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| Open AccessMechanodetection of neighbor plants elicits adaptive leaf movements through calcium dynamics
Pantazopoulou et al. discovered that leaves sense neighbors by mutual touching of hairs on their surface, called trichomes. Using fluorescent biosensors, they show that this triggers a calcium wave to activate leaf movement away from competitors
- Chrysoula K. Pantazopoulou
- , Sara Buti
- & Ronald Pierik
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Article
| Open AccessSer14 phosphorylation of Bcl-xL mediates compensatory cardiac hypertrophy in male mice
The anti-apoptotic function of Bcl-xL in the heart is diminished by Mst1-mediated phosphorylation of Serine14. Here, the authors show that the Bcl-xL phosphorylation is also promoted by hemodynamic stress, which plays an essential role in mediating compensatory cardiac hypertrophy and contractility.
- Michinari Nakamura
- , Mariko Aoyagi Keller
- & Junichi Sadoshima
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Article
| Open AccessMonolayer platform to generate and purify primordial germ-like cells in vitro provides insights into human germline specification
Generation of primordial germ cell-like cells (PGCLCs) from human pluripotent cells (hPSCs) offers insight into the mechanisms underlying human reproduction, but often requires complex methods. Here they describe a simplified monolayer protocol to differentiate and purify PGCLCs for further analysis.
- Sivakamasundari Vijayakumar
- , Roberta Sala
- & Vittorio Sebastiano
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Article
| Open AccessTime space and single-cell resolved tissue lineage trajectories and laterality of body plan at gastrulation
Gastrulation entails a series of events that are highly coordinated in space and time. Here they construct a spatiotemporal molecular atlas of lineage trajectories in the gastrulating mouse embryo by mapping single cells to spatial coordinates in the germ layers with reference to positional data in the transcriptome.
- Ran Wang
- , Xianfa Yang
- & Naihe Jing
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Article
| Open AccessAlk1 acts in non-endothelial VE-cadherin+ perineurial cells to maintain nerve branching during hair homeostasis
Vascular endothelial (VE)-cadherin is a well-recognized endothelial cell marker. Here, the authors unveil unexpected heterogeneity in the skin VE-cadherin lineage, identifying a dynamic, non-endothelial VE-cadherin+ perineurial cell population.
- Gopal Chovatiya
- , Kefei Nina Li
- & Tudorita Tumbar
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Article
| Open AccessHuman blood vessel organoids reveal a critical role for CTGF in maintaining microvascular integrity
The microvasculature is critical for delivery of oxygen and metabolites throughout tissues. Here they use human blood vessel organoids to show that CTGF is a critical paracrine regulator of microvascular integrity that can restore pericyte coverage and vessel structure.
- Sara G. Romeo
- , Ilaria Secco
- & Anna Zampetaki
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Article
| Open AccessCyclic AMP induces reversible EPAC1 condensates that regulate histone transcription
Spatial compartmentalization is central to nuclear function. Here, the authors demonstrate that EPAC1 can enter the nucleus and regulate the transcription of a histone cluster by forming biomolecular condensates in its proximity in response to cAMP.
- Liliana Felicia Iannucci
- , Anna Maria D’Erchia
- & Konstantinos Lefkimmiatis
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Article
| Open AccessActivation of the integrated stress response by inhibitors of its kinases
The integrated stress response (ISR) is the focus of numerous investigations and drug development programs. Here, the authors show that ATP-competitive inhibitors of ISR kinases PERK, PKR and GCN2 inhibit their targets but activate the ISR by directly binding to and activating a sister ISR kinase.
- Maria Szaruga
- , Dino A. Janssen
- & Anne Bertolotti
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Article
| Open AccessSerotonin signaling regulates actomyosin contractility during morphogenesis in evolutionarily divergent lineages
Serotonin signaling is well known for modulating animal behavior. Here the authors discovered it plays a developmental role in regulating actomyosin contractility driven cellular mechanics and tissue flows during gastrulation of insect and bird.
- Sanjay Karki
- , Mehdi Saadaoui
- & Thomas Lecuit
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Article
| Open AccessAstrocyte reactivity and inflammation-induced depression-like behaviors are regulated by Orai1 calcium channels
Neuroinflammation is a common feature of many neurological disorders. Here, the authors show that the Orai1 calcium channel functions as a signaling hub in astrocytes to control astrocyte-driven brain inflammation and inflammation-induced depression-like behaviors in mice.
