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| Open AccessElevated Na is a dynamic and reversible modulator of mitochondrial metabolism in the heart
Heart failure is characterised by a detrimental rise in the intracellular sodium concentration. Here the authors show that this reversibly reprogrammes energy metabolism in the heart making this a possible therapeutic target for the development of new drugs.
- Yu Jin Chung
- , Zoe Hoare
- & Michael J. Shattock
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Article
| Open AccessSleep fragmentation exacerbates myocardial ischemia‒reperfusion injury by promoting copper overload in cardiomyocytes
Sleep disorders increase the risk and mortality of heart disease. Here, the authors show that sleep fragmentation results in elevated copper levels in the male mouse heart and exacerbates myocardial ischemia–reperfusion injury with increased myocardial cuproptosis and apoptosis.
- Na Chen
- , Lizhe Guo
- & E. Wang
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Article
| Open AccessCardiac function is regulated by the sodium-dependent inhibition of the sodium-calcium exchanger NCX1
The sodium-calcium exchanger (NCX1) is the primary calcium extrusion mechanism of cardiac myocytes. Here, the authors show that removal of a long questioned allosteric regulation of NCX1 by intracellular sodium alters cardiac excitation-contraction coupling.
- Kyle Scranton
- , Scott John
- & Michela Ottolia
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Article
| Open AccessLncRNA-LncDACH1 mediated phenotypic switching of smooth muscle cells during neointimal hyperplasia in male arteriovenous fistulas
Arteriovenous fistulas are the most common vascular access points for hemodialysis, but they have a high incidence of postoperative dysfunction, mainly due to excessive neointimal hyperplasia. Here, the author shows that LncDACH1 regulates NIH through the HSP90/ SRPK1/ AKT signaling axis.
- Zhaozheng Li
- , Yao Zhao
- & Jundong Jiao
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Article
| Open AccessBIN1 knockdown rescues systolic dysfunction in aging male mouse hearts
Cardiac dysfunction is a hallmark of aging in humans and mice. Here, the authors show that by restoring youthful Bridging Integrator 1 (BIN1) protein levels in the hearts of 24-month-old mice in vivo cardiac systolic function is rejuvenated, and the aging phenotype partially reversed within two weeks.
- Maartje Westhoff
- , Silvia G. del Villar
- & Rose E. Dixon
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Article
| Open AccessTAD boundary deletion causes PITX2-related cardiac electrical and structural defects
This study identifies an altered chromatin conformation associated to a cardiac disorder observed in 7 independent families. A deletion of 2 diverging CTCF binding sites on 4q25 induces TAD fusion and leads to PITX2 expression dysregulation.
- Manon Baudic
- , Hiroshige Murata
- & Julien Barc
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Article
| Open AccessProtein disulfide isomerase cleaves allosteric disulfides in histidine-rich glycoprotein to regulate thrombosis
Vascular protein disulfide isomerase (PDI) regulates thrombosis and targeting extracellular PDI remains a promising antithrombotic approach. Here, the authors show that PDI cleaves allosteric disulfides on histidine-rich glycoprotein to influence its functions during coagulation and thus fine-tune the kinetics of thrombus formation.
- Keyu Lv
- , Shuai Chen
- & Chao Fang
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Article
| Open AccessStatins improve cardiac endothelial function to prevent heart failure with preserved ejection fraction through upregulating circRNA-RBCK1
Endothelial dysfunction has been shown to occur in HFpEF and we know that statins can target endothelial dysfunction by inhibiting miR-133a. Here the authors show that statins improve diastolic dysfunction in HFpEF by increasing the levels of a circRNA which, in turns, binds to miR-133a modulating its downstream targets.
