The Role of Executive Function at 6 Years in the Association between Behavioral Inhibition at 5 Years and Anxiety at 7 Years.

EF skills play a central role in the etiology and maintenance of anxiety, but it is unclear whether they act as moderators or mediators in the relation between early behavioral inhibition (BI) and later anxiety. The current study tested two models by examining whether two executive functions (EF) skills (cognitive flexibility and working memory) assessed at age 6 acted as moderators or mediators in the relation between BI at 5 years and anxiety symptoms at 7 years. The sample consisted of 422 children from the Quebec Longitudinal Study of Child Development. We tested the moderation model, main and interaction effects using hierarchical multiple regression analyses and the mediation model with the product of coefficients test. Results showed that higher BI at 5 years predicted high anxiety at 7 years only at low levels of cognitive flexibility or working memory at 6 years. This suggests that high levels of cognitive flexibility or working memory at 6 years may act as protective factors. In contrast, neither cognitive flexibility nor working memory at age 6 acted as mediators in the association between BI at 5 years and anxiety at 7 years. Results support the hypothesis that goal-driven cognitive control processes act as moderators and promote adaptive functioning by dampening the effect of early BI on later anxiety.

Intrinsic cancer cell phosphoinositide 3-kinase δ regulates fibrosis and vascular development in cholangiocarcinoma.

BACKGROUND & AIMS: The class I- phosphatidylinositol-3 kinases (PI3Ks) signalling is dysregulated in almost all human cancers whereas the isoform-specific roles remain poorly investigated. We reported that the isoform δ (PI3Kδ) regulated epithelial cell polarity and plasticity and recent developments have heightened its role in hepatocellular carcinoma (HCC) and solid tumour progression. However, its role in cholangiocarcinoma (CCA) still lacks investigation. APPROACH & RESULTS: Immunohistochemical analyses of CCA samples reveal a high expression of PI3Kδ in the less differentiated CCA. The RT-qPCR and immunoblot analyses performed on CCA cells stably overexpressing PI3Kδ using lentiviral construction reveal an increase of mesenchymal and stem cell markers and the pluripotency transcription factors. CCA cells stably overexpressing PI3Kδ cultured in 3D culture display a thick layer of ECM at the basement membrane and a wide single lumen compared to control cells. Similar data are observed in vivo, in xenografted tumours established with PI3Kδ-overexpressing CCA cells in immunodeficient mice. The expression of mesenchymal and stemness genes also increases and tumour tissue displays necrosis and fibrosis, along with a prominent angiogenesis and lymphangiogenesis, as in mice liver of AAV8-based-PI3Kδ overexpression. These PI3Kδ-mediated cell morphogenesis and stroma remodelling were dependent on TGFß/Src/Notch signalling. Whole transcriptome analysis of PI3Kδ using the cancer cell line encyclopedia allows the classification of CCA cells according to cancer progression. CONCLUSIONS: Overall, our results support the critical role of PI3Kδ in the progression and aggressiveness of CCA via TGFß/src/Notch-dependent mechanisms and open new directions for the classification and treatment of CCA patients.

Feasibility of home initiation of an airway clearance device (SIMEOX) by telecare in people with non-cystic fibrosis bronchiectasis: a pilot study.

BACKGROUND: Mucociliary clearance is a cornerstone of the management of people with non-cystic fibrosis bronchiectasis (NCFB). SIMEOX, an innovative device, could facilitate autonomous airway clearance, but its use requires specific training. We hypothesised that telecare would be an effective means to train people with NCFB in the handling of device and to monitor and promote device adherence. OBJECTIVES: (1) To evaluate frequency of use of the SIMEOX for 10 weeks after telecare training. (2) To assess user satisfaction and clinical efficacy of the SIMEOX+telecare. METHODS: Multicentre, prospective, pilot study in adults with NCFB. A SIMEOX was provided to each participant at inclusion. Physiotherapists performed telecare sessions the first 2 weeks (3-5 sessions) for device training and every 10 days to reinforce motivation and provide technical support. RESULTS: 22 individuals were included, 21 analysed (38% male; mean±SD age 53±18 years; Bronchiectasis Severity Index 6.6±3.5). Fourteen participants (66.7%; 95% CI 43.1% to 84.5%) performed ≥3 SIMEOX sessions/week (self-reported adherence, primary outcome). Median (Q1; Q3) number of self-reported sessions/week for the whole group was 3.7 (1.8; 5.7). Adherence including web registration was 80.9%. At week 12, participant satisfaction rating was 9.0 (7.9; 10.0) on a 10-point visual analogue scale; respiratory function did not change but quality of life improved (COPD Assessment Test score -4.7, 95% CI -7.7 to -1.6, p=0.023; St Georges Respiratory Questionnaire -5.8, 95% CI -10.8 to -0.9, p=0.005). CONCLUSION: Adherence to and satisfaction with the SIMEOX airway clearance device supported by telecare were high in people with NCFB. The clinical efficacy needs to be confirmed in a randomised controlled trial. TRIAL REGISTRATION NUMBER: NCT04742270.

