Altered mitochondrial function and energy metabolism is associated with a radioresistant phenotype in oesophageal adenocarcinoma

Neoadjuvant chemoradiation therapy (CRT) is increasingly the standard of care for locally advanced oesophageal cancer. A complete pathological response to CRT is associated with a favourable outcome. Radiation therapy is important for local tumour control, however, radioresistance remains a substantial clinical problem. We hypothesise that alterations in mitochondrial function and energy metabolism are involved in the radioresistance of oesophageal adenocarcinoma (OAC). To investigate this, we used an established isogenic cell line model of radioresistant OAC. Radioresistant cells (OE33 R) demonstrated significantly increased levels of random mitochondrial mutations, which were coupled with alterations in mitochondrial function, size, morphology and gene expression, supporting a role for mitochondrial dysfunction in the radioresistance of this model. OE33 R cells also demonstrated altered bioenergetics, demonstrating significantly increased intracellular ATP levels, which was attributed to enhanced mitochondrial respiration. Radioresistant cells also demonstrated metabolic plasticity, efficiently switching between the glycolysis and oxidative phosphorylation energy metabolism pathways, which were accompanied by enhanced clonogenic survival. This data was supported in vivo, in pre-treatment OAC tumour tissue. Tumour ATP5B expression, a marker of oxidative phosphorylation, was significantly increased in patients who subsequently had a poor pathological response to neoadjuvant CRT. This suggests for the first time, a role for specific mitochondrial alterations and metabolic remodelling in the radioresistance of OAC

Analysis of Attention Mechanisms in Box-Embedding Systems

Large-scale Knowledge Graphs (KGs) have recently gained considerable research attention for their ability to model the inter- and intra- relationships of data. However, the huge scale of KGs has necessitated the use of querying methods to facilitate human use. Question Answering (QA) systems have shown much promise in breaking down this human-machine barrier. A recent QA model that achieved state-of-the-art performance, Query2box, modelled queries on a KG using box embeddings with an attention mechanism backend to compute the intersections of boxes for query resolution. In this paper, we introduce a new model, Query2Geom, which replaces the Query2box attention mechanism with a novel, exact geometric calculation. Our findings show that Query2Geom generally matches the performance of Query2box while having many fewer parameters. Our analysis of the two models leads us to formally describe the interaction between knowledge graph data and box embeddings with the concepts of semantic-geometric alignment and mismatch. We create the Attention Deviation Metric as a measure of how well the geometry of box embeddings captures the semantics of a knowledge graph, and apply it to explain the difference in performance between Query2box and Query2Geom. We conclude that Query2box’s attention mechanism operates using “latent intersections” that attend to the semantic properties in embeddings not expressed in box geometry, acting as a limit on model interpretability. Finally, we generalise our results and propose that semantic-geometric mismatch is a more general property of attention mechanisms, and provide future directions on how to formally model the interaction between attention and latent semantics

Vertebral Bone Mineral Measures and Psychological Wellbeing Among Individuals with Modic Changes

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Methodological “Learning-by-Doing” for Action Design Research

This study shares the direct experiences of designing and implementing methodological “learning-by-doing” for Action Design Research (ADR) within a 5-credit module that condenses the realities of completing a full ADR project without compromising the rigour of the approach. The module is described in detail, along with the specifics of its implementation over two years and the key learnings from doing so. Adopting a confessional writing approach, documented experiences from those involved (both designers and students) provide a rich data source, analysed using autonomous and communicative reflexivity. The underlying contribution of this paper is that it provides insights into the learning of ADR, the doing of ADR, and the outcomes of a technique that simultaneously combines both. As a result, ADR educators and researchers can draw on these insights to further their teaching, learning, and research endeavours. Finally, key insights such as forced pragmatism and the challenge of problematisation add to our understanding of conducting ADR while avoiding issues such as methodological slurring

Self-field effects upon the critical current density of flat superconducting strips

We develop a general theory to account self-consistently for self-field effects upon the average transport critical current density Jc of a flat type-II superconducting strip in the mixed state when the bulk pinning is characterized by a field-dependent depinning critical current density Jp(B), where B is the local magnetic flux density. We first consider the possibility of both bulk and edge-pinning contributions but conclude that bulk pinning dominates over geometrical edge-barrier effects in state-of-the-art YBCO films and prototype second-generation coated conductors. We apply our theory using the Kim model, JpK(B) = JpK(0)/(1+|B|/B0), as an example. We calculate Jc(Ba) as a function of a perpendicular applied magnetic induction Ba and show how Jc(Ba) is related to JpK(B). We find that Jc(Ba) is very nearly equal to JpK(Ba) when Ba > Ba*, where Ba* is the value of Ba that makes the net flux density zero at the strip's edge. However, Jc(Ba) is suppressed relative to JpK(Ba) at low fields when Ba < Ba*, with the largest suppression occurring when Ba*/B0 is of order unity or larger.Comment: 9 pages, 4 figures, minor revisions to add four reference

Intersection of diet and exercise with the gut microbiome and circulating metabolites in male bodybuilders : A pilot study

Diet, exercise and the gut microbiome are all factors recognised to be significant contributors to cardiometabolic health. However, diet and exercise interventions to modify the gut microbiota to improve health are limited by poor understanding of the interactions between them. In this pilot study, we explored diet–exercise–microbiome dynamics in bodybuilders as they represent a distinctive group that typically employ well-defined dietary strategies and exercise regimes to alter their body composition. We performed longitudinal characterisation of diet, exercise, the faecal microbial community composition and serum metabolites in five bodybuilders during competition preparation and post-competition. All participants reduced fat mass while conserving lean mass during competition preparation, corresponding with dietary energy intake and exercise load, respectively. There was individual variability in food choices that aligned to individualised gut microbial community compositions throughout the study. However, there was a common shift from a high protein, low carbohydrate diet during pre-competition to a more macronutrient-balanced diet post-competition, which was associated with similar changes in the gut microbial diversity across participants. The circulating metabolite profiles also reflected individuality, but a subset of metabolites relating to lipid metabolism distinguished between pre- and post-competition. Changes in the gut microbiome and circulating metabolome were distinct for each individual, but showed common patterns. We conclude that further longitudinal studies will have greater potential than cross-sectional studies in informing personalisation of diet and exercise regimes to enhance exercise outcomes and improve health

A Key Role for Subiculum-Fornix Connectivity in Recollection in Older Age

Individual differences in memory during aging are associated with the microstructure of the fornix, a bidirectional tract connecting the hippocampus with the diencephalon, basal forebrain and cortex. To investigate the origin of alterations in fornix microstructure, measurement of hippocampal subfield volumes was combined with diffusion MRI and cognitive evaluation in a new sample of 31 healthy human participants aged 50–89 years. The fornix, uncinate and parahippocampal cingulum were reconstructed using diffusion MRI tractography. Episodic memory was assessed with free and cued verbal recall, visual recognition and paired associate learning tests. Recall performance was associated with fornix microstructure and hippocampal subfield volumes. Subiculum and CA1 volumes remained positively associated with fornix microstructure when controlling for other volumes. Subiculum volume was also associated with fornix microstructure independent of age. Regression analyses showed that subiculum-fornix associations explained more variation in recall than that of CA1-fornix associations. In a multivariable regression model, age and subiculum volume were independent predictors of free recall whilst fornix microstructure and CA1 volume were not. These results suggest that age-related changes in a network that includes the subiculum and fornix are important in cognitive change in healthy aging. These results match anatomical predictions concerning the importance of hippocampal – diencephalic projections for memory