- Bin Li
- , Wen-Wu Bai
- & Shuang-Xi Wang
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Article
| Open AccessNaked mole-rats have distinctive cardiometabolic and genetic adaptations to their underground low-oxygen lifestyles
The naked mole-rat exhibits extreme longevity, resistance to hypoxia and absence of cardiovascular disease. Here, Faulkes et al. identify mechanisms behind these traits by comparing cardiac metabolomes and transcriptomes of naked more-rats to other African mole-rat genera and evolutionary divergent mammals.
- Chris G. Faulkes
- , Thomas R. Eykyn
- & Dunja Aksentijevic
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Article
| Open AccessS100A8/A9 as a prognostic biomarker with causal effects for post-acute myocardial infarction heart failure
Heart failure is the most prevalent complication of acute myocardial infarction. Here, the authors show that circulating S100A8/A9 is a robust predictor and potentially causal medicator for heart failure post-acute myocardial infarction, as such could serve as a promising drug target for cardioprotection.
- Jie Ma
- , Yang Li
- & Yulin Li
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Article
| Open AccessEpigenetic modulators link mitochondrial redox homeostasis to cardiac function in a sex-dependent manner
Efforts to treat heart failure with antioxidants have failed. Here, authors reveal a robust sex-dependent endogenous defense against oxidative damage and demonstrate antioxidative treatment’s efficacy solely in subjects with inadequate redox capacity.
- Zaher ElBeck
- , Mohammad Bakhtiar Hossain
- & Christer Betsholtz
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Article
| Open AccessFibroblast-specific PRMT5 deficiency suppresses cardiac fibrosis and left ventricular dysfunction in male mice
Epigenetic mechanisms play a key role in cardiac fibrosis associated with heart failure. Here, the authors show that protein arginine methyltransferase 5 (PRMT5), an epigenetic writer, regulates fibrotic gene transcription through histone methylation in mice.
- Yasufumi Katanasaka
- , Harumi Yabe
- & Tatsuya Morimoto
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Article
| Open AccessElevated blood remnant cholesterol and triglycerides are causally related to the risks of cardiometabolic multimorbidity
Dysmetabolism of triglyceride-rich lipoproteins is considered a shared risk factor for cardiometabolic diseases, but their associations with cardiometabolic multimorbidity have not been fully understood. Here, the authors show that elevated levels of remnant cholesterol and triglycerides were observationally and genetically associated with a higher risk of cardiometabolic multimorbidity.
- Yimin Zhao
- , Zhenhuang Zhuang
- & Tao Huang
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Article
| Open AccessIntegrative genomic analyses identify candidate causal genes for calcific aortic valve stenosis involving tissue-specific regulation
Here the authors report 20 novel genomic risk loci for calcific aortic valve stenosis, the most common heart valve disorder. Using RNA sequencing in 500 human aortic valves, they prioritize candidate causal genes including TWIST1, a gene involved in endothelial-mesenchymal transition.
- Sébastien Thériault
- , Zhonglin Li
- & Yohan Bossé
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Article
| Open AccessN-Acetyltransferase 10 represses Uqcr11 and Uqcrb independently of ac4C modification to promote heart regeneration
Here, Ma et al. investigate the translational profile of cardiac regeneration, pointing to Nat10 as a key regulator of cardiomyocyte proliferative potential, and describing how it regulates cardiac gene expression.
- Wenya Ma
- , Yanan Tian
- & Benzhi Cai
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Article
| Open AccessALKBH5-mediated m6A modification of IL-11 drives macrophage-to-myofibroblast transition and pathological cardiac fibrosis in mice
Cardiac macrophage contributes to the onset of cardiac fibrosis, but the underneath mechanisms remain unclear. Here the authors show that mouse cardiac macrophages from circulating monocytes may trans-differentiate into myofibroblast under hypertensive conditions for fibrosis development, with an AKLBH5/IL11 molecular axis modulating this macrophage-to-myofibroblast transition.
