Spreading of perturbations in myosin group kinetics along actin filaments

Global changes in the state of spatially distributed systems can often be traced back to perturbations that arise locally. Whether such local perturbations grow into global changes depends on the system geometry and the spatial spreading of these perturbations. Here, we investigate how different spreading behaviors of local perturbations determine their global impact in 1-dimensional systems of different size. Specifically, we assessed sliding arrest events in in vitro motility assays where myosins propel actin, and simulated the underlying mechanochemistry of myosins that bind along the actin filament. We observed spontaneous sliding arrest events that occurred more frequently for shorter actin filaments. This observation could be explained by spontaneous local arrest of myosin kinetics that stabilizes once it spreads throughout an entire actin filament. When we introduced intermediate concentrations of the actin cross-linker filamin, longer actin was arrested more frequently. This observation was reproduced by simulations where filamin binding induces persistent local arrest of myosin kinetics, which subsequently spreads throughout the actin filament. A spin chain model with nearest-neighbor coupling reproduced key features of our experiments and simulations, thus extending to other linear systems with nearest-neighbor coupling the following conclusions: 1) perturbations that are persistent only once they spread throughout the system are more effective in smaller systems, and 2) perturbations that are persistent upon their establishment are more effective in larger systems. Beyond these general conclusions, our work also provides a theoretical model of collective myosin kinetics with a finite range of mechanical coupling along the actin filament

Associations between Children's Genetic Susceptibility to Obesity, Infant's Appetite and Parental Feeding Practices in Toddlerhood.

Previous findings suggest that parental feeding practices may adapt to children's eating behavior and sex, but few studies assessed these associations in toddlerhood. We aimed to study the associations between infant's appetite or children's genetic susceptibility to obesity and parental feeding practices. We assessed infant's appetite (three-category indicator: low, normal or high appetite, labelled 4-to-24-month appetite) and calculated a combined obesity risk-allele score (genetic risk score of body mass index (BMI-GRS)) in a longitudinal study of respectively 1358 and 932 children from the EDEN cohort. Parental feeding practices were assessed at 2-year-follow-up by the CFPQ. Three of the five tested scores were used as continuous variables; others were considered as binary variables, according to the median. Associations between infant's appetite or child's BMI-GRS and parental feeding practices were assessed by linear and logistic regression models, stratified on child's sex if interactions were significant. 4-to-24-month appetite was positively associated with restrictive feeding practices among boys and girls. Among boys, high compared to normal 4-to-24-month appetite was associated with higher use of food to regulate child's emotions (OR [95% CI] = 2.24 [1.36; 3.68]). Child's BMI-GRS was not related to parental feeding practices. Parental feeding practices may adapt to parental perception of infant's appetite and child's sex

A Multi-Scale Approach to Airway Hyperresponsiveness: From Molecule to Organ

Airway hyperresponsiveness (AHR), a characteristic of asthma that involves an excessive reduction in airway caliber, is a complex mechanism reflecting multiple processes that manifest over a large range of length and time scales. At one extreme, molecular interactions determine the force generated by airway smooth muscle (ASM). At the other, the spatially distributed constriction of the branching airways leads to breathing difficulties. Similarly, asthma therapies act at the molecular scale while clinical outcomes are determined by lung function. These extremes are linked by events operating over intermediate scales of length and time. Thus, AHR is an emergent phenomenon that limits our understanding of asthma and confounds the interpretation of studies that address physiological mechanisms over a limited range of scales. A solution is a modular computational model that integrates experimental and mathematical data from multiple scales. This includes, at the molecular scale, kinetics, and force production of actin-myosin contractile proteins during cross-bridge and latch-state cycling; at the cellular scale, Ca2+ signaling mechanisms that regulate ASM force production; at the tissue scale, forces acting between contracting ASM and opposing viscoelastic tissue that determine airway narrowing; at the organ scale, the topographic distribution of ASM contraction dynamics that determine mechanical impedance of the lung. At each scale, models are constructed with iterations between theory and experimentation to identify the parameters that link adjacent scales. This modular model establishes algorithms for modeling over a wide range of scales and provides a framework for the inclusion of other responses such as inflammation or therapeutic regimes. The goal is to develop this lung model so that it can make predictions about bronchoconstriction and identify the pathophysiologic mechanisms having the greatest impact on AHR and its therapy

