Mobilising Knowledge through Global Partnerships to Support Research-informed Teaching: Five Models for Translational Research

Education Futures Collaboration Charity The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link.Improving the quality of teaching is of global concern: UNESCO’s Sustainable Development Goal (SDG) 4c in the Education 2030: Framework for Action calls for high quality teaching for all. The OECD challenges the education system to improve Knowledge Management. JET’s (2015) special issue: Translational Research (TR) and Knowledge Mobilisation in Teacher Education introduced the concept of ‘translational’ or ‘theory to practice’ research - well-established in medicine but not in education. Five TR models were subsequently developed by the MESH charity’s international network with organisations in South Africa, Bangladesh, Australia, Pakistan, UK. These distinct models engage 1) university staff and teachers 2) subject associations, 3) research units, 4) an international NGO working in crisis settings, 5) PhD tutors and students. Each model shares common features forming the MESH Translational Research methodology introduced in this article. A TR repository is part of the MESH knowledge mobilisation strategy giving teachers access to research summaries which, overtime, accumulate knowledge. TR publications called MESHGuides (www.meshguides.org) complement existing forms of publication. This article proposes the MESH TR methodology as one affordable and scalable solution to OECD and UNESCO’s challenges of keeping teachers up-to-date and making new knowledge accessible to teachers regardless of location

Integrative analysis of genomic variants reveals new associations of candidate haploinsufficient genes with congenital heart disease

Congenital Heart Disease (CHD) affects approximately 7-9 children per 1000 live births. Numerous genetic studies have established a role for rare genomic variants at the copy number variation (CNV) and single nucleotide variant level. In particular, the role of de novo mutations (DNM) has been highlighted in syndromic and non-syndromic CHD. To identify novel haploinsufficient CHD disease genes we performed an integrative analysis of CNVs and DNMs identified in probands with CHD including cases with sporadic thoracic aortic aneurysm (TAA). We assembled CNV data from 7,958 cases and 14,082 controls and performed a gene-wise analysis of the burden of rare genomic deletions in cases versus controls. In addition, we performed mutation rate testing for DNMs identified in 2,489 parent-offspring trios. Our combined analysis revealed 21 genes which were significantly affected by rare genomic deletions and/or constrained non-synonymous de novo mutations in probands. Fourteen of these genes have previously been associated with CHD while the remaining genes (FEZ1, MYO16, ARID1B, NALCN, WAC, KDM5B and WHSC1) have only been associated in singletons and small cases series, or show new associations with CHD. In addition, a systems level analysis revealed shared contribution of CNV deletions and DNMs in CHD probands, affecting protein-protein interaction networks involved in Notch signaling pathway, heart morphogenesis, DNA repair and cilia/centrosome function. Taken together, this approach highlights the importance of re-analyzing existing datasets to strengthen disease association and identify novel disease genes

Rare variants in KDR, encoding VEGF Receptor 2, are associated with tetralogy of Fallot

Purpose Rare genetic variants in KDR, encoding the vascular endothelial growth factor receptor 2 (VEGFR2), have been reported in patients with tetralogy of Fallot (TOF). However, their role in disease causality and pathogenesis remains unclear. Methods We conducted exome sequencing in a familial case of TOF and large-scale genetic studies, including burden testing, in >1,500 patients with TOF. We studied gene-targeted mice and conducted cell-based assays to explore the role of KDR genetic variation in the etiology of TOF. Results Exome sequencing in a family with two siblings affected by TOF revealed biallelic missense variants in KDR. Studies in knock-in mice and in HEK 293T cells identified embryonic lethality for one variant when occurring in the homozygous state, and a significantly reduced VEGFR2 phosphorylation for both variants. Rare variant burden analysis conducted in a set of 1,569 patients of European descent with TOF identified a 46-fold enrichment of protein-truncating variants (PTVs) in TOF cases compared to controls (P = 7 x 10(-11)). Conclusion Rare KDR variants, in particular PTVs, strongly associate with TOF, likely in the setting of different inheritance patterns. Supported by genetic and in vivo and in vitro functional analysis, we propose loss-of-function of VEGFR2 as one of the mechanisms involved in the pathogenesis of TOF.Developmen

