Methylomic markers of persistent childhood asthma: a longitudinal study of asthma-discordant monozygotic twins.

This is a freely-available open access publication. Please cite the published version which is available via the DOI link in this record.Asthma is the most common chronic inflammatory disorder in children. The aetiology of asthma pathology is complex and highly heterogeneous, involving the interplay between genetic and environmental risk factors that is hypothesized to involve epigenetic processes. Our aim was to explore whether methylomic variation in early childhood is associated with discordance for asthma symptoms within monozygotic (MZ) twin pairs recruited from the Environmental Risk (E-Risk) longitudinal twin study. We also aimed to identify differences in DNA methylation that are associated with asthma that develops in childhood and persists into early adulthood as these may represent useful prognostic biomarkers. RESULTS: We examined genome-wide patterns of DNA methylation in buccal cell samples collected from 37 MZ twin pairs discordant for asthma at age 10. DNA methylation at individual CpG sites demonstrated significant variability within discordant MZ twin pairs with the top-ranked nominally significant differentially methylated position (DMP) located in the HGSNAT gene. We stratified our analysis by assessing DNA methylation differences in a sub-group of MZ twin pairs who remained persistently discordant for asthma at age 18. The top-ranked nominally significant DMP associated with persisting asthma is located in the vicinity of the HLX gene, which has been previously implicated in childhood asthma. CONCLUSIONS: We identified DNA methylation differences associated with childhood asthma in peripheral DNA samples from discordant MZ twin pairs. Our data suggest that differences in DNA methylation associated with childhood asthma which persists into early adulthood are distinct from those associated with asthma which remits.Medical Research Council (MRC)National Institute of Child Health and Development (NICHD)American Asthma FoundationMRC Centenary Awar

Grip Force Reveals the Context Sensitivity of Language-Induced Motor Activity during “Action Words

Studies demonstrating the involvement of motor brain structures in language processing typically focus on \ud time windows beyond the latencies of lexical-semantic access. Consequently, such studies remain inconclusive regarding whether motor brain structures are recruited directly in language processing or through post-linguistic conceptual imagery. In the present study, we introduce a grip-force sensor that allows online measurements of language-induced motor activity during sentence listening. We use this tool to investigate whether language-induced motor activity remains constant or is modulated in negative, as opposed to affirmative, linguistic contexts. Our findings demonstrate that this simple experimental paradigm can be used to study the online crosstalk between language and the motor systems in an ecological and economical manner. Our data further confirm that the motor brain structures that can be called upon during action word processing are not mandatorily involved; the crosstalk is asymmetrically\ud governed by the linguistic context and not vice versa

Sustainable Implementation of Interprofessional Education Using an Adoption Model Framework

Interprofessional education (IPE) is a growing focus for educators in health professional academic programs. Recommendations to successfully implement IPE are emerging in the literature, but there remains a dearth of evidence informing the bigger challenges of sustainability and scalability. Transformation to interprofessional education for collaborative person-centred practice (IECPCP) is complex and requires “harmonization of motivations” within and between academia, governments, healthcare delivery sectors, and consumers. The main lesson learned at the University of Manitoba was the value of using a formal implementation framework to guide its work. This framework identifies key factors that must be addressed at the micro, meso, and macro levels and emphasizes that interventions occurring only at any single level will likely not lead to sustainable change. This paper describes lessons learned when using the framework and offers recommendations to support other institutions in their efforts to enable the roll out and integration of IECPCP.  L’éducation interprofessionnelle (EIP) fait l’objet d’un intérêt grandissant parmi les enseignants des programmes universitaires pour professionnels de la santé. Bien que des recommandations pour une mise en œuvre réussie de l’EIP fassent leur apparition dans les publications académiques, il existe encore un manque de données probantes sur les défis plus importants que représentent la durabilité et la modularité. La transformation de l’EIP vers une pratique interprofessionnelle et collaborative axée sur la personne (PPCAP) est complexe et nécessite l’« harmonisation des motivations » entre différents secteurs (universitaire, gouvernemental, des soins de la santé et de la consommation), et au sein de ceux-ci. La principale leçon qu’a reçue l’Université du Manitoba a été la nécessité d’employer une structure formelle de mise en place pour diriger ses travaux. Cette structure identifie les caractéristiques essentielles que l’on doit aborder à petite, moyenne et grande échelle et souligne l’importance de ces interventions à plusieurs niveaux, sans quoi le changement n’est pas durable. Cet article décrit les leçons apprises avec la structure et propose des recommandations afin d’aider d’autres institutions dans leurs efforts de création et d’intégration de la PPCAP