- Tao Zhuang
- , Mei-Hua Chen
- & Cheng-Chao Ruan
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Article
| Open AccessTargeting HDAC6 to treat heart failure with preserved ejection fraction in mice
HFpEF has few effective treatments. Here, the authors show that inhibition of histone deacetylase 6 (HDAC6) with TYA-018 reverses established HFpEF symptoms in mice, comparably to the use of a sodium-glucose cotransporter 2 inhibitor; highlighting HDAC6 as a potential target to treat HFpEF.
- Sara Ranjbarvaziri
- , Aliya Zeng
- & Jin Yang
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Article
| Open AccessProtective effects of Pt-N-C single-atom nanozymes against myocardial ischemia-reperfusion injury
Nanozymes can be used for targeting reactive oxygen species (ROS) to alleviate myocardial ischemia/reperfusion (I/R) injury, but hindered by catalytic performance and toxicity concerns. Here the authors report multienzyme-mimicking and biocompatible Pt-NC single-atom nanozymes as an efficient ROS decomposer for restoring cellular homeostasis and mitigating apoptotic progression after I/R injury.
- Tianbao Ye
- , Cheng Chen
- & Chengxing Shen
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Article
| Open AccessRunx1+ vascular smooth muscle cells are essential for hematopoietic stem and progenitor cell development in vivo
Hematopoietic stem cells are supported by niche cells that help balance stem cell self-renewal and differentiation. Here they show that Runx1 deletion in the embryonic perivascular HSC niche impairs hematopoietic development in vivo and causes transcriptional changes in pericytes/vSMCs, endothelial cells and hematopoietic cells in the murine AGM.
- Zaniah N. Gonzalez Galofre
- , Alastair M. Kilpatrick
- & Mihaela Crisan
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Article
| Open AccessPIBF1 regulates trophoblast syncytialization and promotes cardiovascular development
The genetic link between placenta function and congenital heart defects has been established, though the cellular mechanisms underlying this connection is less clear. Here they show that PIBF1 regulates syncytiotrophoblast fusion and that loss of PIBF1 also negatively impacts heart development, providing a potential link between the development of these two organs.
- Jong Geol Lee
- , Jung-Min Yon
- & In-Jeoung Baek
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Article
| Open AccessPro-ferroptotic signaling promotes arterial aging via vascular smooth muscle cell senescence
Ferroptosis is a novel form of regulated cell death associated with lipid oxidation. Here, the authors demonstrate that the proferroptosis signal is activated and drives vascular aging by inducing senescence in vascular smooth muscle cells.
- Di-Yang Sun
- , Wen-Bin Wu
- & Pei Wang
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Article
| Open AccessPalmitic acid in type 2 diabetes mellitus promotes atherosclerotic plaque vulnerability via macrophage Dll4 signaling
Patients with Type 2 Diabetes Mellitus are increasingly susceptible to atherosclerotic plaque vulnerability. Here, the authors show that elevated palmitic acid levels are linked to increased atherosclerotic plaque vulnerability.
- Xiqiang Wang
- , Ling Zhu
- & Zhongwei Liu
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Article
| Open AccessResolvin T4 enhances macrophage cholesterol efflux to reduce vascular disease
Specialized pro-resolving mediators (SPM) are involved in the reprogramming of immune responses. Here the authors show that resolvin (RvT) 4 limits the progression of vascular disease in mouse models of arthritis exacerbated atherosclerotic inflammation.
- Mary E. Walker
- , Roberta De Matteis
- & Jesmond Dalli
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Article
| Open AccessDNMT3A clonal hematopoiesis-driver mutations induce cardiac fibrosis by paracrine activation of fibroblasts
This study uncovers a critical link between DNMT3A-driven CHIP and heart failure and, in particular, it shows that DNMT3A inactivation in monocytes boosts the release of HB-EGF, which activates fibroblasts inducing diffuse fibrosis in the heart.
