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Welcome to OXION, Universities of Oxford, Cambridge, London and MRC Harwell
Obesity and heart failure: exploring the cardiometabolic axis.
Obesity is one of the biggest risks to public health in both developed and developing countries, and yet incidence continues to skyrocket. Being the main risk factor for a large number of life-limiting conditions, obesity has the potential to cause enormous damage unless addressed urgently. Heart failure (HF) is the most common cardiovascular disease associated with obesity. The incidence of HF overall continues to rise and mortality rates remain high, despite the rapid and significant advances in pharmacotherapy which have recently transformed the landscape of HF treatment. Both obesity and heart failure are multisystem disorders which are closely interlinked. Obesity poses the body a number of challenges, ranging from haemodynamic, to neuroendocrine, to inflammatory, to intracellular physiology. This narrative review describes the pathophysiological 'vicious cycle' caused by the combination of obesity and HF. Management of obesity in established heart failure has for years been a controversial topic, and yet an increasing body of evidence suggests that there are numerous benefits to managing obesity and insulin resistance in heart failure. Here we review the existing evidence base, as well as exciting new developments, suggesting that we may finally be on the brink of a revolution in managing obesity in heart failure.
MicroRNA-210 Enhances Cell Survival and Paracrine Potential for Cardiac Cell Therapy While Targeting Mitophagy.
The therapeutic potential of presumed cardiac progenitor cells (CPCs) in heart regeneration has garnered significant interest, yet clinical trials have revealed limited efficacy due to challenges in cell survival, retention, and expansion. Priming CPCs to survive the hostile hypoxic environment may be key to enhancing their regenerative capacity. We demonstrate that microRNA-210 (miR-210), known for its role in hypoxic adaptation, significantly improves CPC survival by inhibiting apoptosis through the downregulation of Casp8ap2, a ~40% reduction in caspase activity, and a ~90% decrease in DNA fragmentation. Contrary to the expected induction of Bnip3-dependent mitophagy by hypoxia, miR-210 did not upregulate Bnip3, indicating a distinct anti-apoptotic mechanism. Instead, miR-210 reduced markers of mitophagy and increased mitochondrial biogenesis and oxidative metabolism, suggesting a role in metabolic reprogramming. Furthermore, miR-210 enhanced the secretion of paracrine growth factors from CPCs, with a ~1.6-fold increase in the release of stem cell factor and of insulin growth factor 1, which promoted in vitro endothelial cell proliferation and cardiomyocyte survival. These findings elucidate the multifaceted role of miR-210 in CPC biology and its potential to enhance cell-based therapies for myocardial repair by promoting cell survival, metabolic adaptation, and paracrine signalling.
Filamentation of hCTPS1 with CTP.
CTP synthase (CTPS) is a key enzyme in de novo CTP synthesis, playing a critical role in nucleotide metabolism and cellular proliferation. Human CTPS1 (hCTPS1), one of the two CTPS isoforms, is essential for immune responses and is highly expressed in proliferating cells, making it a promising therapeutic target for immune-related diseases and cancer. Despite its importance, the regulatory mechanisms governing hCTPS1 activity remain poorly understood. Here, we reveal that CTP, the product of CTPS, acts as a key regulator for hCTPS1 filamentation. Using cryo-electron microscopy (cryo-EM), we resolve the high-resolution structure of CTP-bound hCTPS1 filaments, uncovering the molecular details of CTP binding and its role in filament assembly. Importantly, we demonstrate that CTP generated from the enzymatic reaction does not trigger filament disassembly, suggesting a conserved regulatory pattern. Furthermore, by analyzing the binding modes of two distinct CTP-binding pockets, we provide evidence that this filamentation mechanism is evolutionarily conserved across species, particularly in eukaryotic CTPS. Our findings not only elucidate a novel regulatory mechanism of hCTPS1 activity but also deepen the understanding of how metabolic enzymes utilize filamentation as a conserved strategy for functional regulation. This study opens new avenues for targeting hCTPS1 in therapeutic interventions.
Spatio-Temporal Proliferative Heterogeneity of Intra-Organ Endothelial Cells.
