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| Open AccessGenetically personalised organ-specific metabolic models in health and disease
Here, the authors present a method to build genetically personalised metabolic models across tissues to estimate individualised reaction fluxes. A fluxome-wide association study in UK Biobank identifies fluxes associated with metabolites and coronary artery disease.
- Carles Foguet
- , Yu Xu
- & Michael Inouye
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Article
| Open AccessThrombosis and thrombocytopenia after vaccination against and infection with SARS-CoV-2 in the United Kingdom
Population-based studies can provide information on the safety of COVID-19 vaccines. Here the authors report the rates thrombosis and thrombocytopenia after vaccination against and infection with SARS-CoV-2 in the United Kingdom and compare them with the background (expected) rates in the general population.
- Edward Burn
- , Xintong Li
- & Daniel Prieto-Alhambra
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Article
| Open AccessFunctionally integrating nanoparticles alleviate deep vein thrombosis in pregnancy and rescue intrauterine growth restriction
There is still an unmet need for effective and safe drugs to treat deep vein thrombosis during pregnancy, a life-threatening condition for the mother and fetus. Here, the authors show that engineered multifunctional nanoparticles can site-specifically dissolve thrombi and reverse deep vein thrombosis-mediated intrauterine growth restriction and delayed development of fetuses in pregnant rats.
- Juan Cheng
- , Siqi Zhang
- & Jianxiang Zhang
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Article
| Open AccessGenome-wide association and multi-trait analyses characterize the common genetic architecture of heart failure
Heart failure is a major cause of cardiovascular morbidity and mortality. Here, the authors report results of a genome-wide association study meta-analysis, characterizing the role of common genetic variants in heart failure, finding overlap with common cardiovascular risk factors and imaging measures of cardiac structure/function.
- Michael G. Levin
- , Noah L. Tsao
- & Scott M. Damrauer
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Article
| Open AccessMETTL14 is required for exercise-induced cardiac hypertrophy and protects against myocardial ischemia-reperfusion injury
The benefit of regular exercise on the heart has been well documented but the role of RNA m6A modification in exercise-induced cardiac remodelling remains largely unknown. In this study, the authors report that METTL14 plays an important role in RNA m6A modification in exercise-induced physiological cardiac hypertrophy.
- Lijun Wang
- , Jiaqi Wang
- & Junjie Xiao
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Article
| Open Access2′–5′ oligoadenylate synthetase‑like 1 (OASL1) protects against atherosclerosis by maintaining endothelial nitric oxide synthase mRNA stability
Maintaining optimal eNOS levels is important during cardiovascular events, although little is known regarding the mechanism of eNOS protection. Here, the authors show a regulatory role of endothelial OASL1 in maintaining eNOS mRNA stability and vascular biology under atheroprone conditions.
- Tae Kyeong Kim
- , Sejin Jeon
- & Goo Taeg Oh
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Article
| Open AccessMitochondrial Fission Process 1 controls inner membrane integrity and protects against heart failure
Mitochondria power the beating heart. Here, Donnarumma et al. show that loss of the inner mitochondrial membrane protein MTFP1 in cardiomyocytes reduces bioenergetic efficiency and cell death resistance leading to heart failure in mice.
- Erminia Donnarumma
- , Michael Kohlhaas
- & Timothy Wai
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Article
| Open Accessvon Willebrand factor links primary hemostasis to innate immunity
von Willebrand factor (VWF) plays a critical role in primary hemostasis following vascular injury by tethering platelets to exposed collagen. Here, VWF binding to macrophages is shown to trigger NF-κB activation and induce pro-inflammatory responses.
- Clive Drakeford
- , Sonia Aguila
- & James S. O’Donnell
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Article
| Open AccessSmall molecule-assisted assembly of multifunctional ceria nanozymes for synergistic treatment of atherosclerosis
Regulating reactive oxygen species and inflammation are important for treating atherosclerosis. Here, the authors create a cell membrane coated zoledronic acid ceria nanocomposite loaded with probucol for synergistic drug and scavenging nanozyme treatment of atherosclerosis demonstrating application in vivo.
- Xiaoxue Fu
- , Xiaojuan Yu
- & Chao Yu
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Article
| Open AccessIntramyocardial hemorrhage drives fatty degeneration of infarcted myocardium
It is unclear why hemorrhagic myocardial infarctions (hMI) are destined for adverse outcomes. Here, the authors show that hMI drives fatty degeneration of infarct territories and contributes to adverse remodeling of the heart, which can be mitigated via timely depletion of iron within the hMI zone.