Early determinants of food liking among 5y-old children: a longitudinal study from the EDEN mother-child cohort

International audienceAbstractBackgroundIdentifying the determinants of child’s liking for different foods may help to prevent future choices of unhealthy food.ObjectiveTo study early-life food-related characteristics associated with child’s liking for different foods at 5y with a longitudinal study.Design1142 5y- old children completed a liking test for “fruit and vegetables”, “meat, fish and eggs”, desserts and cheese. Data related to maternal food intake before pregnancy, infant feeding during the first year of life, maternal feeding practices at 2y, child’s food intake at 3y, and child’s food neophobia from 1 to 4y were collected prospectively from the mother. The associations between these factors and child‘s liking for each category of foods were analyzed using structural equation modelling.ResultsHigh food neophobia at 4 y was related to lower child’s liking for all food groups. Maternal feeding practices at 2y were associated with liking for dessert: negatively for the practices allowing child to control his/her own food intake, positively for restriction of child’s food intake for weight reasons. Moreover, child’s food intake at 3y was positively associated with child’s liking for “fruit and vegetables” as well as for cheese. Finally, adherence to the infant feeding pattern “long breastfeeding, later introduction of main meal components and use of home-made products” was positively associated with child’s liking for meat/fish/eggs.ConclusionsFor all food groups, food neophobia was a common determinant of child’s liking for food at 5y, whereas other factors were associated with food liking for specific food groups

Association between genetic obesity susceptibility and mother-reported eating behaviour in children up to 5 years.

BACKGROUND: Many genetic polymorphisms identified by genome-wide association studies for adult body mass index (BMI) have been suggested to regulate food intake. OBJECTIVE: The objective was to study the associations between a genetic obesity risk score, appetitive traits, and growth of children up to age 5 years, with a longitudinal design. METHODS: In 1142 children from the Etude des Déterminants pre et post natals de la santé de l'ENfant (EDEN) birth cohort, a combined obesity risk-allele score (BMI genetic risk score [GRS]) was related to appetitive traits (energy intake up to 12 mo, a single item on appetite from 4 mo to 3 y, a validated appetite score at 5 y) using Poisson regressions with robust standard errors. The potential mediation of appetitive traits on the association between BMI-GRS and growth was assessed by the Sobel test. RESULTS: Children with a high BMI-GRS were more likely to have high energy intake at 1 year and high appetite at 2 and 5 years. High energy intake in infancy and high appetite from 1 year were related to higher subsequent BMI. High 2-year appetite seemed to partially mediate the associations between BMI-GRS and BMI from 2 to 5 years (all P ≤ 0.05). CONCLUSIONS: Genetic susceptibility to childhood obesity seems to be partially explained by appetitive traits in infancy, followed by an early childhood rise in BMI.The EDEN study is supported by Fondation pour la Recherche Médicale (FRM), French Ministry of Research: Federative Research Institutes and Cohort Program, INSERM Human Nutrition National Research Program, and Diabetes National Research Program (through a collaboration with the French Association of Diabetic Patients [AFD]), French Ministry of Health, French Agency for Environment Security (AFSSET), French National Institute for Population Health Surveillance (InVS), Paris‐Sud University, French National Institute for Health Education (INPES), Nestlé, Mutuelle Générale de l'Education Nationale (MGEN), French‐speaking Association for the Study of Diabetes and Metabolism (ALFEDIAM), National Agency for Research (ANR non‐thematic programme), and National Institute for Research in Public Health (IRESP: TGIR 2008 cohort in health programme). The genotyping was funded by a Collaborative Research Grant from the European Society for Paediatric Endocrinology. K.K.O. is supported by the Medical Research Council (unit program: MC_UU_12015/2)

Association between perinatal factors, genetic susceptibility to obesity and age at adiposity rebound in children of the EDEN mother–child cohort