Food availability, accessibility and dietary practices during the COVID-19 pandemic: a multi-country survey

Objective: To investigate the perceived effects of the coronavirus disease (COVID-19) pandemic lockdown measures on food availability, accessibility, dietary practices and strategies used by participants to cope with these measures. Design: We conducted a cross-sectional multi-country online survey between May and July 2020. We used a study-specific questionnaire mainly based on the adaptation of questions to assess food security and coping strategies from the World Food Programme’s ‘Emergency Food Security Assessment’ and ‘The Coping Strategy Index’. Setting: The questionnaire was hosted online using Google Forms and shared using social media platforms. Participants: A total of 1075 adult participants from eighty-two countries completed the questionnaire. Results: As a prelude to COVID-19 lockdowns, 62·7 % of the participants reported to have stockpiled food, mainly cereals (59·5 % of the respondents) and legumes (48·8 %). An increase in the prices of staples, such as cereals and legumes, was widely reported. Price increases have been identified as an obstacle to food acquisition by 32·7 % of participants. Participants reported having lesser variety (50·4 %), quality (30·2 %) and quantity (39·2 %) of foods, with disparities across regions. Vulnerable groups were reported to be facing some struggle to acquire adequate food, especially people with chronic diseases (20·2 %), the elderly (17·3 %) and children (14·5 %). To cope with the situation, participants mostly relied on less preferred foods (49 %), reduced portion sizes (30 %) and/or reduced the number of meals (25·7 %). Conclusions: The COVID-19 pandemic negatively impacted food accessibility and availability, altered dietary practices and worsened the food insecurity situation, particularly in the most fragile regions

Extensive identification of genes involved in congenital and structural heart disorders and cardiomyopathy

Clinical presentation of congenital heart disease is heterogeneous, making identification of the disease-causing genes and their genetic pathways and mechanisms of action challenging. By using in vivo electrocardiography, transthoracic echocardiography and microcomputed tomography imaging to screen 3,894 single-gene-null mouse lines for structural and functional cardiac abnormalities, here we identify 705 lines with cardiac arrhythmia, myocardial hypertrophy and/or ventricular dilation. Among these 705 genes, 486 have not been previously associated with cardiac dysfunction in humans, and some of them represent variants of unknown relevance (VUR). Mice with mutations in Casz1, Dnajc18, Pde4dip, Rnf38 or Tmem161b genes show developmental cardiac structural abnormalities, with their human orthologs being categorized as VUR. Using UK Biobank data, we validate the importance of the DNAJC18 gene for cardiac homeostasis by showing that its loss of function is associated with altered left ventricular systolic function. Our results identify hundreds of previously unappreciated genes with potential function in congenital heart disease and suggest causal function of five VUR in congenital heart disease

Integrative analysis of genomic variants reveals new associations of candidate haploinsufficient genes with congenital heart disease

Numerous genetic studies have established a role for rare genomic variants in Congenital Heart Disease (CHD) at the copy number variation (CNV) and de novo variant (DNV) level. To identify novel haploinsufficient CHD disease genes, we performed an integrative analysis of CNVs and DNVs identified in probands with CHD including cases with sporadic thoracic aortic aneurysm. We assembled CNV data from 7,958 cases and 14,082 controls and performed a gene-wise analysis of the burden of rare genomic deletions in cases versus controls. In addition, we performed variation rate testing for DNVs identified in 2,489 parent-offspring trios. Our analysis revealed 21 genes which were significantly affected by rare CNVs and/or DNVs in probands. Fourteen of these genes have previously been associated with CHD while the remaining genes (FEZ1, MYO16, ARID1B, NALCN, WAC, KDM5B and WHSC1) have only been associated in small cases series or show new associations with CHD. In addition, a systems level analysis revealed affected protein-protein interaction networks involved in Notch signaling pathway, heart morphogenesis, DNA repair and cilia/centrosome function. Taken together, this approach highlights the importance of re-analyzing existing datasets to strengthen disease association and identify novel disease genes and pathways