BACKGROUND: Blood vessels play a crucial role in supplying tissues with oxygen and nutrients. The maintenance of normal blood vessel number and integrity requires a continuous supply of new endothelial cells (ECs) through self-replication. While it is established that ECs across different tissues exhibit heterogeneity in molecular signatures and regenerative capacities, the extent of proliferation heterogeneity among ECs within the same organ or tissue remains largely unexplored. METHODS: An EC-specific proliferation tracing system was developed to investigate the proliferative heterogeneity of ECs in the heart, liver, and lung. A combination of RNA sequencing, spatial transcriptomics, and single-cell RNA sequencing was used to uncover the underlying mechanisms of this heterogeneity. An MAPK signaling inhibitor was administered in vivo to functionally assess pathway involvement. Injury models, including transverse aortic constriction, myocardial infarction, partial hepatectomy, and pneumonectomy, were utilized to assess stress-induced EC proliferation. RESULTS: EC proliferation exhibits marked intraorgan heterogeneity. In the heart, ECs in the upper part of the ventricular septum, the superior-inner left ventricle wall, and the apex showed elevated proliferation. In the liver, E-CAD (e-cadherin)±1 liver sinusoidal EC displayed a distinct proliferative advantage. In the lung, PLVAP (plasma membrane vesicle-associated protein)+ ECs renew more actively than CAR4 (carbonic anhydrase 4)+ ECs. Multiomics analysis revealed regional transcription diversity. In vivo MAPK inhibition confirmed its role in regulating EC proliferative heterogeneity. CONCLUSIONS: This study uncovers regional and subtype-specific proliferation in the heart, liver, and lung, driven by distinct gene expression programs. These findings highlight the spatial and functional diversity of microvascular ECs and offer a framework for developing organ-specific vascular regenerative strategies.
An ALPK3 truncation variant causing autosomal dominant hypertrophic cardiomyopathy is partially rescued by mavacamten.
The ALPK3 gene encodes alpha-protein kinase 3, a cardiac pseudo-kinase of unknown function. Heterozygous truncating variants (ALPK3tv) can cause dominant adult-onset hypertrophic cardiomyopathy (HCM). Here we confirm an excess of ALPK3tv in sarcomere-gene negative HCM patients. Moreover, we generated a novel knock-in mouse model carrying an ALPK3tv (K201X). Homozygous animals displayed hypertrophy and systolic dysfunction. Heterozygous animals demonstrated no obvious baseline; however, they had an aggravated hypertrophic response upon chronic adrenergic challenge. Isolated, unloaded cardiomyocytes from heterozygous and homozygous mice showed reduced basal sarcomere length with prolonged relaxation, whilst calcium transients showed increased diastolic calcium levels. Protein kinase A-mediated phosphorylation, including that of cardiac troponin I, was significantly decreased. In agreement with the cellular HCM phenotype, reduced ratios of myosin heads in the super-relaxed state were measured. Contractile and calcium handling defects were partly corrected by treatment with mavacamten, a novel myosin inhibitor. For the first time with a non-sarcomere HCM variant, we have demonstrated hallmark changes in cardiac contractility and calcium handling. Mavacamten is able to partially rescue the cellular phenotype, hence could be beneficial to HCM patients with ALPK3tv. Moreover, our data points at a potential role of ALPK3 as a modulator of protein kinase A signalling.
Understanding human dopamine neuron biology in Parkinson's patient cells
Human-induced pluripotent stem cell (hiPSC) technology has revolutionized Parkinson's disease (PD) research, offering opportunities for disease modeling, drug discovery, and personalized medicine. In this chapter, we summarize the impact of hiPSC-derived dopamine neurons (DaNs) on understanding various aspects of PD. This includes exploring PD dopamine neuron biology within the context of voltage-gated calcium channels and electrophysiology, emphasizing the role of calcium channels in neuronal vulnerability and in regulating dopamine release. We address findings related to α-synuclein pathology, highlighting its aggregation, secretion, and intracellular interactions. We also look into the details of the main PD pathology-related organelles: lysosomes, mitochondria, and the endoplasmic reticulum (ER). Lysosomal pathology is investigated, encompassing GBA1-related PD phenotypes, pH regulation, lysosomal calcium channels, and autophagy. Mitochondrial dysfunction is summarized in terms of bioenergetics, α-synuclein/mitochondria interplay, and the mitophagy pathway. We examine ER-related pathology through ER stress and calcium regulation, and the ER-mitochondria contact sites are discussed as a pivotal link between mitochondria and the ER. Finally, we provide a summary of the integration of CRISPR technology into hiPSC-PD research, with a specific focus on its potential in target identification, drug discovery, and therapeutic interventions for dopamine neuron pathology.
