14 research outputs found
A Novel GUSB Mutation in Brazilian Terriers with Severe Skeletal Abnormalities Defines the Disease as Mucopolysaccharidosis VII
Peer reviewe
Cholesterol Crystals Activate the NLRP3 Inflammasome in Human Macrophages: A Novel Link between Cholesterol Metabolism and Inflammation
Chronic inflammation of the arterial wall is a key element in the pathogenesis of atherosclerosis, yet the factors that trigger and sustain the inflammation remain elusive. Inflammasomes are cytoplasmic caspase-1-activating protein complexes that promote maturation and secretion of the proinflammatory cytokines interleukin(IL)-1beta and IL-18. The most intensively studied inflammasome, NLRP3 inflammasome, is activated by diverse substances, including crystalline and particulate materials. As cholesterol crystals are abundant in atherosclerotic lesions, and IL-1beta has been linked to atherogenesis, we explored the possibility that cholesterol crystals promote inflammation by activating the inflammasome pathway.Here we show that human macrophages avidly phagocytose cholesterol crystals and store the ingested cholesterol as cholesteryl esters. Importantly, cholesterol crystals induced dose-dependent secretion of mature IL-1beta from human monocytes and macrophages. The cholesterol crystal-induced secretion of IL-1beta was caspase-1-dependent, suggesting the involvement of an inflammasome-mediated pathway. Silencing of the NLRP3 receptor, the crucial component in NLRP3 inflammasome, completely abolished crystal-induced IL-1beta secretion, thus identifying NLRP3 inflammasome as the cholesterol crystal-responsive element in macrophages. The crystals were shown to induce leakage of the lysosomal protease cathepsin B into the cytoplasm and inhibition of this enzyme reduced cholesterol crystal-induced IL-1beta secretion, suggesting that NLRP3 inflammasome activation occurred via lysosomal destabilization.The cholesterol crystal-induced inflammasome activation in macrophages may represent an important link between cholesterol metabolism and inflammation in atherosclerotic lesions
Distribution and medical impact of loss-of-function variants in the Finnish founder population.
Exome sequencing studies in complex diseases are challenged by the allelic heterogeneity, large number and modest effect sizes of associated variants on disease risk and the presence of large numbers of neutral variants, even in phenotypically relevant genes. Isolated populations with recent bottlenecks offer advantages for studying rare variants in complex diseases as they have deleterious variants that are present at higher frequencies as well as a substantial reduction in rare neutral variation. To explore the potential of the Finnish founder population for studying low-frequency (0.5-5%) variants in complex diseases, we compared exome sequence data on 3,000 Finns to the same number of non-Finnish Europeans and discovered that, despite having fewer variable sites overall, the average Finn has more low-frequency loss-of-function variants and complete gene knockouts. We then used several well-characterized Finnish population cohorts to study the phenotypic effects of 83 enriched loss-of-function variants across 60 phenotypes in 36,262 Finns. Using a deep set of quantitative traits collected on these cohorts, we show 5 associations (p<5×10⁻⁸) including splice variants in LPA that lowered plasma lipoprotein(a) levels (P = 1.5×10⁻¹¹⁷). Through accessing the national medical records of these participants, we evaluate the LPA finding via Mendelian randomization and confirm that these splice variants confer protection from cardiovascular disease (OR = 0.84, P = 3×10⁻⁴), demonstrating for the first time the correlation between very low levels of LPA in humans with potential therapeutic implications for cardiovascular diseases. More generally, this study articulates substantial advantages for studying the role of rare variation in complex phenotypes in founder populations like the Finns and by combining a unique population genetic history with data from large population cohorts and centralized research access to National Health Registers
Longitudinal associations of student–teacher relationships and behavioural and emotional strengths on academic achievement
Positive student–teacher relationships are related to students’ academic achievement and behavioural and emotional adjustment. How a student’s behavioural and emotional strengths are associated with these relationships and how the relationships influence students’ academic performance remains unknown. We examined this framework using a cross-lagged panel model with a group of Finnish students and their parents from Grade 5 to Grade 7. The results revealed that the parents rated behavioural and emotional strengths are stable over a 1-year (r = .78) and 2-year (r = .71) period and that students’ perceptions of student–teacher relationships demonstrated greater change over time (r’s = .54, .35). Behavioural and emotional strengths demonstrated a positive relationship with student–teacher relationships as well as academic achievement (β = .39, p < .01). Strengths were also indirectly associated with academic achievement via student–teacher relationships. Study limitations, implications and future research are discussed.peerReviewe
Longitudinal associations of student–teacher relationships and behavioural and emotional strengths on academic achievement
A multidimensional adapted process model of teaching
Abstract
In the present study, we aimed to specify the key competence domains perceived to be critical for the teaching profession and depict them as a comprehensive teacher competence model. An expert panel that included representatives from seven units providing university-based initial teacher education in Finland carried out this process. To produce an active construction of a shared understanding and an interpretation of the discourse in the field, the experts reviewed literature on teaching. The resulting teacher competence model, the multidimensional adapted process model of teaching (MAP), represents a collective conception of the relevant empirical literature and prevailing discourses on teaching. The MAP is based on Blömeke et al.’s, Zeitschrift für Psychologie, 223, 3–13, (2015) model which distinguishes among teacher competences (referring to effective performance of teachers’ work), competencies (knowledge, skills, and other individual competencies underlying and enabling effective teaching), and situation-specific skills of perceiving, interpreting, and making decisions in situations involving teaching and learning. The implications of the MAP for teacher education and student selection for initial teacher education are discussed