- Ivan Cokic
- , Shing Fai Chan
- & Rohan Dharmakumar
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Article
| Open AccessMyocardial TRPC6-mediated Zn2+ influx induces beneficial positive inotropy through β-adrenoceptors
Baroreflex control of cardiac contractility is essential to maintain cardiocirculatory homeostasis. Here, Oda et al show that α1 adrenoceptor-stimulated Zn2+ entry through TRPC6 channels boosts β adrenoceptor-dependent myocardial positive inotropy.
- Sayaka Oda
- , Kazuhiro Nishiyama
- & Motohiro Nishida
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Article
| Open AccessKynurenine promotes neonatal heart regeneration by stimulating cardiomyocyte proliferation and cardiac angiogenesis
Failed cardiac regeneration to repair adult acute myocardial ischemia is the leading cause of heart failure. Here, the authors show that IDO1-derived kynurenine metabolism promotes cardiomyocyte proliferation and cardiac angiogenesis via cytoplasmic aryl hydrocarbon receptor (AhR) and nucleic AhR translocation signalling.
- Donghong Zhang
- , Jinfeng Ning
- & Ming-Hui Zou
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Article
| Open AccessE-cigarettes and their lone constituents induce cardiac arrhythmia and conduction defects in mice
The use of E-cigarettes has increased despite the unknown long-term effects. Here the authors show that e-cigarette aerosols alter cardiac conduction, repolarization, and autonomic regulation in mice, contingent on the chemical composition of e-liquids and partly through parasympathetic modulation.
- Alex P. Carll
- , Claudia Arab
- & Daniel J. Conklin
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Article
| Open AccessCryogenic contrast-enhanced microCT enables nondestructive 3D quantitative histopathology of soft biological tissues
The authors present cryogenic contrast-enhanced MicroCT (cryo-CECT), which by freezing stained samples at optimal freezing rates improves the visualization of the tissue microstructure. They demonstrate quantitative 3D analysis of individual tissue constituents, such as muscle and collagen fibers.
- Arne Maes
- , Camille Pestiaux
- & Greet Kerckhofs
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Article
| Open AccessTmem65 is critical for the structure and function of the intercalated discs in mouse hearts
The intercalated disc (ICD) is a membrane structure of the cardiac muscle involved in normal heart function. Here the authors report that knockdown of the ICD-bound transmembrane protein 65 results in impaired ICD structure, abnormal cardiac electrophysiology and cardiomyopathy in mice.
- Allen C. T. Teng
- , Liyang Gu
- & Anthony O. Gramolini
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Article
| Open AccessSystematic Mendelian randomization using the human plasma proteome to discover potential therapeutic targets for stroke
Mendelian randomization can be used to mimic the effects of protein-targeting drugs in a population of individuals. Here, the authors have identified potential causal proteins for stroke in a two-sample Mendelian randomization framework, providing potential stroke therapeutic targets.
- Lingyan Chen
- , James E. Peters
- & Joanna M. M. Howson
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Article
| Open AccessIntrinsic myocardial defects underlie an Rbfox-deficient zebrafish model of hypoplastic left heart syndrome
The developmental mechanisms responsible for the structural defects observed in hypoplastic left heart syndrome remain controversial. Using rbfox-deficient zebrafish, the authors implicate impaired cardiac function as a primary driver of disease.
- Mengmeng Huang
- , Alexander A. Akerberg
- & Caroline E. Burns
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Article
| Open AccessSingle-cell transcriptomics reveal cellular diversity of aortic valve and the immunomodulation by PPARγ during hyperlipidemia
Identifying the mechanisms underlying the early inflammatory phase of aortic valve disease is crucial for disease prevention. Here the authors perform single-cell RNA sequencing to show the immunomodulatory role of PPARγ in valvular endothelial cells during hyperlipidemia.
- Seung Hyun Lee
- , Nayoung Kim
- & Jae-Hoon Choi
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Article
| Open AccessThe complement C3-complement factor D-C3a receptor signalling axis regulates cardiac remodelling in right ventricular failure
Right ventricular (RV) failure is clinically crucial, but there is no specific therapy. Here, the authors show that the complement alternative pathway is activated in RV failure and that blockade of the pathway ameliorates RV failure in mice.
- Shogo Ito
- , Hisayuki Hashimoto
- & Shinsuke Yuasa
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Article
| Open AccessMild dyslipidemia accelerates tumorigenesis through expansion of Ly6Chi monocytes and differentiation to pro-angiogenic myeloid cells
Obesity and inflammation have been associated to cancer progression. Here, the authors show that high fat and cholesterol diet, in a non-obese context, promotes tumourigenesis through increasing inflammatory monocytes and myeloid-derived pro-angiogenic factors.