Costs of Underfunding Brain Development.
BACKGROUND: Healthcare costs are rising at an exponential rate. Given the constraints of limited resources, it is essential to make informed decisions about priorities to ensure the best possible health outcomes globally. The history of medicine illustrates how these priorities have shifted over time - from early focus on infectious diseases to later emphasis on noncommunicable conditions such as metabolic disorders. Today, neurodegenerative diseases and aging brain are the forefront of medical research, as these conditions profoundly affect individuals, families, and society. SUMMARY: One in three people will experience a mental health disorder in their lifetime, yet it is not widely recognized that many of these conditions may have origins in pre-birth experiences and early life influences. Disruptions in progenitor proliferation, neuronal and glial migration, and differentiation during prenatal development can contribute to lifelong neurodevelopmental abnormalities. Despite the fundamental importance of brain development, most of the neuroscience funding is allocated to studying neurodegeneration, such as dementia and Parkinson's disease, while early life influences remain underexplored. Crucially, the impact of developmental factors begins even before conception. Environmental risks extend beyond direct maternal exposures during pregnancy; they include cumulative parental exposure to teratogenic agents affecting both male and female gametes, as well as early life environmental exposures affecting newborns, infants, and children. These influences are complex yet highly relevant to long-term health outcomes. KEY MESSAGES: We urge greater recognition of the developmental origins of disease and advocate for increased investment in preventive strategies. These include lifestyle modifications, dietary improvements, targeted supplementation, regular exercise, and minimizing exposure to environmental pollutants. Addressing these factors proactively could yield profound benefits for both individual and public health.
Nitric oxide promotes cysteine N-degron proteolysis through control of oxygen availability
Selected proteins containing an N-terminal cysteine (Nt-Cys) are subjected to rapid, O 2 -dependent proteolysis via the Cys/Arg-branch of the N-degron pathway. Cysteine dioxygenation is catalyzed in mammalian cells by 2-aminoethanethiol dioxygenase (ADO), an enzyme that manifests extreme O 2 sensitivity. The canonical substrates of this pathway in mammalia are the regulators of G-protein signaling 4, 5, and 16, as well as interleukin-32. In addition to operating as an O 2 -sensing mechanism, this pathway has previously been described as a sensor of nitric oxide (NO), with robust effects on substrate stability upon modulation of NO bioavailability being widely demonstrated. Despite this, no mechanism to describe the action of NO on the Cys/Arg N-degron pathway has yet been substantiated. We demonstrate that NO can regulate the stability of Cys N-degron substrates indirectly via the regulation of ADO cosubstrate availability. Through competitive, O 2 -dependent inhibition of cytochrome C oxidase, NO can substantially modify cellular O 2 consumption rate and, in doing so, alter the availability of O 2 for Nt-Cys dioxygenation. We show that this increase in O 2 availability in response to NO exposure is sufficient to alter both dynamic and steady-state ADO substrate levels. It is likely that this mechanism operates to couple O 2 supply and mitochondrial respiration with responses to G-protein-coupled receptor stimulation.
Cardiac intermediary metabolism in heart failure: substrate use, signalling roles and therapeutic targets.
