Osteoarthritis causes pain and functional disability for over 500 million people worldwide. To develop disease-stratifying tools and modifying therapies, we need a better understanding of the ...molecular basis of the disease in relevant tissue and cell types. Here, we study primary cartilage and synovium from 115 patients with osteoarthritis to construct a deep molecular signature map of the disease. By integrating genetics with transcriptomics and proteomics, we discover molecular trait loci in each tissue type and omics level, identify likely effector genes for osteoarthritis-associated genetic signals and highlight high-value targets for drug development and repurposing. These findings provide insights into disease aetiopathology, and offer translational opportunities in response to the global clinical challenge of osteoarthritis.
Professional practice knowledge for beginning teachers involves grappling with the extent to which 'theory' and 'practice' should be evident. This thesis contributes an analysis of the particular way ...that the theory/practice relationship has been structured within the Teachers' Standards and the impact that this form has had on professional agency. The prioritisation of the observable is contrasted with manifestations that recognise that within a moment of practice, invisible yet durable knowledge structuring mechanisms are also present. In order to accord these mechanisms due agency, the concept of diffraction (the physical phenomenon of wave interference), (Barad 2007) was drawn upon to enrich Bernstein's (2000) social realist analysis of discourse. The data was gathered from a School Centered Initial Teacher Training (SCITT) provider in the West Midlands. The findings suggest that when context-transcending forms of knowledge specialise observable practices relationally, there is increased potential for coherent professional knowledges to result. Structuring professional practice knowledge in this way, contrasts with forms of knowledge particularisation evident within the Teachers' Standards. Therefore a challenge is offered to existing forms of professional practice knowledge structuring by drawing on quantum (entangling materials and minds) rather than Cartesian (separation of mind and matter) conceptions of time and space.
This article argues that an understanding of disciplinary knowledge production helps to underpin a conceptual structure for the humanities curriculum. This is important as a conceptual curriculum ...more overtly supports knowledge production for both pupils and teachers than one that is solely focused on propositional knowledge. It can mean the difference between learning isolated bits of information for recall that hold little significance to the learner and engaging with new information for a purpose. A concept orientated curriculum places an emphasis on understanding transferable ideas and principles, one in which deeper understanding or improved capability is the focus.
Abstract
Osteoarthritis is a prevalent, complex disease of the joints, and affects multiple intra-articular tissues. Here, we have examined genome-wide DNA methylation profiles of primary ...infrapatellar fat pad and matched blood samples from 70 osteoarthritis patients undergoing total knee replacement surgery. Comparing the DNA methylation profiles between these tissues reveal widespread epigenetic differences. We produce the first genome-wide methylation quantitative trait locus (mQTL) map of fat pad, and make the resource available to the wider community. Using two-sample Mendelian randomization and colocalization analyses, we resolve osteoarthritis GWAS signals and provide insights into the molecular mechanisms underpinning disease aetiopathology. Our findings provide the first view of the epigenetic landscape of infrapatellar fat pad primary tissue in osteoarthritis.
Abstract
Osteoarthritis is a prevalent joint disease and a major cause of disability worldwide with no curative therapy. Development of disease-modifying therapies requires a better understanding of ...the molecular mechanisms underpinning disease. A hallmark of osteoarthritis is cartilage degradation. To define molecular events characterizing osteoarthritis at the whole transcriptome level, we performed deep RNA sequencing in paired samples of low- and high-osteoarthritis grade knee cartilage derived from 124 patients undergoing total joint replacement. We detected differential expression between low- and high-osteoarthritis grade articular cartilage for 365 genes and identified a 38-gene signature in osteoarthritis cartilage by replicating our findings in an independent dataset. We also found differential expression for 25 novel long non-coding RNA genes (lncRNAs) and identified potential lncRNA interactions with RNA-binding proteins in osteoarthritis. We assessed alterations in the relative usage of individual gene transcripts and identified differential transcript usage for 82 genes, including ABI3BP, coding for an extracellular matrix protein, AKT1S1, a negative regulator of the mTOR pathway and TPRM4, coding for a transient receptor potential channel. We further assessed genome-wide differential splicing, for the first time in osteoarthritis, and detected differential splicing for 209 genes, which were enriched for extracellular matrix, proteoglycans and integrin surface interactions terms. In the largest study of its kind in osteoarthritis, we find that isoform and splicing changes, in addition to extensive differences in both coding and non-coding sequence expression, are associated with disease and demonstrate a novel layer of genomic complexity to osteoarthritis pathogenesis.
Abstract Background/Aims Osteoarthritis is a complex disease with a huge public health burden. Genome-wide association studies (GWAS) have identified hundreds of osteoarthritis-associated sequence ...variants, but the effector genes underpinning these signals remain largely elusive. Understanding chromosome organisation in 3D space is essential for identifying long-range contacts between distant genomic features (e.g., between genes and regulatory elements), in a tissue-specific manner. Here, we generate the first whole genome chromosome conformation analysis (Hi-C) map of primary osteoarthritis chondrocytes and identify novel effector genes for the disease. Methods Primary chondrocytes collected from eight knee osteoarthritis patients underwent Hi-C analysis to link chromosomal structure to genomic sequence. The identified loops were then combined with osteoarthritis GWAS results to identify variants involved in gene regulation via enhancer-promoter interactions. Results We identified 36 genetic variants residing within chromatin loop anchors that are associated with 13 osteoarthritis GWAS signals. Five of these variants reside directly in enhancer regions of 3 enhancer-promoter loops newly described in chondrocytes, pointing to high-confidence effector genes: PAPPA, NSD2 and NCOA6. PAPPA is directly associated with the turnover of IGF-1 transport proteins, and IGF-1 is an important factor in the repair of damaged chondrocytes. Conclusion We have constructed the first Hi-C map of primary human chondrocytes and have made it available as a resource for the scientific community. By integrating 3D-genomics with large-scale genetic association data, we identify high-confidence osteoarthritis effector genes which enhance our understanding of disease and can serve as putative high-value novel targets. Disclosure N. Bittner: None. C. Shi: None. D. Zhao: None. J. Ding: None. L. Southam: None. D. Swift: None. P. Kreitmaier: None. M. Tutino: None. J. Hankinson: None. M. Wilkinson: None. G. Orozco: None. E. Zeggini: None.
PDF