- Michaela M. Novakovic
- , Kirill S. Korshunov
- & Murali Prakriya
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Article
| Open AccessAryl hydrocarbon receptor utilises cellular zinc signals to maintain the gut epithelial barrier
Dietary zinc and plant-derived aryl hydrocarbon receptor (AHR) agonists are involved in maintaining intestinal epithelium integrity. The authors show that combined supplementation with AHR ligands and zinc might be effective in preventing inflammatory gut disorders.
- Xiuchuan (Lucas) Hu
- , Wenfeng Xiao
- & Christer Hogstrand
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Article
| Open AccessLrig1-expression confers suppressive function to CD4+ cells and is essential for averting autoimmunity via the Smad2/3/Foxp3 axis
Regulatory T cells, and to certain extent other T cell subsets, limit the immune response to avoid harmful inflammation and tissue damage. Here authors identify a surface molecule, Lrig1, that is directly responsible for the suppressive function in regulatory T cells and in Il-17-producing helper T cells.
- Jae-Seung Moon
- , Chun-Chang Ho
- & Sang-Kyou Lee
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Article
| Open AccessCENP-E activation by Aurora A and B controls kinetochore fibrous corona disassembly
It is unknown how the kinetochore fibrous corona is disassembled. Here, the authors reveal that Aurora A and B kinases-mediated phosphorylation activates CENP-E, which is essential to prevent the premature removal of corona proteins by dynein.
- Susana Eibes
- , Girish Rajendraprasad
- & Marin Barisic
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Article
| Open AccessNacα protects the larval fat body from cell death by maintaining cellular proteostasis in Drosophila
Protein homeostasis is crucial for maintaining cellular homeostasis. Here, the authors show that proteotoxic stress caused by Nacalpha mutants specifically and progressively induces cell death in the apoptosis-resistant Drosophila larval fat body.
- Takayuki Yamada
- , Yuto Yoshinari
- & Takashi Nishimura
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Article
| Open AccessLoss of LCMT1 and biased protein phosphatase 2A heterotrimerization drive prostate cancer progression and therapy resistance
Loss of PP2A activity is often associated with cancer but the underlying mechanism remains unclear. Here, the authors show that decreased methylation of PP2A catalytic C subunit caused by loss of LCMT-1 in prostate cancer abrogates the tumor suppressor activity of PP2A on AR/MED1-dependent gene expression, proposing decreased methyl-PP2A-C as a prognostic marker for prostate cancer progression.
- Reyaz ur Rasool
- , Caitlin M. O’Connor
- & Irfan A. Asangani
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Article
| Open AccessNeuronal ER-plasma membrane junctions couple excitation to Ca2+-activated PKA signaling
A-kinase anchoring proteins (AKAPs) target protein kinase A to specific locations within the cell. Here, the authors identify SPHKAP as an AKAP that enriches protein kinase A near ER-plasma membrane contact sites in brain neurons.
- Nicholas C. Vierra
- , Luisa Ribeiro-Silva
- & James S. Trimmer
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Article
| Open AccessPINK1 and Parkin regulate IP3R-mediated ER calcium release
Loss of two PD genes, PINK1 and Parkin, leads to a robust increase in ER calcium release. Here, the authors show that suppression of IP3R activity via inhibiting CISD1 is sufficient to rescue the PD-related phenotypes in PINK1 or Parkin null animal models.
- Su Jin Ham
- , Heesuk Yoo
- & Jongkyeong Chung
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Article
| Open AccessTIGIT can inhibit T cell activation via ligation-induced nanoclusters, independent of CD226 co-stimulation
CD226 provides a co-stimulatory signal to the T cell receptor during activation, and TIGIT is believed to inhibit this process by competing for the CD226 ligand CD155. Here authors show that ligand binding induces dense nanocluster formation by TIGIT which initiates intrinsic, CD226 independent inhibitory signals, proximal to T cell receptor signalling.
- Jonathan D. Worboys
- , Katherine N. Vowell
- & Daniel M. Davis
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Article
| Open AccessEndothelial ERα promotes glucose tolerance by enhancing endothelial insulin transport to skeletal muscle
Estrogen has anti-diabetic effects via estrogen receptor alpha (ERα). Here, authors show that via coupled nuclear and non-nuclear actions, ERα in endothelial cells promotes insulin transport to skeletal muscle to foster normal glucose homeostasis.