PI3Kδ activity controls plasticity and discriminates between EMT and stemness based on distinct TGFß signaling.

The stem cells involved in formation of the complex human body are epithelial cells that undergo apicobasal polarization and form a hollow lumen. Epithelial plasticity manifests as epithelial to mesenchymal transition (EMT), a process by which epithelial cells switch their polarity and epithelial features to adopt a mesenchymal phenotype. The connection between the EMT program and acquisition of stemness is now supported by a substantial number of reports, although what discriminates these two processes remains largely elusive. In this study, based on 3D organoid culture of hepatocellular carcinoma (HCC)-derived cell lines and AAV8-based protein overexpression in the mouse liver, we show that activity modulation of isoform δ of phosphoinositide 3-kinase (PI3Kδ) controls differentiation and discriminates between stemness and EMT by regulating the transforming growth factor ß (TGFß) signaling. This study provides an important tool to control epithelial cell fate and represents a step forward in understanding the development of aggressive carcinoma.

Endothelial extracellular vesicles promote tumour growth by tumour-associated macrophage reprogramming.

Tumour-derived extracellular vesicles (EVs) participate in tumour progression by deregulating various physiological processes including angiogenesis and inflammation. Here we report that EVs released by endothelial cells in a mammary tumour environment participate in the recruitment of macrophages within the tumour, leading to an immunomodulatory phenotype permissive for tumour growth. Using RNA-Seq approaches, we identified several microRNAs (miRNAs) found in endothelial EVs sharing common targets involved in the regulation of the immune system. To further study the impact of these miRNAs in a mouse tumour model, we focused on three miRNAs that are conserved between humans and mouse, that is, miR-142-5p, miR-183-5p and miR-222-3p. These miRNAs are released from endothelial cells in a tumour microenvironment and are transferred via EVs to macrophages. In mouse mammary tumour models, treatment with EVs enriched in these miRNAs leads to a polarization of macrophages toward an M2-like phenotype, which in turn promotes tumour growth.

Transactional longitudinal relations between accuracy and reaction time on a measure of cognitive flexibility at 5, 6, and 7 years of age.

Whereas accuracy is used as an indicator of cognitive flexibility in preschool-age children, reaction time (RT), or a combination of accuracy and RT, provide better indices of performance as children transition to school. Theoretical models and cross-sectional studies suggest that a speed-accuracy tradeoff may be operating across this transition, but the lack of longitudinal studies makes this transition difficult to understand. The current study explored the longitudinal and bidirectional associations between accuracy and RT on the DCCS (mixed block) at 5, 6, and 7 years of age using cross-lagged panel analyses. The study also examined the roles of working memory and language, as potential longitudinal mediators between RT at Time X and accuracy at Time X + 1, and explored the role of inhibitory control. The sample consisted of 425 children from the Quebec Longitudinal Study of Child Development. Results show lagged associations from slower RT to greater improvements in accuracy between 5 and 6 years and between 6 and 7 years. Further, higher accuracy at 6 years predicted faster RT at 7 years. Only working memory acted as a partial mediator between RT at 5 years and accuracy at 6 years. These results provide needed longitudinal evidence to support theoretical claims that slower RT precedes improved accuracy in the development of cognitive flexibility, that working memory may be involved in the early stage of this process, and that accuracy and reaction time become more efficient in later stages of this process.