The number of patients with heart failure is expected to rise sharply owing to ageing populations, poor dietary habits, unhealthy lifestyles and improved survival rates from conditions such as hypertension and myocardial infarction. Heart failure is classified into two main types: heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). These forms fundamentally differ, especially in how metabolism is regulated, but they also have shared features such as mitochondrial dysfunction. HFrEF is typically driven by neuroendocrine activation and mechanical strain, which demands a higher ATP production to sustain cardiac contraction. However, the primary energy source in a healthy heart (fatty acid β-oxidation) is often suppressed in HFrEF. Although glucose uptake increases in HFrEF, mitochondrial dysfunction disrupts glucose oxidation, and glycolysis and ketone oxidation only partially compensate for this imbalance. Conversely, HFpEF, particularly in individuals with metabolic diseases, such as obesity or type 2 diabetes mellitus, results from both mechanical and metabolic overload. Elevated glucose and lipid levels overwhelm normal metabolic pathways, leading to an accumulation of harmful metabolic byproducts that impair mitochondrial and cellular function. In this Review, we explore how disruptions in cardiac metabolism are not only markers of heart failure but also key drivers of disease progression. We also examine how metabolic intermediates influence signalling pathways that modify proteins and regulate gene expression in the heart. The growing recognition of the role of metabolic alterations in heart failure has led to groundbreaking treatments that target these metabolic disruptions, offering new hope for these patients.
Changes in sensorimotor network dynamics in resting-state recordings in Parkinson's disease.
Non-invasive recordings of magnetoencephalography have been used for developing biomarkers for neural changes associated with Parkinson's disease that can be measured across the entire course of the disease. These studies, however, have yielded inconsistent findings. Here, we investigated whether analysing motor cortical activity within the context of large-scale brain network activity provides a more sensitive marker of changes in Parkinson's disease using magnetoencephalography. We extracted motor cortical beta power and beta bursts from resting-state magnetoencephalography scans of patients with Parkinson's disease (N = 28) and well-matched healthy controls (N = 36). To situate beta bursts in their brain network contexts, we used a time-delay-embedded hidden Markov model to extract brain network activity and investigated co-occurrence patterns between brain networks and beta bursts. Parkinson's disease was associated with decreased beta power in motor cortical power spectra, but no significant differences in motor cortical beta-burst dynamics occurred when using a conventional beta-burst analysis. Dynamics of a large-scale sensorimotor network extracted with the time-delay-embedded hidden Markov model approach revealed significant decreases in the occurrence of this network with Parkinson's disease. By comparing conventional burst and time-delay-embedded hidden Markov model state occurrences, we observed that motor beta bursts occurred during both sensorimotor and non-sensorimotor network activations. When using the large-scale network information provided by the time-delay-embedded hidden Markov model to focus on bursts that were active during sensorimotor network activations, significant decreases in burst dynamics could be observed in patients with Parkinson's disease. In conclusion, our findings suggest that decreased motor cortical beta power in Parkinson's disease is prominently associated with changes in sensorimotor network dynamics using magnetoencephalography. Thus, investigating large-scale networks or considering the large-scale network context of motor cortical activations may be crucial for identifying alterations in the sensorimotor network that are prevalent in Parkinson's disease and might help resolve contradicting findings in the literature.
The effects of lacosamide, pregabalin, and tapentadol on peripheral nerve excitability: A randomized, double-blind, placebo-controlled, crossover, multi-center trial in healthy subjects.