- Anastasia Sacharidou
- , Ken Chambliss
- & Philip W. Shaul
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Article
| Open AccessIntegrin β3 directly inhibits the Gα13-p115RhoGEF interaction to regulate G protein signaling and platelet exocytosis
Zhang et al. show that the adhesion receptor integrin β3 directly inhibits G protein mediated RhoA activation and granule secretion. A peptide mimicking this effect selectively inhibits platelet secretion but not integrin-mediated platelet adhesion.
- Yaping Zhang
- , Xiaojuan Zhao
- & Xiaoping Du
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Article
| Open AccessSpinal cord repair is modulated by the neurogenic factor Hb-egf under direction of a regeneration-associated enhancer
Zebrafish can regenerate after paralyzing spine injuries and regain locomotor ability, unlike mammals. Here authors show that the neurogenic factor Hb-egf promotes spinal cord regeneration in zebrafish and is regulated by an enhancer that can similarly direct expression in the pro-regenerative setting of neonatal mice.
- Valentina Cigliola
- , Adam Shoffner
- & Kenneth D. Poss
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Article
| Open AccessMTH1 protects platelet mitochondria from oxidative damage and regulates platelet function and thrombosis
MTH1 hydrolyzes oxidized nucleotides to prevent their mis-incorporation into DNA under oxidative stress. Here, the authors show that MTH1 is expressed in platelets and its deficiency increases mitochondrial DNA oxidative damage, impairs platelet function and hemostasis.
- Yangyang Ding
- , Xiang Gui
- & Jianlin Qiao
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Article
| Open AccessA HIF independent oxygen-sensitive pathway for controlling cholesterol synthesis
Cholesterol synthesis is highly oxygen consuming but how it is regulated by oxygen levels has not been clear. Here, Dickson et al. identify a HIF-independent, oxygen-sensing pathway for controlling cholesterol synthesis in human cells involving hypoxic-mediated degradation of SREBP2.
- Anna S. Dickson
- , Tekle Pauzaite
- & James A. Nathan
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Article
| Open AccessPathway selectivity in Frizzleds is achieved by conserved micro-switches defining pathway-determining, active conformations
Signaling pathway selectivity downstream of GPCRs is not fully understood. Here, authors perform functional analysis of Frizzled mutants to uncover state-stabilizing residues or ‘micro-switches’ mediating selectivity towards Disheveled over G proteins.
- Lukas Grätz
- , Maria Kowalski-Jahn
- & Gunnar Schulte
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Article
| Open AccessModulating p38 MAPK signaling by proteostasis mechanisms supports tissue integrity during growth and aging
The extent of phosphorylated p38 MAPK is known to determine signaling. Here, the authors show the relative pool of non-phosphorylated p38 MAPK modulates signaling output to control growth, lysosome formation and neuronal integrity during early aging.
- Wang Yuan
- , Yi M. Weaver
- & Benjamin P. Weaver
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Article
| Open AccessCircular RNA encoded MET variant promotes glioblastoma tumorigenesis
MET signalling is required for glioblastoma (GBM) stem cell maintenance. Here the authors identify a circular RNA from the MET gene (circMET) that encodes a MET variant protein (MET404) and show that it can promote GBM tumorigenesis by directly activating the MET receptor independent of HGF stimulation.
- Jian Zhong
- , Xujia Wu
- & Nu Zhang
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Article
| Open AccessMacrophage-to-endothelial cell crosstalk by the cholesterol metabolite 27HC promotes atherosclerosis in male mice
Hypercholesterolemia and vascular inflammation both contribute to the pathogenesis of atherosclerosis, but how hypercholesterolemia initiates vascular inflammation is not fully understood. Here the authors report that crosstalk between macrophages and endothelial cells mediated by the cholesterol metabolite 27-hydroxycholesterol drives vascular inflammation and contributes to atherosclerosis in male mice.
- Liming Yu
- , Lin Xu
- & Philip W. Shaul
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Article
| Open AccessHighly specific and non-invasive imaging of Piezo1-dependent activity across scales using GenEPi
Stretch-activated ion channel Piezo1 contribures to mechanotransduction in many tissues, but its output is mostly measured indirectly. Here, the authors introduce GenEPi, a fluorescent reporter for directly visualizing Piezo1 activation-dependent calcium influx.
- Sine Yaganoglu
- , Konstantinos Kalyviotis
- & Periklis Pantazis
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Article
| Open AccessNuclear translocation of mitochondrial dehydrogenases as an adaptive cardioprotective mechanism
Chemotherapy can cause severe damage to cardiomyocytes in some patients but it is unclear how cardiomyocytes protect themselves against such stress. Here the authors show that cardiomyocytes initiate an endogenous protective response when exposed to chemotherapeutic agents by translocating mitochondrial enzymes to the nucleus.