Dual-specificity phosphatase 3 deletion promotes obesity, non-alcoholic steatohepatitis and hepatocellular carcinoma.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic hepatic pathology in Western countries. It encompasses a spectrum of conditions ranging from simple steatosis to more severe and progressive non-alcoholic steatohepatitis (NASH) that can lead to hepatocellular carcinoma (HCC). Obesity and related metabolic syndrome are important risk factors for the development of NAFLD, NASH and HCC. DUSP3 is a small dual-specificity protein phosphatase with a poorly known physiological function. We investigated its role in metabolic syndrome manifestations and in HCC using a mouse knockout (KO) model. While aging, DUSP3-KO mice became obese, exhibited insulin resistance, NAFLD and associated liver damage. These phenotypes were exacerbated under high fat diet (HFD). In addition, DEN administration combined to HFD led to rapid HCC development in DUSP3-KO compared to wild type (WT) mice. DUSP3-KO mice had more serum triglycerides, cholesterol, AST and ALT compared to control WT mice under both regular chow diet (CD) and HFD. The level of fasting insulin was higher compared to WT mice, though, fasting glucose as well as glucose tolerance were normal. At the molecular level, HFD led to decreased expression of DUSP3 in WT mice. DUSP3 deletion was associated with increased and consistent phosphorylation of the insulin receptor (IR) and with higher activation of the downstream signaling pathway. In conclusion, our results support a new role for DUSP3 in obesity, insulin resistance, NAFLD and liver damage.

Modelling vocabulary development among multilingual children prior to and following the transition to school entry.

Differences between monolingual and multilingual vocabulary development have been observed but few studies provide a longitudinal perspective on vocabulary development before and following school entry. This study compares vocabulary growth profiles of 106 multilingual children to 211 monolingual peers before and after school entry to examine whether: (1) school entry coincides with different rates of vocabulary growth compared to prior to school entry, (2) compared to monolingual peers, multilingual children show different vocabulary sizes or rates of vocabulary growth, (3) the age of onset of second-language acquisition for multilingual children is associated with vocabulary size or rate of vocabulary growth, and (4) the sociolinguistic context of the languages spoken by multilingual children is associated with vocabulary size or rate of vocabulary growth. Results showed increases in vocabulary size across time for all children, with a steeper increase prior to school entry. A significant difference between monolingual and multilingual children who speak a minority language was observed with regards to vocabulary size at school entry and vocabulary growth prior to school entry, but growth rate differences were no longer present following school entry. Taken together, results suggest that which languages children speak may matter more than being multilingual per se.

Dyadic analysis of siblings' relationship quality, behavioural responses, and pain experiences during experimental pain.

Research on family factors in paediatric pain has primarily focused on parents; the role of siblings has been largely ignored. This study examined whether sibling relationship quality was related to siblings' behaviours during experimental pain, and whether the behaviours of an observing sibling were related to children's pain outcomes. Ninety-two sibling dyads between 8 and 12 years old completed both observational and questionnaire measures of sibling relationship quality. Children took turns completing the cold-pressor task (CPT) in a counterbalanced order with their sibling present. Pain outcomes (intensity, fear, and tolerance) were recorded for each sibling, and the behaviour of the observing and participating siblings during the CPT were coded as attending, nonattending, and coping/encouragement. Structural equation modelling, using the actor-partner interdependence model, was conducted to analyse the dyadic data. While participating in the CPT with their sibling present, greater levels of warmth and positivity in the sibling relationship were related to children engaging in more nonattending behaviours and less attending behaviours. Greater levels of attending behaviours by the observing child was related to the sibling having a lower pain tolerance, and greater levels of coping/encouragement behaviours by the observing child was related to the sibling reporting greater pain intensity and fear during the CPT. Children with warmer/positive sibling relationships were more likely to respond to acute pain by shifting the focus away from their pain experience (eg, through distraction) when a sibling was present. Pain-focused behaviours by an observing sibling are related to greater child pain and fear during experimental pain.

Dusp3 deletion in mice promotes experimental lung tumour metastasis in a macrophage dependent manner.