Quantifying Interprofessional Learning In Health Professional Programs: The University of Manitoba Experience

Internationally, a growing number of interprofessional education (IPE) offices are being established within academic institutions. However, few are applying educational improvement methodologies to evaluate and improve the interprofessional (IP) learning opportunities offered. The University of Manitoba IPE Initiative was established in 2008 to facilitate the development of IP learning opportunities for pre-licensure learners. The research question for this secondary analysis was: what, if any, changes in the number and attributes of IP learning opportunities occurred in the academic year 2008–2009 compared to 2011–2012? The Points for Interprofessional Scoring (PIPES) tool was used to quantify the attributes of each IP learning opportunity. Most notably in 2012, eight (73%) of 11 IP learning opportunities achieved the highest PIPES score (> 55), compared to only four (36%) in 2009. The concept of the PIPES score is introduced as an educational improvement strategy and a potential predictor of achieving the desired educational outcome: collaborative competence.   Les institutions académiques du monde accueillent de plus en plus de bureaux d’éducation interprofessionnelle. Par contre, très peu mettent en pratique des méthodologies d’amélioration de l’enseignement pour évaluer et améliorer ces occasions d’apprentissage interprofessionnelles (OAI). En 2008, afin de faciliter la création de telles occasions pour les apprenants avant l’obtention de leur permis de pratique, l’Université du Manitoba lançait l’initiative d’éducation interprofessionnelle. Elle voulait savoir s’il existait des différences dans les nombres et les attributs des OAI entre les années 2008-2009 et 2011-2012. Les attributs de chaque OAI ont été quantifiés en utilisant une version adaptée de l’outil « Points for Interprofessional Scoring » ou (PIPEs). En 2012 notamment, 73 % d’occasions d’apprentissage interprofessionnel (soit 8 sur 11) avait atteint le score PIPES (>55) le plus élevé, comparativement à 36 % en 2009. Le concept du score « PIPES » est présenté comme une stratégie d’amélioration du secteur de l’éducation et comme un potentiel de prédiction du résultat éducationnel désiré : une compétence collaborative

Human TLR1 Deficiency Is Associated with Impaired Mycobacterial Signaling and Protection from Leprosy Reversal Reaction

Toll-like receptors (TLRs) are important regulators of the innate immune response to pathogens, including Mycobacterium leprae, which is recognized by TLR1/2 heterodimers. We previously identified a transmembrane domain polymorphism, TLR1_T1805G, that encodes an isoleucine to serine substitution and is associated with impaired signaling. We hypothesized that this TLR1 SNP regulates the innate immune response and susceptibility to leprosy. In HEK293 cells transfected with the 1805T or 1805G variant and stimulated with extracts of M. leprae, NF-κB activity was impaired in cells with the 1805G polymorphism. We next stimulated PBMCs from individuals with different genotypes for this SNP and found that 1805GG individuals had significantly reduced cytokine responses to both whole irradiated M. leprae and cell wall extracts. To investigate whether TLR1 variation is associated with clinical presentations of leprosy or leprosy immune reactions, we examined 933 Nepalese leprosy patients, including 238 with reversal reaction (RR), an immune reaction characterized by a Th1 T cell cytokine response. We found that the 1805G allele was associated with protection from RR with an odds ratio (OR) of 0.51 (95% CI 0.29–0.87, p = 0.01). Individuals with 1805 genotypes GG or TG also had a reduced risk of RR in comparison to genotype TT with an OR of 0.55 (95% CI 0.31–0.97, p = 0.04). To our knowledge, this is the first association of TLR1 with a Th1-mediated immune response. Our findings suggest that TLR1 deficiency influences adaptive immunity during leprosy infection to affect clinical manifestations such as nerve damage and disability

Sex-specific associations between placental corticotropin releasing hormone and problem behaviors in childhood.