- Mariana Shumliakivska
- , Guillermo Luxán
- & Stefanie Dimmeler
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Article
| Open AccessEnhancing aortic valve drug delivery with PAR2-targeting magnetic nano-cargoes for calcification alleviation
Achieving targeted drug delivery for calcified aortic valve is challenging. Here, the authors find that protease activated receptor 2 (PAR2) is up-regulated on calcified valves and develop a magnetic nanocarrier functionalized with PAR2-targeting peptide for dual-active drug delivery.
- Jinyong Chen
- , Tanchen Ren
- & Xianbao Liu
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Article
| Open AccessLarge scale plasma proteomics identifies novel proteins and protein networks associated with heart failure development
The pathobiology of heart failure (HF) is incompletely understood. The authors identify 37 circulating proteins and 5 protein modules associated with HF risk, with several demonstrating causal effects on HF, risk factors, or cardiac dysfunction by Mendelian randomization analysis.
- Amil M. Shah
- , Peder L. Myhre
- & Bing Yu
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Article
| Open AccessAmyloid beta 42 alters cardiac metabolism and impairs cardiac function in male mice with obesity
Epidemiological evidence has identified associations among obesity, Alzheimer’s disease, and cardiovascular disease. Here, the authors report that adipose tissue releases amyloid beta 42 (Aβ42) and that antagonizing Aβ42 protects cardiac function in obesity murine models.
- Liam G. Hall
- , Juliane K. Czeczor
- & Sean L. McGee
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Article
| Open AccessBlood DNA methylation profiling identifies cathepsin Z dysregulation in pulmonary arterial hypertension
Pulmonary arterial hypertension is a complex disease characterised by high morbidity and mortality. Here, the authors report methylation profiling of patients, finding disease associations in genes CTSZ, COG6 and ZNF678.
- Anna Ulrich
- , Yukyee Wu
- & Christopher J. Rhodes
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Article
| Open AccessSpatiotemporal signaling underlies progressive vascular rarefaction in myocardial infarction
Enhancing vascularization to improve cardiac disease outcomes is a therapeutic approach with limited success. Here, the authors show that cardiac repair is governed by spatiotemporally regulated programs and underline the signaling mechanisms driving vascular deterioration.
- Lin Wei Tung
- , Elena Groppa
- & Fabio Rossi
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Article
| Open AccessHydrogels with tunable mechanical plasticity regulate endothelial cell outgrowth in vasculogenesis and angiogenesis
It is vital to unveil the effects of extracellular matrix cues on endothelial cell (EC) outgrowth for desirably governing vasculature formation, but the role of matrix plasticity on EC outgrowth is elusive. Here, the authors develop hydrogels with tunable mechanical plasticity independent of stiffness, and elucidate the plasticity-mediated responses of ECs during vasculogenesis and angiogenesis.
- Zhao Wei
- , Meng Lei
- & Feng Xu
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Article
| Open AccessA patterned human primitive heart organoid model generated by pluripotent stem cell self-organization
Pluripotent stem cell-derived organoids can recapitulate significant hallmarks of human organ development and are becoming critical tools for human research. Here, the authors report significant technical steps for generating sophisticated synthetic human primitive heart organoids.
- Brett Volmert
- , Artem Kiselev
- & Aitor Aguirre
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Article
| Open AccessModeling cardiac fibroblast heterogeneity from human pluripotent stem cell-derived epicardial cells
Cardiac fibroblasts play an essential role in heart development. Here Fernandes et al. describe a human pluripotent stem cell-derived epicardial organoid system to investigate the role of fibroblasts in cardiovascular development and disease.
- Ian Fernandes
- , Shunsuke Funakoshi
- & Gordon Keller
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Article
| Open AccessGRAF1 integrates PINK1-Parkin signaling and actin dynamics to mediate cardiac mitochondrial homeostasis
Cytoskeletal remodeling is known to facilitate mitophagy, but the mechanism is not fully understood. Here, the authors show that damaged mitochondria recruit a RhoA GTPase activating protein that promotes their capture and encasement by autophagosomes.