Vaccinia-H1 Related (VHR) dual-specificity phosphatase, or DUSP3, plays an important role in cell cycle regulation and its expression is altered in several human cancers. In mouse model, DUSP3 deletion prevents neo-angiogenesis and b-FGF-induced microvessel outgrowth. Considering the importance of angiogenesis in metastasis formation, our study aimed to investigate the role of DUSP3 in tumour cell dissemination. Using a Lewis Lung carcinoma (LLC) experimental metastasis model, we observed that DUSP3-/- mice developed larger lung metastases than littermate controls. DUSP3-/- bone marrow transfer to lethally irradiated DUSP3+/+ mice was sufficient to transfer the phenotype to DUSP3+/+ mice, indicating that hematopoietic cells compartment was involved in the increased tumour cell dissemination to lung tissues. Interestingly, we found a higher percentage of tumour-promoting Ly6Cint macrophages in DUSP3-/- LLC-bearing lung homogenates that was at least partially due to a better recruitment of these cells. This was confirmed by 1) the presence of higher number of the Ly6Bhi macrophages in DUSP3-/- lung homogenates and by 2) the better migration of DUSP3-/- bone marrow sorted monocytes, peritoneal macrophages and bone marrow derived macrophages (BMDMs), compared to DUSP3+/+ monocytes, macrophages and BMDMs, in response to LLC-conditioned medium. Our study demonstrates that DUSP3 phosphatase plays a key role in metastatic growth through a mechanism involving the recruitment of macrophages towards LLC-bearing lungs.

Dual-Specificity Phosphatase 3 Deletion Protects Female, but Not Male, Mice from Endotoxemia-Induced and Polymicrobial-Induced Septic Shock.

Dual-specificity phosphatase 3 (DUSP3) is a small phosphatase with poorly known physiological functions and for which only a few substrates are known. Using knockout mice, we recently reported that DUSP3 deficiency confers resistance to endotoxin- and polymicrobial-induced septic shock. We showed that this protection was macrophage dependent. In this study, we further investigated the role of DUSP3 in sepsis tolerance and showed that the resistance is sex dependent. Using adoptive-transfer experiments and ovariectomized mice, we highlighted the role of female sex hormones in the phenotype. Indeed, in ovariectomized females and in male mice, the dominance of M2-like macrophages observed in DUSP3-/- female mice was reduced, suggesting a role for this cell subset in sepsis tolerance. At the molecular level, DUSP3 deletion was associated with estrogen-dependent decreased phosphorylation of ERK1/2 and Akt in peritoneal macrophages stimulated ex vivo by LPS. Our results demonstrate that estrogens may modulate M2-like responses during endotoxemia in a DUSP3-dependent manner.

Put on a happy face! Inhibitory control and socioemotional knowledge predict emotion regulation in 5- to 7-year-olds.

Children's developing capacity to regulate emotions may depend on individual characteristics and other abilities, including age, sex, inhibitory control, theory of mind, and emotion and display rule knowledge. In the current study, we examined the relations between these variables and children's (N=107) regulation of emotion in a disappointing gift paradigm as well as their relations with the amount of effort to control emotion children exhibited after receiving the disappointing gift. Regression analyses were also conducted to identify unique predictors. Children's understanding of others' emotions and emotion display rules, as well as their inhibitory control skills, emerged as significant correlates of emotion regulation and predicted children's responses to the disappointing gift even after controlling for other relevant variables. Age and inhibitory control significantly predicted the amount of overt effort that went into regulating emotions, as did emotion knowledge (albeit only marginally). Together, findings suggest that effectively regulating emotions requires (a) knowledge of context-appropriate emotions along with (b) inhibitory skills to implement that knowledge.

Cognitive flexibility among individuals with Down syndrome: assessing the influence of verbal and nonverbal abilities.

The influences of verbal mental age (VMA) and performance mental age (PMA) on cognitive flexibility were examined among a group of participants with Down syndrome (DS), in order to disentangle the relative contributions of each. The impaired cognitive flexibility typically observed among individuals with DS in combination with uneven VMA and PMA development suggests an opportunity to further understand the developmental relationship between VMA, PMA, and cognitive flexibility. We examined the performance of 22 participants with DS on the Flexible Item Selection Task (FIST), used for measuring cognitive flexibility among preschoolers. Partial correlations revealed that only VMA was related to the FIST after controlling for PMA, highlighting the role of verbal abilities in the development of cognitive flexibility.