- Shubhi Srivastava
- , Priyanka Gajwani
- & Jalees Rehman
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Article
| Open AccessLysosomal cystine export regulates mTORC1 signaling to guide kidney epithelial cell fate specialization
Cystinosis is a lysosomal storage disease that affects the kidney. Here, the authors use preclinical models and advanced profiling techniques to discover the mechanism by which defective cystine mobilization from lysosomes disrupts kidney cell function, offering insights into potential therapies.
- Marine Berquez
- , Zhiyong Chen
- & Alessandro Luciani
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Article
| Open AccessReprogramming of the transcriptome after heat stress mediates heat hormesis in Caenorhabditis elegans
Xu and colleagues report that the poly-U-specific endoribonuclease ENDU-2/ENDOU activates a transcriptional reprogramming after a brief heat shock and this has a long-term beneficial effect in the model organism C. elegans.
- Fan Xu
- , Ruoyao Li
- & Wenjing Qi
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Article
| Open AccessDeciphering intercellular signaling complexes by interaction-guided chemical proteomics
Systematic profiling of the indirect cell–cell interactions remains challenging. Here, the authors report a chemical proteomics method to identify ligand-receptor complexes formed between cell surface receptors and secreted proteins from neighboring cells.
- Jiangnan Zheng
- , Zhendong Zheng
- & Ruijun Tian
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Comment
| Open AccessLimited choice of natural amino acids as mimetics restricts design of protein lysine methylation studies
Protein lysine methylation plays important biological roles but its experimental characterization is limited by the lack of suitable mimetics of methylated and unmethylated lysine among the natural amino acids. Here, we summarize the consequent challenges and discuss alternative approaches for biochemical and cellular lysine methylation studies.
- Sara Weirich
- & Albert Jeltsch
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Article
| Open AccessImbalanced unfolded protein response signaling contributes to 1-deoxysphingolipid retinal toxicity
The accumulation of cytotoxic deoxysphingolipids causes retinopathies through unknown mechanisms. Here the authors use retinal organoids to show that photoreceptor toxicity is mediated by unfolded protein response signaling.
- Jessica D. Rosarda
- , Sarah Giles
- & Kevin T. Eade
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Article
| Open AccessEndothelial cell CD36 regulates membrane ceramide formation, exosome fatty acid transfer and circulating fatty acid levels
Endothelial cell CD36 controls tissue fatty acid uptake. Here the authors show how fatty acid uptake by endothelial cells involves regulation of membrane ceramide production, caveolae dynamics, and exosome generation, these events facilitate transfer of circulating fatty acids to tissues and communication between endothelium and parenchyma.
- V. S. Peche
- , T. A. Pietka
- & N. A. Abumrad
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Article
| Open AccessSpatialDM for rapid identification of spatially co-expressed ligand–receptor and revealing cell–cell communication patterns
Spatial omics are increasingly being recognised to study cell-cell communications. Here, the authors present a bioinformatics toolbox for rapid identification of spatially co-expressed ligand-receptor and revealing cell-cell communication patterns.
- Zhuoxuan Li
- , Tianjie Wang
- & Yuanhua Huang
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Matters Arising
| Open AccessPotential contribution of PEP carboxykinase-dependent malate dismutation to the hypoxia response in C. elegans
- Rosina Comas-Ghierra
- , Laura Romanelli-Cedrez
- & Gustavo Salinas
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Matters Arising
| Open AccessReply to: Potential contribution of PEP carboxykinase-dependent malate dismutation to the hypoxia response in C. elegans
- Mehul Vora
- , Stephanie M. Pyonteck
- & Christopher Rongo
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Article
| Open AccessTargeted protein degradation reveals BET bromodomains as the cellular target of Hedgehog pathway inhibitor-1
Understanding the cellular target of hit compounds from phenotypic screens presents a major challenge yet is essential in the development of chemical probes. Here, the authors reveal the target of Hedgehog Pathway Inhibitor-1, by converting it to a bifunctional degrader, to be BET bromodomains.
- Meropi Bagka
- , Hyeonyi Choi
- & Sascha Hoogendoorn
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Article
| Open AccessSubcellular second messenger networks drive distinct repellent-induced axon behaviors
Signals from extracellular cues orienting growing axons are thought to be integrated by second messenger molecules. Here, Baudet et al. instead demonstrate that distinct axon guidance cues induce cAMP, cGMP and Ca2+ signals restricted to separate cellular nanodomains.
