients and their supporters over time to respond to changing patient health needs and priorities. Trial registration ClinicalTrials.gov, NCT02328326 . Registered on 31 December 2014.https://deepblue.lib.umich.edu/bitstream/2027.42/145179/1/13063_2018_Article_2785.pd

Engaging family supporters of adult patients with diabetes to improve clinical and patient-centered outcomes: study protocol for a randomized controlled trial

Abstract Background Most adults with diabetes who are at high risk for complications have family or friends who are involved in their medical and self-care (“family supporters”). These family supporters are an important resource who could be leveraged to improve patients’ engagement in their care and patient health outcomes. However, healthcare teams lack structured and feasible approaches to effectively engage family supporters in patient self-management support. This trial tests a strategy to strengthen the capacity of family supporters to help adults with high-risk diabetes engage in healthcare, successfully enact care plans, and lower risk of diabetes complications. Methods/design We will conduct a randomized trial evaluating the CO-IMPACT (Caring Others Increasing EnageMent in Patient Aligned Care Teams) intervention. Two hunded forty adults with diabetes who are at high risk for diabetes complications due to poor glycemic control or high blood pressure will be randomized, along with a family supporter (living either with the patient or remotely), to CO-IMPACT or enhanced usual primary care for 12 months. CO-IMPACT provides patient-supporter dyads: it provides one coaching session addressing supporter techniques for helping patients with behavior change motivation, action planning, and proactive communication with healthcare providers; biweekly automated phone calls to prompt dyad action on new patient health concerns; phone calls to prompt preparation for patients’ primary care visits; and primary care visit summaries sent to both patient and supporter. Primary outcomes are changes in patient activation, as measured by the Patient Activation Measure-13, and change in 5-year cardiac event risk, as measured by the United Kingdom Prospective Diabetes Study cardiac risk score for people with diabetes. Secondary outcomes include patients’ diabetes self-management behaviors, diabetes distress, and glycemic and blood pressure control. Measures among supporters will include use of effective support techniques, burden, and distress about patient’s diabetes care. Discussion If effective in improving patient activation and diabetes management, CO-IMPACT will provide healthcare teams with evidence-based tools and techniques to engage patients’ available family or friends in supporting patient self-management, even if they live remotely. The core skills addressed by CO-IMPACT can be used by patients and their supporters over time to respond to changing patient health needs and priorities. Trial registration ClinicalTrials.gov, NCT02328326 . Registered on 31 December 2014.https://deepblue.lib.umich.edu/bitstream/2027.42/145179/1/13063_2018_Article_2785.pd

Becoming a research participant : decision-making needs of individuals with neuromuscular diseases

BACKGROUND: Research has shown that some people with neuromuscular diseases may have a lower level of education due to lower socioeconomic status and possibly compromised health literacy. In view of these data, it appears important to document their decision-making needs to ensure better support when faced with the decision to participate or not in research projects. OBJECTIVES: 1) To document the decision-making needs of individuals with neuromuscular diseases to participate in research; 2) To explore their preferences regarding the format of knowledge translation tools related to research participation. METHODS: This qualitative study is based on the Ottawa Decision Support Framework. A two-step descriptive study was conducted to capture the decision-making needs of people with neuromuscular diseases related to research participation: 1) Individual semi-directed interviews (with people with neuromuscular diseases) and focus groups (with healthcare professionals); 2) Synthesis of the literature. RESULTS: The semi-directed interviews (n = 11), the two focus groups (n = 11) and the literature synthesis (n = 50 articles) identified information needs such as learning about ongoing research projects, scientific advances and research results, the potential benefits and risks associated with different types of research projects, and identified values surrounding research participation: helping other generations, trust, obtaining better clinical follow-up, and socialization. CONCLUSION: This paper provides useful recommendations to support researchers and clinicians in developing material to inform individuals with neuromuscular diseases about research participation

Antitumor Activity and Mechanism of Action of the Cyclopenta[b]benzofuran, Silvestrol

BACKGROUND. Flavaglines are a family of natural products from the genus Aglaia that exhibit anti-cancer activity in vitro and in vivo and inhibit translation initiation. They have been shown to modulate the activity of eIF4A, the DEAD-box RNA helicase subunit of the eukaryotic initiation factor (eIF) 4F complex, a complex that stimulates ribosome recruitment during translation initiation. One flavagline, silvestrol, is capable of modulating chemosensitivity in a mechanism-based mouse model. METHODOLOGY/PRINCIPAL FINDINGS. Among a number of flavagline family members tested herein, we find that silvestrol is the more potent translation inhibitor among these. We find that silvestrol impairs the ribosome recruitment step of translation initiation by affecting the composition of the eukaryotic initiation factor (eIF) 4F complex. We show that silvestrol exhibits significant anticancer activity in human breast and prostate cancer xenograft models, and that this is associated with increased apoptosis, decreased proliferation, and inhibition of angiogenesis. We demonstrate that targeting translation by silvestrol results in preferential inhibition of weakly initiating mRNAs. CONCLUSIONS/SIGNIFICANCE. Our results indicate that silvestrol is a potent anti-cancer compound in vivo that exerts its activity by affecting survival pathways as well as angiogenesis. We propose that silvestrol mediates its effects by preferentially inhibiting translation of malignancy-related mRNAs. Silvestrol appears to be well tolerated in animals.Canadian Institutes of Health Research (16512, Cancer Consortium Training Grant Award, CancerConsortium Training Grant Award); US Lymphoma Foundation Award; National Institute of Health (RO1 GM073855); National Crime Information Center (017099); Cole Foundation Awar