[This corrects the article DOI: 10.3389/fimmu.2020.02080.].
\n \n\n \n \nCellular signaling relies on the activity of transmembrane receptors and their presentation on the cellular surface. Their continuous insertion in the plasma membrane is balanced by constitutive and activity-dependent internalization, which is orchestrated by adaptor proteins recognizing semispecific motifs within the receptors\u2019 intracellular regions. Here, we describe a complementary trafficking mechanism for G protein\u2013coupled receptors (GPCRs) that is evolutionary conserved and refined. This mechanism relies on the insertion of their amphipathic helix 8 into the inner leaflet of lipid membranes, orthogonal to the transmembrane helices. These amphipathic helices dictate subcellular localization of the receptors and autonomously drive their endocytosis by cooperative assembly and association with areas of high membrane curvature. The strength of helix 8 membrane insertion propensity quantitatively predicts the rate of constitutive internalization of GPCRs. This discovery advances our understanding of membrane protein trafficking and highlights a principle of receptor-lipid interactions that may have broad implications for cellular signaling and therapeutic targeting.
\n \n\n \n \nAbstract\nUnderstanding the cognitive trajectory of a neurological disease can provide important insight on underlying mechanisms and disease progression. Cognitive impairment is now well established as beginning many years before the diagnosis of Alzheimer\u2019s disease, but pre-diagnostic profiles are unclear for other neurological conditions that may be associated with cognitive impairment.\nWe analysed data from the prospective UK Biobank cohort with study baseline assessment performed between 2006-2010 and participants followed until 2021. We examined data from 497,252 participants, aged between 38 and 72 years at baseline, with an imaging sub-sample of 42,468 participants. Using time-to-diagnosis and time-from-diagnosis data in relation to time of assessment, we compared a continuous measure of executive function and magnetic resonance imaging brain measures of total grey matter and hippocampal volume in individuals with ischaemic stroke, focal epilepsy, Parkinson\u2019s disease, multiple sclerosis, motor neurone disease (amyotrophic lateral sclerosis) and migraine.\nOf the 497,252 participants (226,206 [45.5%] men, mean [SD] age, 57.5[8.1] years), 12,755 had ischaemic stroke, 6,758 had a diagnosis of focal epilepsy, 3,315 had Parkinson\u2019s disease, 2,315 had multiple sclerosis, 559 had motor neurone disease and 18,254 had migraine either at study baseline or diagnosed during the follow-up period. Apart from motor neurone disease, all conditions had lower pre-diagnosis executive function compared to controls (assessment performed median 7.4 years before diagnosis). At a group level, focal epilepsy and multiple sclerosis showed a gradual worsening in executive function up to 15 years prior to diagnosis, while ischaemic stroke was characterised by a modest decline for a few years followed by a substantial reduction at the time of diagnosis. By contrast, participants with migraine showed a mild reduction in pre-diagnosis cognition compared to controls which improved following clinical diagnosis. Pre-diagnosis MRI grey matter volume was lower than controls for stroke, Parkinson\u2019s disease and multiple sclerosis (scans performed median 1.7 years before diagnosis), while other conditions had lower volumes post-diagnosis.\nThese cognitive trajectory models reveal disease-specific temporal patterns at a group level, including a long cognitive prodrome associated with focal epilepsy and multiple sclerosis. The findings may help to prioritise risk management of individual diseases and inform clinical decision-making.
\n \n\n \n \nThe 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.
\n \n\n \n \nBACKGROUND: 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)\u00b11 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.
\n \n\n \n \nThe direct coupling of ion-exchange chromatography with mass spectrometry using electrochemical ion suppression creates a hyphenated technique with selectivity and specificity for the analysis of highly polar and ionic compounds. The technique has enabled new applications in environmental chemistry, food chemistry, forensics, cell biology and, more recently, metabolomics. Robust, reproducible and quantitative methods for the analysis of highly polar and ionic metabolites help meet a longstanding analytical need in metabolomics. Here, we provide step-by-step instructions for both untargeted and semi-targeted metabolite analysis from cell, tissue or biofluid samples by using anion-exchange chromatography-high-resolution tandem mass spectrometry (AEC-MS/MS). The method requires minimal sample preparation and is robust, sensitive and selective. It provides comprehensive coverage of hundreds of metabolites found in primary and secondary metabolic pathways, including glycolysis, the pentose phosphate pathway, the tricarboxylic acid cycle, purine and pyrimidine metabolism, amino acid degradation and redox metabolism. An inline electrolytic ion suppressor is used to quantitatively neutralize OH- ions in the eluent stream, after chromatographic separation, enabling AEC to be directly coupled with MS. Counter ions are also removed during this process, creating a neutral pH, aqueous eluent with a simplified matrix optimal for negative ion MS analysis. Sample preparation through to data analysis and interpretation is described in the protocol, including a guide to which metabolites and metabolic pathways are suitable for analysis by using AEC-MS/MS.
