Mast cell tryptase stimulates myoblast proliferation; a mechanism relying on protease-activated receptor-2 and cyclooxygenase-2

<p>Abstract</p> <p>Background</p> <p>Mast cells contribute to tissue repair in fibrous tissues by stimulating proliferation of fibroblasts through the release of tryptase which activates protease-activated receptor-2 (PAR-2). The possibility that a tryptase/PAR-2 signaling pathway exists in skeletal muscle cell has never been investigated. The aim of this study was to evaluate whether tryptase can stimulate myoblast proliferation and determine the downstream cascade.</p> <p>Methods</p> <p>Proliferation of L6 rat skeletal myoblasts stimulated with PAR-2 agonists (tryptase, trypsin and SLIGKV) was assessed. The specificity of the tryptase effect was evaluated with a specific inhibitor, APC-366. Western blot analyses were used to evaluate the expression and functionality of PAR-2 receptor and to assess the expression of COX-2. COX-2 activity was evaluated with a commercial activity assay kit and by measurement of PGF₂α production. Proliferation assays were also performed in presence of different prostaglandins (PGs).</p> <p>Results</p> <p>Tryptase increased L6 myoblast proliferation by 35% above control group and this effect was completely inhibited by APC-366. We confirmed the expression of PAR-2 receptor <it>in vivo </it>in skeletal muscle cells and in satellite cells and <it>in vitro </it>in L6 cells, where PAR-2 was found to be functional. Trypsin and SLIGKV increased L6 cells proliferation by 76% and 26% above control, respectively. COX-2 activity was increased following stimulation with PAR-2 agonist but its expression remained unchanged. Inhibition of COX-2 activity by NS-398 abolished the stimulation of cell proliferation induced by tryptase and trypsin. Finally, 15-deoxy-Δ-^12,14-prostaglandin J₂(15Δ-PGJ₂), a product of COX-2-derived prostaglandin D₂, stimulated myoblast proliferation, but not PGE₂and PGF₂α.</p> <p>Conclusions</p> <p>Taken together, our data show that tryptase can stimulate myoblast proliferation and this effect is part of a signaling cascade dependent on PAR-2 activation and on the downstream activation of COX-2.</p

Grammar-based column generation for personalized multi-activity shift scheduling

We present a branch-and-price algorithm to solve personalized multi-activity shift scheduling problems. The subproblems in the column generation method are formulated using grammars and solved with dynamic programming. The expressiveness of context-free grammars is exploited to easily model restrictions over shifts, allowing the branch-and-price algorithm to solve large-scale problem instances. We present computational experiments on two types of multi-activity shift scheduling problems and compare our approach with existing methods in the literature. These experiments show that our approach can efficiently solve large-scale instances and is flexible enough to model different classes of problems. </jats:p

JAMA Netw Open

IMPORTANCE: Although longitudinal studies have reported associations between early life factors (ie, in-utero/perinatal/infancy) and long-term suicidal behavior, they have concentrated on 1 or few selected factors, and established associations, but did not investigate if early-life factors predict suicidal behavior. OBJECTIVE: To identify and evaluate the ability of early-life factors to predict suicide attempt in adolescents and young adults from the general population. DESIGN, SETTING, AND PARTICIPANTS: This prognostic study used data from the Québec Longitudinal Study of Child Development, a population-based longitudinal study from Québec province, Canada. Participants were followed-up from birth to age 20 years. Random forest classification algorithms were developed to predict suicide attempt. To avoid overfitting, prediction performance indices were assessed across 50 randomly split subsamples, and then the mean was calculated. Data were analyzed from November 2019 to June 2020. EXPOSURES: Factors considered in the analysis included 150 variables, spanning virtually all early life domains, including pregnancy and birth information; child, parents, and neighborhood characteristics; parenting and family functioning; parents’ mental health; and child temperament, as assessed by mothers, fathers, and hospital birth records. MAIN OUTCOMES AND MEASURES: The main outcome was self-reported suicide attempt by age 20 years. RESULTS: Among 1623 included youths aged 20 years, 845 (52.1%) were female and 778 (47.9%) were male. Models show moderate prediction performance. The areas under the curve for the prediction of suicide attempt were 0.72 (95% CI, 0.71-0.73) for females and 0.62 (95% CI, 0.60-0.62) for males. The models showed low sensitivity (females, 0.50; males, 0.32), moderate positive predictive values (females, 0.60; males, 0.62), and good specificity (females, 0.76; males, 0.82) and negative predicted values (females, 0.75; males, 0.71). The most important factors contributing to the prediction included socioeconomic and demographic characteristics of the family (eg, mother and father education and age, socioeconomic status, neighborhood characteristics), parents’ psychological state (specifically parents’ antisocial behaviors) and parenting practices. Birth-related variables also contributed to the prediction of suicidal behavior (eg, prematurity). Sex differences were also identified, with family-related socioeconomic and demographic characteristics being the top factors for females and parents’ antisocial behavior being the top factor for males. CONCLUSIONS AND RELEVANCE: These findings suggest that early life factors contributed modestly to the prediction of suicidal behavior in adolescence and young adulthood. Although these factors may inform the understanding of the etiological processes of suicide, their utility in the long-term prediction of suicide attempt was limited.European Union’s Horizon 2020 research and innovation programm