- Sarah Baudet
- , Yvrick Zagar
- & Xavier Nicol
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Article
| Open AccessAn optogenetic-phosphoproteomic study reveals dynamic Akt1 signaling profiles in endothelial cells
Different activation patterns of Akt kinase direct downstream signaling outcomes. Here, the authors run phosphoproteomics on optogenetically-activated Akt1 to characterize the phosphorylation circuits induced by different intensities, durations, and patterns of stimulation.
- Wenping Zhou
- , Wenxue Li
- & Yansheng Liu
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Article
| Open AccessStructural basis of the interaction between BCL9-Pygo and LDB-SSBP complexes in assembling the Wnt enhanceosome
The Wnt enhanceosome is responsible for the transactivation of Wnt target genes in response to stimulation of cells by extracellular Wnt signals. Here, Wang et al. show BCL9, Pygo, LDB1 and SSBP form a stable core complex within the Wnt enhanceosome. Furthermore, they determine the crystal structure of the Pygo2-LDB1-SSBP2 ternary complex, which provides a promising therapeutic target for blocking Wnt/β-catenin signaling in cancer.
- Hongyang Wang
- , Mariann Bienz
- & Wenqing Xu
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Article
| Open AccessMitochondrial aconitase suppresses immunity by modulating oxaloacetate and the mitochondrial unfolded protein response
Mitochondrial function has been linked to immunity but the role of the Krebs’s cycle in regards the immune response is not well characterised. Here the authors show that Krebs’s cycle enzyme ACO2 suppresses immunity via modulation of oxaloacetate and the mitochondrial unfolded protein response.
- Eunah Kim
- , Andrea Annibal
- & Seung-Jae V. Lee
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Article
| Open AccessStructural insights into regulation of the PEAK3 pseudokinase scaffold by 14-3-3
PEAK pseudokinases are emerging disease targets, which regulate cell migration and proliferation through protein scaffolding. Here, the authors present the cryo-EM structure of the PEAK3/14-3-3 complex and reveal how 14-3-3 modulates PEAK3 localization and protein-protein interactions.
- Hayarpi Torosyan
- , Michael D. Paul
- & Kliment A. Verba
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Article
| Open AccessA convolutional neural network STIFMap reveals associations between stromal stiffness and EMT in breast cancer
The link between stiffness heterogeneity and tumor cell heterogeneity remains poorly understood. Here, authors propose an AI-informed method that reveals correlations between stromal stiffness and breast cancer cells with a heterogeneous EMT phenotype.
- Connor Stashko
- , Mary-Kate Hayward
- & Valerie M. Weaver
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Article
| Open AccessCNK2 promotes cancer cell motility by mediating ARF6 activation downstream of AXL signalling
Cancer cell motility is necessary for cell invasion and metastasis. Here, the authors identify CNK2 as a key mediator of cancer cell motility, linking extracellular stimuli via AXL signalling and downstream activation of ARF6 GTPase, resulting in increased metastasis in preclinical models.
- Guillaume Serwe
- , David Kachaner
- & Marc Therrien
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Article
| Open Accesshapln1a+ cells guide coronary growth during heart morphogenesis and regeneration
The guidance cues critical for coronary growth remain unclear. Here, Sun et al. reveal the requirement of hapln1a+ cells and serpine1 to establish a microenvironment for guided coronary growth during zebrafish heart morphogenesis and regeneration.
- Jisheng Sun
- , Elizabeth A. Peterson
- & Jinhu Wang
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Article
| Open AccessSERCA2 phosphorylation at serine 663 is a key regulator of Ca2+ homeostasis in heart diseases
Despite advances in cardioprotection, new therapeutic strategies precluding ischemia-reperfusion injury of patients are still needed. Here, the authors show that preventing serine 663 phosphorylation of SERCA2, significantly increases its activity and protects against cell death, by counteracting cytosolic and mitochondrial Ca2+ overload.
- Fabrice Gonnot
- , Laura Boulogne
- & Ludovic Gomez
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Article
| Open AccessSystematic literature review reveals suboptimal use of chemical probes in cell-based biomedical research
Chemical probes and their correct use are essential for accurate and robust data. Here, authors show that only 4% of analyzed publications used chemical probes in line with recommendations. This indicates that the best practice with chemical probes is yet to be implemented in research.
- Jayden Sterling
- , Jennifer R. Baker
- & Lenka Munoz