- Thi Tran
- , Jean-Remi Lavillegrand
- & Stephane Potteaux
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Article
| Open AccessClonal hematopoiesis of indeterminate potential, DNA methylation, and risk for coronary artery disease
Clonal hematopoiesis, often caused by mutations in DNMT3A and TET2, is associated with blood cancer and coronary artery disease. Here, the authors conduct an epigenome-wide association study, finding that clonal hematopoiesis caused by DNMT3A vs. TET2 mutations has directionally opposing changes in DNA methylation profiles, with both promoting stem cell self-renewal.
- M d Mesbah Uddin
- , Ngoc Quynh H. Nguyen
- & Karen N. Conneely
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Article
| Open AccessBeiging of perivascular adipose tissue regulates its inflammation and vascular remodeling
Perivascular adipose tissue (PVAT) has been reported to undergo inflammatory changes in response to vascular injury. Here, the authors show that vascular injury induces the beiging (brown adipose tissue-like phenotype change) of PVAT, which fine-tunes inflammatory response as a protective mechanism.
- Yusuke Adachi
- , Kazutaka Ueda
- & Issei Komuro
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Article
| Open AccessIdentification of risk loci for primary aldosteronism in genome-wide association studies
Detection of primary aldosteronism, the most common form of secondary arterial hypertension, is essential for targeted management and prevention of cardiovascular complications. Here, the authors identify genetic loci associated with primary aldosteronism, suggesting new mechanisms of disease.
- Edith Le Floch
- , Teresa Cosentino
- & Maria-Christina Zennaro
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Article
| Open AccessEndophenotype effect sizes support variant pathogenicity in monogenic disease susceptibility genes
Accurate classification of genetic variants is critical for research and patient care. Here, the authors report that population-based associations between rare variants and quantitative endophenotypes for monogenic diseases can provide support for variant pathogenicity.
- Jennifer L. Halford
- , Valerie N. Morrill
- & Steven A. Lubitz
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Article
| Open AccessAMPK deficiency in smooth muscles causes persistent pulmonary hypertension of the new-born and premature death
AMPK modulates idiopathic and hypoxic pulmonary hypertension in adults, largely via unknown mechanisms. Here, the authors show that AMPK deficiency in smooth muscles causes persistent pulmonary hypertension of the new born and premature death in mice, due to increased muscularisation and remodeling of pulmonary arteries, reduced alveolar numbers and alveolar membrane thickening
- Javier Moral-Sanz
- , Sophronia A. Lewis
- & A. Mark Evans
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Article
| Open AccessTransferability of genetic loci and polygenic scores for cardiometabolic traits in British Pakistani and Bangladeshi individuals
Most genetic studies of disease have been done in European ancestry cohorts, and the relevance to other populations is not guaranteed. Here, the authors use data from 22,000 British South Asian individuals and find that the transferability of polygenic scores was high for lipids and blood pressure, and lower for BMI and coronary artery disease.
- Qin Qin Huang
- , Neneh Sallah
- & Karoline Kuchenbaecker
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Article
| Open AccessSpatiotemporal dynamics of macrophage heterogeneity and a potential function of Trem2hi macrophages in infarcted hearts
Cellular composition and function are not clearly defined in heart failure after myocardial infarction. Here, using single cell and spatial transcriptomics in a MI-HF mouse model, the authors show that macrophages expressing Trem2 are found within the infarcts and this could be a useful biomarker.
- Seung-Hyun Jung
- , Byung-Hee Hwang
- & Yeun-Jun Chung
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Article
| Open AccessTargeting transcription in heart failure via CDK7/12/13 inhibition
In this study, Hsu et al. show that inhibition of CDK7/12/13 attenuates maladaptive transcriptional activation in cultured cardiomyocytes and a mouse model of heart failure, suggesting that targeting the transcription machinery might be a therapeutic approach to treat heart failure with reduced ejection fraction.
- Austin Hsu
- , Qiming Duan
- & Saptarsi M. Haldar
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| Open AccessThe RalGAPα1–RalA signal module protects cardiac function through regulating calcium homeostasis
Here the authors show that a RalGAPα1-RalA signal nexus regulates calcium homeostasis in cardiomyocytes via the calcium pump SERCA2a, which plays a protective role to maintain cardiac function under pressure overload conditions.