Educational needs and type 1 diabetes mellitus: The voices of adolescents, parents and caregivers

Objectives: The aim of this study was to describe the needs of adolescents with type 1 diabetes mellitus for acquiring self-care and psychosocial skills for the progressive self-management of the disease, as a prelude to the development of an educational programme. The parents and health care professionals who supported young people were also asked to provide their insight into adolescents’ needs. Methods, design and setting: Qualitative focus group design with a thematic analysis informed by social-cognitive theory. Results: Findings highlight gaps and divergence in the perceived needs of adolescents engaged with in existing structured educational programmes. Suggestions for change to future programmes were identified, including the implementation of educational follow-ups outside of hospital settings and an educational programme open to family and friends to foster support from the adolescents’ social circle. The use of digital media is proposed as an on-demand (rather than planned) educational method. Conclusion: This study provides information relevant to the development of new educational programmes for adolescents with type 1 diabetes in the south of France. Future programmes should be structured so as to promote active participation by adolescents from the start of the programme through to its evaluation

Br J Psychiatry

Background Low birth weight is associated with adult mental health, cognitive and socioeconomic problems. However, the causal nature of these associations remains difficult to establish owing to confounding. Aims To estimate the contribution of birth weight to adult mental health, cognitive and socioeconomic outcomes using two-sample Mendelian randomisation, an instrumental variable approach strengthening causal inference. Method We used 48 independent single-nucleotide polymorphisms as genetic instruments for birth weight (genome-wide association studies’ total sample: n = 264 498) and considered mental health (attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder, bipolar disorder, major depressive disorder, obsessive–compulsive disorder, post-traumatic stress disorder (PTSD), schizophrenia, suicide attempt), cognitive (intelligence) and socioeconomic (educational attainment, income, social deprivation) outcomes. Results We found evidence for a contribution of birth weight to ADHD (OR for 1 s.d. unit decrease (~464 g) in birth weight, 1.29; 95% CI 1.03–1.62), PTSD (OR = 1.69; 95% CI 1.06–2.71) and suicide attempt (OR = 1.39; 95% CI 1.05–1.84), as well as for intelligence (β = −0.07; 95% CI −0.13 to −0.02) and socioeconomic outcomes, i.e. educational attainment (β = −0.05; 95% CI −0.09 to −0.01), income (β = −0.08; 95% CI −0.15 to −0.02) and social deprivation (β = 0.08; 95% CI 0.03–0.13). However, no evidence was found for a contribution of birth weight to the other examined mental health outcomes. Results were consistent across a wide range of sensitivity analyses. Conclusions These findings support the hypothesis that birth weight could be an important element on the causal pathway to mental health, cognitive and socioeconomic outcomes

Identifying environmental pathways between irritability during childhood and suicidal ideation and attempt in adolescence: findings from a 20-year population-based study

BACKGROUND: Irritable children are at increased risk of suicidal ideation and suicide attempt, but the underlying environmental mechanisms accounting for these associations are largely unknown. We aimed to investigate the mediating role of peer victimization and harsh parenting in the association between childhood irritability and adolescent suicidal ideation and attempt. METHOD: N = 1,483 participants from the Québec Longitudinal Study of Child Development followed up from 5 months until 20 years of age (2018) with annual or biannual assessments. Irritability was operationalized using assessments of teacher-reported temper tantrums and reactive aggression. Suicidal ideation and suicide attempt at ages 13, 15, 17, and 20 years were self-reported. Peer victimization (self-reported at age 13) and harsh parenting (mothers reported at age 13) were considered as potential mediators. RESULTS: We identified four trajectories of teacher-reported irritability symptoms from 6 to 12 years: low (74.8%), rising (12.9%), declining (7.3%), and persistent (4.9%). In adjusted models, children in the persistent and rising trajectories had, respectively, 2.81-fold (CI, 1.27-6.22) and 2.14-fold (CI, 1.20-3.81) increased odds of suicide attempt in adolescence, but not suicidal ideation. We found that a significant proportion of the association between irritability trajectories and suicide attempt was mediated by peer victimization (33% and 35% for rising and persistent, respectively), but there was no mediation via harsh parenting. CONCLUSIONS: Our findings suggest that peer victimization may be a key mechanism explaining the increased suicide attempt risk of children presenting with persistently high or increasing irritability. Interventions to reduce peer victimization may be helpful to reduce suicide risk among irritable children