Placental corticotropin-releasing hormone (pCRH) is a neuroactive peptide produced in high concentrations in mid-late pregnancy, during key periods of fetal brain development. Some evidence suggests that higher pCRH exposure during gestation is associated with adverse neurodevelopment, particularly in female offspring. In 858 mother-child dyads from the sociodemographically diverse CANDLE cohort (Memphis, TN), we examined: (1) the slope of pCRH rise in mid-late pregnancy and (2) estimated pCRH at delivery as a measure of cumulative prenatal exposure. When children were 4 years-old, mothers reported on problem behaviors using the Child Behavior Checklist (CBCL) and cognitive performance was assessed by trained psychologists using the Stanford-Binet Intelligence Scales. We fitted linear regression models examining pCRH in relation to behavioral and cognitive performance measures, adjusting for covariates. Using interaction models, we evaluated whether associations differed by fetal sex, breastfeeding, and postnatal neighborhood opportunity. In the full cohort, log-transformed pCRH measures were not associated with outcomes; however, we observed sex differences in some models (interaction p-values≤0.01). In male offspring, an interquartile (IQR) increase in pCRH slope (but not estimated pCRH at delivery), was positively associated with raw Total (β=3.06, 95%CI: 0.40, 5.72), Internalizing (β=0.89, 95%CI: 0.03, 1.76), and Externalizing (β=1.25, 95%CI: 0.27, 2.22) Problem scores, whereas, in females, all associations were negative (Total Problems: β=-1.99, 95%CI: -3.89, -0.09; Internalizing: β=-0.82, 95%CI: -1.42, -0.23; Externalizing: β=-0.56, 95%CI: -1.34, 0.22). No associations with cognitive performance were observed nor did we observe moderation by breastfeeding or postnatal neighborhood opportunity. Our results provide further evidence that prenatal pCRH exposure may impact subsequent child behavior in sex-specific ways, however in contrast to prior studies suggesting adverse impacts in females, steeper mid-gestation pCRH rise was associated with more problem behaviors in males, but fewer in females

Methylomic markers of persistent childhood asthma: a longitudinal study of asthma-discordant monozygotic twins

Asthma is the most common chronic inflammatory disorder in children. The etiology of asthma pathology is complex and highly heterogeneous, involving the interplay between genetic and environmental risk factors that is hypothesized to involve epigenetic processes. Our aim was to explore whether methylomic variation in early childhood is associated with discordance for asthma symptoms within monozygotic (MZ) twin-pairs recruited from the Environmental Risk (E-Risk) longitudinal twin study. We also aimed to identify differences in DNA methylation that are associated with asthma that develops in childhood and persists into early adulthood as these may represent useful prognostic biomarkers

The Biological Deep Sea Hydrothermal Vent as a Model to Study Carbon Dioxide Capturing Enzymes

Deep sea hydrothermal vents are located along the mid-ocean ridge system, near volcanically active areas, where tectonic plates are moving away from each other. Sea water penetrates the fissures of the volcanic bed and is heated by magma. This heated sea water rises to the surface dissolving large amounts of minerals which provide a source of energy and nutrients to chemoautotrophic organisms. Although this environment is characterized by extreme conditions (high temperature, high pressure, chemical toxicity, acidic pH and absence of photosynthesis) a diversity of microorganisms and many animal species are specially adapted to this hostile environment. These organisms have developed a very efficient metabolism for the assimilation of inorganic CO2 from the external environment. In order to develop technology for the capture of carbon dioxide to reduce greenhouse gases in the atmosphere, enzymes involved in CO2 fixation and assimilation might be very useful. This review describes some current research concerning CO2 fixation and assimilation in the deep sea environment and possible biotechnological application of enzymes for carbon dioxide capture

Involvement of the Intrinsic/Default System in Movement-Related Self Recognition

The question of how people recognize themselves and separate themselves from the environment and others has long intrigued philosophers and scientists. Recent findings have linked regions of the ‘default brain’ or ‘intrinsic system’ to self-related processing. We used a paradigm in which subjects had to rely on subtle sensory-motor synchronization differences to determine whether a viewed movement belonged to them or to another person, while stimuli and task demands associated with the “responded self” and “responded other” conditions were precisely matched. Self recognition was associated with enhanced brain activity in several ROIs of the intrinsic system, whereas no differences emerged within the extrinsic system. This self-related effect was found even in cases where the sensory-motor aspects were precisely matched. Control conditions ruled out task difficulty as the source of the differential self-related effects. The findings shed light on the neural systems underlying bodily self recognition

The dispositionalist deity: how God creates laws and why theists should care

How does God govern the world? For many theists “laws of nature” play a vital role. But what are these laws, metaphysically speaking? I shall argue that laws of nature are not external to the objects they govern, but instead should be thought of as reducible to internal features of properties. Recent work in metaphysics and philosophy of science has revived a dispositionalist conception of nature, according to which nature is not passive, but active and dynamic. Disposition theorists see particulars as being internally powerful rather than being governed by external laws of nature, making external laws in effect ontologically otiose. I will argue that theists should prefer a dispositionalist ontology, since it leads them toward the theory of concurrentism in divine conservation, rather than occasionalism, and revives the distinction between internal and external teleology. God on this view does not govern the world through external laws of nature, but rather through internal aspects of powerful properties