- Qiang Zhu
- , Matthew E. Combs
- & Joan M. Taylor
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Article
| Open AccessChoroidal and retinal thinning in chronic kidney disease independently associate with eGFR decline and are modifiable with treatment
In patients with CKD, there is an unmet need for biomarkers that reliably track kidney injury. Here, in a series of prospective studies, the authors show that retinal OCT metrics reflect kidney injury, are modified by treatments for kidney disease and can predict future decline of kidney function.
- Tariq E. Farrah
- , Dan Pugh
- & Neeraj Dhaun
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Article
| Open AccessGenome-wide association analysis of left ventricular imaging-derived phenotypes identifies 72 risk loci and yields genetic insights into hypertrophic cardiomyopathy
Changes of left ventricular structure are used to predict morbidity and mortality in cardiovascular diseases. Here the authors conducted a study using advanced deep learning technology to analyze left ventricular regional wall thickness (LVRWT) in a large population, identifying 72 significant genetic loci linked to LVRWT traits.
- Caibo Ning
- , Linyun Fan
- & Xiaoping Miao
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Matters Arising
| Open AccessHow carvedilol does not activate β2-adrenoceptors
- Robert J. Lefkowitz
- , Howard A. Rockman
- & Milton Packer
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Article
| Open AccessDbh+ catecholaminergic cardiomyocytes contribute to the structure and function of the cardiac conduction system in murine heart
Catecholaminergic transmitters are critical signalling effectors known to be released by sympathetic nerves and adrenomedullary endocrine cells in response to physiological stress. In this paper, the authors demonstrate a uniquely distributed group of catecholaminergic cardiomyocytes with key regulatory roles in cardiac excitation conduction.
- Tianyi Sun
- , Alexander Grassam-Rowe
- & Ming Lei
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Article
| Open AccessCis-trans isomerization of peptoid residues in the collagen triple-helix
The cis-peptide bond is rare in natural proteins and its impact on protein folding is elusive. Here the authors break the conventional understanding that cis-amide-favoring residues destabilize proteins, elucidate the principles of peptoid cis-trans isomerization in collagen folding, and showcase the use of cis-amide-favoring residues in building programmable and functional peptidomimetics.
- Rongmao Qiu
- , Xiaojing Li
- & Yang Li
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Article
| Open AccessProtective effects of macrophage-specific integrin α5 in myocardial infarction are associated with accentuated angiogenesis
During myocardial infarction, cardiac macrophages expand, become activated and play an important role in cardiac repair and remodelling. Here the authors show that integrin α5 is upregulated in infarct macrophages and contributes to myocardial repair, triggering an angiogenic phenotype and protecting from adverse remodelling.
- Ruoshui Li
- , Bijun Chen
- & Nikolaos G. Frangogiannis
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Article
| Open AccessEicosanoid and eicosanoid-related inflammatory mediators and exercise intolerance in heart failure with preserved ejection fraction
Systemic inflammation is recognized as a central pathobiologic feature in heart failure with preserved ejection fraction (HFpEF). Here, the authors report 70 pro- and anti-inflammatory eicosanoid and eicosanoid-related metabolites associated with HFpEF status.
- Emily S. Lau
- , Athar Roshandelpoor
- & Jennifer E. Ho
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Article
| Open AccessGut butyrate-producers confer post-infarction cardiac protection
Here, Chen et. al. characterize the relationship between the gut microbiota and plasma metabolite changes in the context of ST-elevation myocardial infarction (STEMI), unveiling a role of butyrate-producing bacteria and their ketogenesis in post-STEMI cardiac repair, a finding validated in nonhuman primate and mouse models. They show that butyrate supplementation reduces myocardial infarction severity in mice, underscoring the significance of butyrate-producing bacteria and beta-hydroxybutyrate in improving post-MI outcomes.