- Sangsang Zhu
- , Chao Quan
- & Shuai Chen
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Article
| Open AccessPost-recovery COVID-19 and incident heart failure in the National COVID Cohort Collaborative (N3C) study
The relationship between post-recovery COVID-19 and incident heart failure has not been investigated at scale. Here, the authors use electronic health records for ~600,000 patients in the US and find a higher rate of post-discharge incident heart failure in those hospitalised with COVID-19 than without.
- Husam M. Salah
- , Marat Fudim
- & Melissa C. Caughey
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Article
| Open AccessCardiac disruption of SDHAF4-mediated mitochondrial complex II assembly promotes dilated cardiomyopathy
Functional succinate dehydrogenase (SDH) complex is vital to mitochondrial homeostasis. Here the authors show that disruption of SDH assembly in the heart causes dilated cardiomyopathy via impairing the mitochondrial integrity and metabolism and that mitochondrial interventions can be an effective approach to ameliorate the disease progression.
- Xueqiang Wang
- , Xing Zhang
- & Zhihui Feng
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Article
| Open AccessSex differences in heart mitochondria regulate diastolic dysfunction
In this paper, the authors show that sex differences in mitochondrial DNA levels and function in the heart contribute to sex biases in functions relevant to heart failure, identifying Acsl6 as a mitochondrial sex-biased regulator of diastolic function.
- Yang Cao
- , Laurent Vergnes
- & Aldons J. Lusis
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Article
| Open AccessT cell cholesterol efflux suppresses apoptosis and senescence and increases atherosclerosis in middle aged mice
Cholesterol efflux is mediated by specific transporters in T cells. Here the authors show that when the ABCA1/ABCG1 cholesterol transporters are absent, peripheral T cell numbers are reduced but activation increased with a premature aging phenotype of T cell senescence and apoptosis in middle aged Ldlr−/− mice.
- Venetia Bazioti
- , Anouk M. La Rose
- & Marit Westerterp
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| Open AccessA multi-ethnic polygenic risk score is associated with hypertension prevalence and progression throughout adulthood
Polygenic risk scores have potential to predict an individual’s risk of disease based on genetic markers. Here, the authors develop a polygenic risk score for hypertension and test it in a multi-ethnic cohort, finding that the score is associated with higher likelihood of hypertension development 4-6 years later.
- Nuzulul Kurniansyah
- , Matthew O. Goodman
- & Tamar Sofer
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Article
| Open AccessCardiac fibroblasts regulate the development of heart failure via Htra3-TGF-β-IGFBP7 axis
Cardiac fibrosis is a hallmark of heart failure. Here the authors use single-cell RNA-sequencing, spatial transcriptomics, and genetic manipulations, to show that Htra3 regulates cardiac fibrosis by keeping fibroblasts quiescent and by degrading TGF-beta.
- Toshiyuki Ko
- , Seitaro Nomura
- & Issei Komuro
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Article
| Open AccessPerirenal adipose afferent nerves sustain pathological high blood pressure in rats
The sympathetic nervous system can contribute to the development of hypertension, but the neurogenic mechanisms involved are incompletely understood. Here the authors report that afferent nerves in the perirenal adipose tissue (PRAT) contribute to the maintenance of high blood pressure, and PRAT ablation, denervation or upregulation of calcitonin gene-related peptide reduce blood pressure in hypertensive rats.
- Peng Li
- , Boxun Liu
- & Xiangqing Kong
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Article
| Open AccessComprehensive genetic analysis of the human lipidome identifies loci associated with lipid homeostasis with links to coronary artery disease
Dysregulation of lipid metabolism is associated with coronary artery disease (CAD). Here, the authors perform GWAS of the serum lipidome to identify variants associated with lipid species that are putatively in the mechanistic pathway to CAD.
- Gemma Cadby
- , Corey Giles
- & Eric K. Moses
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Article
| Open AccessGenome-wide association analysis and replication in 810,625 individuals with varicose veins
Although varicose veins are a common condition, the genetic basis is not well understood. Here, the authors find genetic variants associated with varicose veins and show that a higher polygenic risk score for varicose veins correlates with a greater likelihood of patients undergoing surgical treatment.
- Waheed-Ul-Rahman Ahmed
- , Sam Kleeman
- & Dominic Furniss
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Article
| Open AccessMapping the cardiac vascular niche in heart failure
The cardiac vascular niche is of major importance in homeostasis and disease, but knowledge of its complexity in response to injury remains limited. Here we combine lineage tracing with single cell RNA sequencing to show alterations in fibroblasts, endothelial and mural cells in hypertrophic remodeling.
