Abstract figure legend Schematic diagram depicting astrocytic potassium (K⁺) clearance in the hippocampus of healthy brain (left) and during progression of Alzheimer's disease. Reduced conductivity through Kir channels and gap junctions in hippocampal astrocytes impair their ability to clear K⁺ from the extracellular milleu, which results in a transient increase in extracellular K⁺ that affects the excitability profile of nearby neurons.

Abstract figure legend This study examined the effects of aerobic capacity diet, and sex on brain and liver health in the context of the Alzheimer's disease (AD) biomarker amyloid beta (Aβ₄₂). The data suggest reduced liver health with a high-fat diet (HFD) and reduced aerobic capacity leads to increased peripheral amyloid beta compared to a low- fat diet (LFD) with high aerobic capacity. Brain amyloid beta load was also influenced by diet and aerobic capacity-induced alterations to liver health. These data highlight the importance in understanding systemic contributions to AD biomarkers and pathologies.

Abstract figure legend Tumour necrosis factor-alpha (TNF), produced by tubular epithelial cells (TECs), plays a critical role in regulating ion transport pathways along the nephron via autocrine and paracrine mechanisms. Its effects depend on the stimulus, the amount of TNF generated and the presence or absence of ongoing renal inflammation. Under homeostatic conditions, TNF can act as a braking mechanism to maintain balance. However, in inflammatory settings, it may contribute to renal damage and dysfunction. Additionally, TNF modulates interactions between TECs and infiltrating immune cells, influencing the resolution or exacerbation of inflammatory responses in the kidney.

Abstract figure legend Age-related progression of brain activity over time. This review article proposes a developmental process in the ageing brain, from compensation to negative overcompensation to chronic maladaptive overcompensation, which leads to dedifferentiation and desegregation. When comparing brain activation patterns in young and old for the same ‘absolute task difficulty’, shifts in brain activity from an automatic, lower level towards a more cortically controlled, attention-demanding control of motor actions can be seen, resulting in more bilateral and frontal activation patterns in the elderly (see changes in red activation hotspots in the figure). Importantly elderly subjects utilize motor control strategies, such as increased cortical activity, down-regulation of inhibitory processes and less-segregated and lateralized brain activation patterns, that can also be found in healthy young adults when task challenges increase. We propose that this age-related strategy is beneficial and compensatory to account for the perceived increases in ‘relative task difficulty’. However with progression of ageing and deterioration of the central nervous system, this compensatory brain activity may turn into non-efficient overactivation, already apparent during execution of the very simplest motor tasks.

Abstract figure legend An evaluation of the effectiveness of resveratrol as an anti-obesogenic nutritional strategy to mitigate the adverse effects of a high-fat diet on skeletal muscle health. Resveratrol, when consumed with a high-fat diet, reduces adipose accumulation in female CD-1 mice (∼18 weeks old), compared to a high-fat diet only. Using the work loop technique, we further show that resveratrol preserves fast-twitch extensor digitorum longus (EDL) muscle function by preventing the high-fat diet-induced decline in acute power output and cumulative work during fatiguing contractions. Notably, EDL performance in the high-fat diet + resveratrol group was comparable to that of standard laboratory diet-fed mice. Resveratrol did not alter skeletal muscle morphology or contractility when consumed with a standard laboratory diet. Despite previous reports linking resveratrol's anti-obesogenic effects to increased expression of silent information regulator 2 mammalian ortholog (SIRT1), we found no difference in SIRT1 protein expression in isolated soleus and EDL muscles across all groups. These findings suggest that resveratrol could be an effective nutritional strategy in negating some of the detrimental effects of high-fat diet consumption on skeletal muscle health.

Abstract figure legend Schematic overview of the experimental and computational framework for investigating hiPSC-CM electrophysiology with MEA systems. The MEA-based model integrates experimental data with phenotype-specific ionic models and tissue-level heterogeneity. Colour-coded maps highlight the impact of heterogeneity on conduction velocity, which increases with a higher percentage of atrial-like (AL) cells. Brugada syndrome simulations reveal locally reduced conduction velocity, consistent with adult tissue observations. Drug simulations for mexiletine, dofetilide, nifedipine and E-4031 demonstrate the model's capability to predict extracellular potential changes and ionic current dynamics. This integrative framework offers a comprehensive approach to assess disease-specific and pharmacological electrophysiological responses.

Abstract figure legend Using a multiscale computational model of left ventricular electromechanics, we investigated how sarcomere dynamics influence the end-systolic pressure-volume (ESPV) relationship in ejecting beats compared to isovolumetric beats. Our results indicate that the ejecting ESPV relationship emerges from the interplay of two opposing mechanisms. On one hand, ejecting beats exhibit a memory effect due to the higher thin filament activation in early systole, driven by the increased apparent calcium sensitivity at high sarcomere length (SL), leading to pressure enhancement. On the other hand, fibre shortening limits cross-bridge (XB) cycling efficiency through to the well-known inverse force-velocity relationship, resulting in pressure attenuation. When the first mechanism outweighs the second, ejection has a net activating effect, causing the ejecting ESPV relationship to exceed the isovolumetric one. Conversely, when the second mechanism dominates, shortening has a deactivating effect. In particular the first mechanism is enhanced by a prolonged calcium transient, whereas the second is favoured by reduced XB kinetics.

Abstract figure legend This double-blind, placebo-controlled, randomized cross-over trial investigated the effects of ketone monoester (KME) ingestion on resting cerebral blood flow (CBF) in young adults. We demonstrate that KME supplementation lowers CBF in a dose-dependent manner over 2-houra post-ingestion, whereas CBF remained unchanged following placebo ingestion. KME ingestion also lowered end-tidal CO₂ in a dose-dependent manner. KME ingestion increased heart rate but did not affect mean arterial pressure. KME, ketone monoester; CBF, cerebral blood flow; ICA, internal carotid artery; VA, vertebral artery.