Abstract: Background: Early adiposity rebound (AR) has been associated with increased risk of overweight or obesity in adulthood. However, little is known about early predictors of age at AR. We aimed to study the role of perinatal factors and genetic susceptibility to obesity in the kinetics of AR. Methods: Body mass index (BMI) curves were modelled by using mixed-effects cubic models, and age at AR was estimated for 1415 children of the EDEN mother–child cohort study. A combined obesity risk-allele score was calculated from genotypes for 27 variants identified by genome-wide association studies of adult BMI. Perinatal factors of interest were maternal age at delivery, parental education, parental BMI, gestational weight gain, maternal smoking during pregnancy, and newborn characteristics (sex, prematurity, and birth weight). We used a hierarchical level approach with multivariable linear regression model to investigate the association between these factors, obesity risk-allele score, and age at AR. Results: A higher genetic susceptibility to obesity score was associated with an earlier age at AR. At the most distal level of the hierarchical model, maternal and paternal educational levels were positively associated with age at AR. Children born to parents with higher BMI were more likely to exhibit earlier age at AR. In addition, higher gestational weight gain was related to earlier age at AR. For children born small for gestational age, the average age at AR was 88 [±39] days lower than for children born appropriate for gestational age and 91 [±56] days lower than for children born large for gestational age. Conclusion: The timing of AR seems to be an early childhood manifestation of the genetic susceptibility to adult obesity. We further identified low birth weight and gestational weight gain as novel predictors of early AR, highlighting the role of the intrauterine environment in the kinetics of adiposity

The Quebec Respiratory Health Network Biobank

The Quebec Respiratory Health Network (RHN) Biobank is a multi-site infrastructure located in the province of Quebec (Canada) to collect, store, and supply high-quality human biological specimens for research on respiratory diseases. The sample types are diverse (plasma, serum, buffy coat, primary lung cells, lung parenchyma, bronchial biopsies, polyps, others), disease-oriented, and mirror research activities conducted at each site. The biobank currently manages approximately 57,000 specimens from 8,000 research participants or patients treated by standard of care. Specimens’ inventory and corresponding clinical data from all sites are denominalized and linked to a centralized database with retrieval and querying capabilities. Archival samples from recent to nearly 20-year collections are available to academic and industry researchers studying respiratory diseases.   Funding statement: The infrastructure is supported by the Quebec Respiratory Health Network (rsr.chus.qc.ca) of the 'Fonds de la recherche du Québec – Santé' (FRQS), the research centers involved, local foundations and users of the biobank. Each biobank site is responsible to sustain their activities

The clinical application of genome-wide sequencing for monogenic diseases in Canada: Position statement of the Canadian College of medical geneticists

Purpose and scope: The aim of this Position Statement is to provide recommendations for Canadian medical geneticists, clinical laboratory geneticists, genetic counsellors and other physicians regarding the use of genome-wide sequencing of germline DNA in the context of clinical genetic diagnosis. This statement has been developed to facilitate the clinical translation and development of best practices for clinical genome-wide sequencing for genetic diagnosis of monogenic diseases in Canada; it does not address the clinical application of this technology in other fields such as molecular investigation of cancer or for population screening of healthy individuals. Methods of statement development: Two multidisciplinary groups consisting of medical geneticists, clinical laboratory geneticists, genetic counsellors, ethicists, lawyers and genetic researchers were assembled to review existing literature and guidelines on genome-wide sequencing for clinical genetic diagnosis in the context of monogenic diseases, and to make recommendations relevant to the Canadian context. The statement was circulated for comment to the Canadian College of Medical Geneticists (CCMG) membership-at-large and, following incorporation of feedback, approved by the CCMG Board of Directors. The CCMG is a Canadian organisation responsible for certifying medical geneticists and clinical laboratory geneticists, and for establishing professional and ethical standards for clinical genetics services in Canada. Results and conclusions: Recommendations include (1) clinical genome-wide sequencing is an appropriate approach in the diagnostic assessment of a patient for whom there is suspicion of a significant monogenic disease that is associated with a high degree of genetic heterogeneity, or where specific genetic tests have failed to provide a diagnosis; (2) until the benefits of reporting incidental findings are established, we do not endorse the intentional clinical analysis of disease-associated genes other than those linked to the primary indication; and (3) clinicians should provide genetic counselling and obtain informed consent prior to undertaking clinical genome-wide sequencing. Counselling should include discussion of the limitations of testing, likelihood and implications of diagnosis and incidental findings, and the potential need for further analysis to facilitate clinical interpretation, including studies performed in a research setting. These recommendations will be routinely reevaluated as knowledge of diagnostic and clinical utility of clinical genome-wide sequencing improves. While the document was developed to direct practice in Canada, the applicability of the statement is broader and will be of interest to clinicians and health jurisdictions internationally