- Fabian Peisker
- , Maurice Halder
- & Rafael Kramann
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Article
| Open AccessOmega-3 fatty acid epoxides produced by PAF-AH2 in mast cells regulate pulmonary vascular remodeling
Pulmonary hypertension is a fatal disease that causes right heart failure due to pulmonary artery stenosis. Here, the authors find that ω-3 epoxides produced by the phospholipase PAF-AH2 in mast cells regulate pulmonary vascular remodeling.
- Hidenori Moriyama
- , Jin Endo
- & Motoaki Sano
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Article
| Open AccessThe gut microbiota-bile acid axis links the positive association between chronic insomnia and cardiometabolic diseases
Chronic insomnia is associated with cardiometabolic diseases. Here, in two clinical cohorts (n = 7,931), authors show that gut microbiota-bile acid axis may be an intervention target to attenuate the impact of chronic insomnia on cardiometabolic health.
- Zengliang Jiang
- , Lai-bao Zhuo
- & Ju-Sheng Zheng
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Article
| Open AccessMitochondrial calcium uniporter stabilization preserves energetic homeostasis during Complex I impairment
Mitochondrial complex I deficiency is frequent in congenital, neurologic and cardiovascular disease. Here the authors demonstrate that Complex I stimulates the turnover of a mitochondrial calcium channel, which becomes stabilized during Complex I deficiency, preserving energetic homeostasis.
- Enrique Balderas
- , David R. Eberhardt
- & Dipayan Chaudhuri
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Article
| Open AccessStructural identification of vasodilator binding sites on the SUR2 subunit
SUR2-containing KATP channels are drug targets for certain vasodilators. Here, the authors determine high-resolution cryo-EM structures of SUR2 in complex with two vasodilators, P1075 and levcromakalim, uncovering the mechanisms of these drugs.
- Dian Ding
- , Jing-Xiang Wu
- & Lei Chen
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Article
| Open AccessMeta-analysis of sub-Saharan African studies provides insights into genetic architecture of lipid traits
Genetic associations and polygenic scores for lipid traits have low transferability to African individuals. Here, the authors perform a large sub-Sarahan African lipid GWAS and find that larger datasets and better global representation in discovery GWAS help to bridge this gap.
- Ananyo Choudhury
- , Jean-Tristan Brandenburg
- & Michèle Ramsay
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Article
| Open AccessCrystal structures of BMPRII extracellular domain in binary and ternary receptor complexes with BMP10
Mutations in BMPR2 is the major genetic cause for pulmonary arterial hypertension (PAH). Here by solving crystal structures of BMPRII in binary and ternary receptor complexes with BMP10, the authors report the molecular recognition between BMPRII and BMP10, and its implication in PAH.
- Jingxu Guo
- , Bin Liu
- & Wei Li
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Article
| Open AccessPlacental multi-omics integration identifies candidate functional genes for birthweight
The placenta plays key roles in fetal development and subsequent health. Here, the authors integrate placental methylation and transcriptome data with genetic loci associated with birthweight to identify functional genes underpinning fetal growth regulation.
- Fasil Tekola-Ayele
- , Xuehuo Zeng
- & Ronald Wapner
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Article
| Open AccessCMYA5 establishes cardiac dyad architecture and positioning
Heart muscle cells exhibit exquisitely organized subcellular features that enable efficient and coordinated heart muscle contraction, but little is known about how it is achieved. Here the authors show that CMYA5 organizes cardiomyocyte calcium release units and aligns them to sarcomeres, leading to abnormal calcium release, cardiac dysfunction, and inability to tolerate pressure overload, when absent.
- Fujian Lu
- , Qing Ma
- & William T. Pu
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Article
| Open AccessACKR3 regulates platelet activation and ischemia-reperfusion tissue injury
ACKR3 is a critical regulator of platelet-mediated thrombosis and organ injury following ischemia/reperfusion. Platelet ACKR3 surface expression is independently associated with all-cause mortality in patients with cardiovascular diseases.
- Anne-Katrin Rohlfing
- , Kyra Kolb
- & Meinrad Gawaz
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Article
| Open AccessSelective optogenetic control of Gq signaling using human Neuropsin
Gq proteins are one of four major classes of G proteins; optogenetic receptors for selective and repetitive activation of Gq proteins with fast kinetics are lacking. Here the authors report UV light-dependent Gq signalling using human Neuropsin (hOPN5) and demonstrate its potential as an optogenetic tool.
- Ahmed Wagdi
- , Daniela Malan
- & Tobias Bruegmann