BACKGROUND: Chronic pain is a leading cause of disability globally, with limited treatment options and frequent adverse effects. The IMI-PainCare-BioPain project aimed to enhance analgesic drug development by standardizing biomarkers. This study, IMI2-PainCare-BioPain-RCT1, evaluated the effects of lacosamide, pregabalin, and tapentadol on peripheral nerve excitability in healthy subjects through a randomized, double-blind, placebo-controlled crossover trial. METHODS: The study included 43 healthy participants aged 18-45 years. Participants underwent four treatment periods where they received single doses of lacosamide (200 mg), pregabalin (150 mg), tapentadol (100 mg), or placebo. High-frequency stimulation was applied to induce hyperalgesia. The two primary endpoints were changes in Strength Duration Time Constant (SDTC) in large sensory and motor fibers between lacosamide and placebo periods at the first post-dose timepoint compared to baseline (60 min). Other predefined endpoints included recovery cycle, threshold electrotonus (TEd), and S2 accommodation as well as effects of pregabalin and tapentadol. RESULTS: Lacosamide statistically significantly reduced SDTC in large sensory fibers (mean reduction 0.04 (95% CI 0.01-0.08), p = 0.012) and in motor fibers (mean reduction 0.04 (95% CI 0.00-0.07), p = 0.039) but had no effect on small sensory fibers at the first timepoint compared to placebo. There were no effects of pregabalin and tapentadol on SDTC. Of other predefined endpoints, lacosamide produced statistically significant changes in subexcitability, S2 accommodation TEd(peak), and TEd40(Accom) in large sensory fibers. No statistically significant changes were observed in refractoriness, relative refractory period, or accommodation half-time at the first timepoint compared to placebo. CONCLUSIONS: This study demonstrates that nerve excitability testing can detect pharmacodynamic effects on large myelinated fibers in healthy subjects. Lacosamide statistically significantly reduced peripheral nerve excitability, particularly in large sensory fibers.
Defective Olfactomedin-2 connects adipocyte dysfunction to obesity.
Olfactomedin-2 (OLFM2) is a pleiotropic glycoprotein emerging as a regulator of energy homeostasis. We here show the expression of OLFM2 to be adipocyte-specific and inversely associated with obesity. OLFM2 levels increase during adipogenesis and are suppressed in inflamed adipocytes. Functionally, OLFM2 deficiency impairs adipocyte differentiation, while its over-production enhances the adipogenic transformation of fat cell progenitors. Loss and gain of function experiments revealed that OLFM2 modulates key metabolic and structural pathways, including PPAR signaling, citrate cycle, fatty acid degradation, axon guidance and focal adhesion in 3T3 cell lines and primary human adipocytes. On the molecular level, OLFM2 deficiency in differentiated adipocytes predominantly downregulates genes involved in cell cycle. Extending these findings in vivo, both whole-body Olfm2 knockout and adipose-specific Olfm2 depletion in mice resulted in impaired adipose cell cycle gene expression, with the latter also displaying fat mass accretion and metabolic dysfunction. Collectively, our results underscore a critical role for OLFM2 in adipocyte biology, and support a causative link between reduced adipose OLFM2 and the pathophysiology of obesity.
Compartmentalisation in cAMP signalling: A phase separation perspective.
Cells rely on precise spatiotemporal control of signalling pathways to ensure functional specificity. The compartmentalisation of cyclic AMP (cAMP) and protein kinase A (PKA) signalling enables distinct cellular responses within a crowded cytoplasmic space. Traditionally, compartmentalisation has been attributed to PKA anchoring, phosphodiesterase-mediated cAMP degradation, and restricted cAMP diffusion. Emerging evidence suggests that liquid-liquid phase separation (LLPS) can play a significant role in organising cAMP signalling. LLPS has been implicated in receptor clustering, cyclic nucleotide synthesis, effector activation, signal termination, and offers a dynamic mechanism for spatially restricting cAMP activity. Notably, PKA RIα condensates appear to act as cAMP reservoirs, modulating local cAMP availability and phosphodiesterase-mediated degradation. Disrupting LLPS-mediated condensation of cAMP/PKA pathway components has been linked to cancer and neurodegeneration, pointing to physiological relevance. This review explores current evidence of LLPS in cAMP signalling, highlighting implications for signal compartmentalisation and functional specificity.
Extracellular Vesicles as Targeted Communicators in Complementary Medical Treatments.
The supposed meridians of traditional oriental medicine have been a cause of conflict between traditional and modern medical science. A possible resolution has been proposed: That extracellular vesicles, including exosomes, may be the transmitters of traditional therapies such as massage and acupuncture. This article develops that idea by proposing that the pathways between surface and deep structures may be laid down during the embryonic migration of cells from one region of the developing body to distant regions. This hypothesis depends on the proven targeting of vesicular communication via cell surface binding molecules and their complementary binding sites on target cells. The hypothesis is therefore experimentally testable. The article also draws attention to a strong analogy with Charles Darwin's theory of pangenesis for particulate communication between the soma and germline.