- Hung-Chih Chen
- , Yen-Wen Liu
- & Patrick C. H. Hsieh
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Article
| Open AccessThe lncRNA Sweetheart regulates compensatory cardiac hypertrophy after myocardial injury in murine males
LncRNAs take part in fine-tuning gene regulatory networks in development, homeostasis, and disease settings. Here, the authors show that the lncRNA Sweetheart has an important role in cardiomyocytes after myocardial injury to act together with NKX2-5 in adapting gene programs after myocardial stress.
- Sandra Rogala
- , Tamer Ali
- & Phillip Grote
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Article
| Open AccessSingle-nucleus DNA sequencing reveals hidden somatic loss-of-heterozygosity in Cerebral Cavernous Malformations
Here the authors establish somatic loss-of-heterozygosity as a genetic underpinning of Cerebral Cavernous Malformations (CCMs): using single-nucleus DNA sequencing, they show homozygosity of chromosomes 7p and/or 7q leads to biallelic inactivation of CCM genes in resected lesions.
- Andrew K. Ressler
- , Daniel A. Snellings
- & Douglas A. Marchuk
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Article
| Open AccessDIAPH1-MFN2 interaction regulates mitochondria-SR/ER contact and modulates ischemic/hypoxic stress
Proximity between mitochondria and endoplasmic reticulum regulates mitochondria fitness and is adversely affected by tissue ischemia. This work reveals that Diaphanous1-Mitofusin2 interaction regulates this proximity and impairs recovery in ischemia.
- Gautham Yepuri
- , Lisa M. Ramirez
- & Ravichandran Ramasamy
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Article
| Open AccessEndothelial discoidin domain receptor 1 senses flow to modulate YAP activation
Mechanotransduction in endothelial cells is critical to maintain vascular homeostasis. Here, the authors show that the discoidin domain receptor 1 tyrosine kinase is a mechanosensor is essential for connecting the force imposed by shear to endothelial responses.
- Jiayu Liu
- , Chuanrong Zhao
- & Jing Zhou
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Article
| Open AccessMYH10 activation rescues contractile defects in arrhythmogenic cardiomyopathy (ACM)
Arrhythmogenic cardiomyopathy is an untreatable heart muscle disease and a common cause of sudden cardiac death in young athletes. The authors show a link between actomyosin dysregulation and cardiac dysfunction by studying nonsense PKP2 mutants classified as pathogenic to identify a potential treatment.
- Nieves García-Quintáns
- , Silvia Sacristán
- & Juan A. Bernal
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Article
| Open AccessIn vivo noninvasive systemic myography of acute systemic vasoactivity in female pregnant mice
The assessment of selective therapeutics targeted to treat altered vasoactivity, a major characteristic of cardiovascular and oncological diseases, is still challenging due to unknown whole-body selectivity. Here the authors demonstrate that photoacoustic tomography has the potential to capture significant acute vasodilation of major arteries and vasculature selectivity.
- Kristie Huda
- , Dylan J. Lawrence
- & Carolyn L. Bayer
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Article
| Open AccessComprehensive assessment of physiological responses in women during the ESA dry immersion VIVALDI microgravity simulation
To consider the impact of sex on adaptation to space, the European Space Agency initiated VIVALDI dry immersion microgravity simulation in female subjects. Here, the authors show marked deconditioning with 5-day exposure, and propose comprehensive multi-system physiological assessment in 18 healthy women.
- Adrien Robin
- , Angelique Van Ombergen
- & Nastassia Navasiolava
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Article
| Open AccessMechanically induced pyroptosis enhances cardiosphere oxidative stress resistance and metabolism for myocardial infarction therapy
Therapeutic options for myocardial infarction therapy remain limited. Here the authors report the application of an optimized liquid crystal substrate in the mass production and effective preconditioning of cardiospheres, which could generate cardiospheres with improved cell bioactivity and resistance to oxidative stress for myocardial infarction therapy.
- Yingwei Wang
- , Qi Li
- & Zheng Wu