Selective attention to emotional pictures as a function of gambling motives in problem and nonproblem gamblers.

Problem gambling may reflect a maladaptive means of fulfilling specific affect-regulation motives, such as enhancing positive affect or coping with negative affect. Research with clinical populations indicates that disorders with prominent affective symptoms are characterized by attentional biases for symptom-congruent information. Thus, we assessed whether problem gamblers with enhancement motives for gambling would demonstrate attentional biases for positive emotional information, relative to other types of emotional information, and problem gamblers with coping motives for gambling would demonstrate attentional biases for negative emotional information, compared with other types of emotional information. In addition, we expected motive-congruent biases to be stronger in problem gamblers than nonproblem gamblers. To test these hypotheses, problem and nonproblem gamblers received an emotional orienting task in which neutral, negative, and positive pictorial cues appeared to one side of the computer screen, followed by target words in cued or uncued locations. In a look-away condition, participants had to shift attention away from pictures to respond to predominantly uncued targets, whereas in a look-toward condition, they had to orient to pictures to categorize predominantly cued targets. The results revealed motive-congruent orienting biases and disengagement lags for emotional pictures in problem gamblers. The link between motives and affective biases was less apparent in nonproblem gamblers. Results suggest that attentional measures may provide a useful complement to the subjective methodologies that are typically employed in studying problem gamblers.

Categorical flexibility in preschoolers: contributions of conceptual knowledge and executive control.

The current study evaluated the relative roles of conceptual knowledge and executive control on the development of categorical flexibility, the ability to switch between simultaneously available but conflicting categorical representations of an object. Experiment 1 assessed conceptual knowledge and executive control together; Experiment 2 differentiated conceptual knowledge from costly executive processes. In Experiment 1, 3- to 5-year-olds were given a three-choice (taxonomic, thematic, and nonassociate) match-to-sample task and asked to match two associates. In Experiment 2, same-aged children were assessed on another match-to-sample task that reduced executive costs by presenting thematic and taxonomic associates on separate trials. By comparing performance across tasks, age-related changes resulting from conceptual knowledge and executive control indicated that conceptual knowledge of superordinate relations showed gains between 3 and 4 years, whereas gains in executive control were seen between 4 and 5 years, suggesting a décalage in the development of conceptual and executive processes underlying categorical flexibility.

Social information processing in elementary-school aged children with ADHD: medication effects and comparisons with typical children.

Examined social information processing (SIP) in medicated and unmedicated children with ADHD and in controls. Participants were 75 children (56 boys, 19 girls) aged 6-12 years, including 41 children with ADHD and 34 controls. Children were randomized into medication conditions such that 20 children with ADHD participated after receiving placebo and 21 participated after receiving methylphenidate (MPH). Children were shown scenarios depicting peer interactions and asked to interpret each scenario and to generate possible responses to the scenario. Results showed that children with ADHD who received MPH generated more hostile responses to provocation than controls, but children with ADHD on placebo did not. Results also showed that children with ADHD regardless of medication generated more hostile responses to provocation than to peer entry, whereas controls did not. Findings suggest that children with ADHD generate more aggressive responses to provocation than controls and that this may be exacerbated by administration of MPH. Limitations and future directions are discussed.

Subtypes of aggression in children with attention deficit hyperactivity disorder: medication effects and comparison with typical children.

We examined aggressive behavior in 6- to 12-year-old children, including 20 children with attention deficit hyperactivity disorder (ADHD) on stimulant medication, 19 children with ADHD on placebo (n = 19), and 32 controls. Children completed a laboratory provocation task designed to measure hostile, instrumental, reactive, and proactive aggression. Children in the ADHD-placebo group exhibited increased proactive and reactive aggression following high levels of provocation compared to controls. On the last trials, instrumental aggression dissipated for controls and hostile aggression dissipated for children in the ADHD-placebo group. Both instrumental and hostile aggression dissipated for children in the ADHD-medication group.