\n \n\n \n \nOBJECTIVE: To determine whether established heart rate parameters of exercise, related to cardiac autonomic function, are associated with incident Parkinson's disease, independent of both clinical and autonomic prodromal features. METHODS: A study of UK Biobank participants who performed a standardized bicycle exercise test (2009-2013), followed until November 2022, and analyzed in January 2024, was carried out. Heart rate increase from rest to exercise, and heart rate decrease from peak exercise to recovery were associated with incident Parkinson's disease. Multivariable adjustment was performed both for clinical characteristics and for prodromal non-cardiac autonomic features. RESULTS: A total of 69,288 eligible participants (men 48%, mean age 56.8\u2009years [SD 8.2\u2009years]) were followed for 12.5\u2009years: among the 319 (0.5%) who developed Parkinson's disease, recognized prodromal markers (constipation, bladder dysfunction) were more common at baseline. The median lag time to diagnosis was 9.3\u2009years (interquartile range 4.4). Both heart rate increase (37.5 [SD 11.5] vs 40.8 [SD 12.4] b.p.m., p\u2009
\n \n\n \n \nObesity 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.
\n \n\n \n \nAtrial fibrillation (AF) is the most common sustained arrhythmia, with a particularly high prevalence in the elderly. As the global aging population rapidly expands, it is increasingly important to examine how alterations to the aging heart contribute to an increased AF susceptibility. This work critically reviews the key molecular mechanisms that may underpin the complex association between aging and AF. Moreover, we identify emerging novel opportunities for therapeutic intervention that may be able to prevent and/or improve the current treatment paradigms for age-related AF. This review contributes to a holistic understanding of the intricate relationship between aging and AF.
\n \n\n \n \nEchocardiography has established itself as a vital component in the diagnosis and management of cardiovascular disease, evolving alongside advancements in imaging technology and clinical research methodologies. Since its inception in the 1950s, echocardiographic research has progressed from small-scale, observational studies to large cohort investigations and randomised controlled trials. This evolution has paralleled advancements in disease diagnosis and facilitated the use of echocardiography as an important player in other disciplines such as cardio-oncology and interventional cardiology. Echocardiography research has made great progress, with new developments rapidly shaping the field. This continued innovation underscores the singular focus of improving patient care. As digital and technological advancements accelerate, the potential for research in echocardiography to enhance diagnostic precision, guide personalised treatment, and improve outcomes on a global scale is greater than ever. Collaborative efforts and sustained investment in research will be key to realising these goals and advancing the care of patients with cardiovascular disease. This review explores the historical and ongoing contributions of echocardiography research to better understanding cardiac disease, emphasising the pivotal roles of early feasibility studies and large-scale trials in refining techniques and establishing clinical utility. Key infrastructure requirements for advancing echocardiography research are identified, including workforce development, academic and healthcare collaborations, clinical trial support, and access to big data and computational expertise. Emerging technologies, such as advanced imaging techniques, handheld devices, and AI-driven analytics, are highlighted as transformative tools poised to address current limitations in clinical practice.
\n \n\n \n \nBACKGROUND: Bariatric surgery presents a significant alleviation for non-alcoholic fatty liver disease (NAFLD), which relies in part on achieving substantial weight loss in post-surgical period.\u00a0We aimed to understand the effect of bariatric surgery on NAFLD remission via metabolomics and to validate the results in a general population-based cohort. METHODS: In a pilot study, ten patients with NAFLD who underwent bariatric surgery were enrolled. The remission of hepatic steatosis was assessed by MRI-derived proton density fat fraction (PDFF) before and 3-month after surgery. Temporal associations of body mass index (BMI) reduction, alteration in metabolomic biomarkers, and NAFLD remission were quantified by using cross-lagged models, which were then validated in a general population-based cohort (n\u2009=\u20091258). RESULTS: At 3-month after surgery, BMI reduction of 6.9 (SD 1.9) kg/m2 and MRI-PDFF reduction of 9.6% (5.4) (all p-value\u00a0
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