Featured
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Article
| Open AccessPhenylalanine impairs insulin signaling and inhibits glucose uptake through modification of IRβ
Whether amino acids act on cellular insulin signaling remains unclear. Here, the authors find that phenylalanine modifies insulin receptor beta (IRβ) and inactivates insulin signaling and glucose uptake and positively correlated with T2D onset.
- Qian Zhou
- , Wan-Wan Sun
- & Shi-Min Zhao
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Article
| Open AccessMalaria parasite heme biosynthesis promotes and griseofulvin protects against cerebral malaria in mice
Malaria parasite heme pathway is non-essential for blood stages, but essential for mosquito and liver stages. Here, the authors show that heme pathway promotes cerebral pathogenesis by enhancing hemozoin formation and that targeting it with griseofulvin inhibits cerebral malaria in mice.
- Manjunatha Chandana
- , Aditya Anand
- & Viswanathan Arun Nagaraj
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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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Article
| Open AccessWASp modulates RPA function on single-stranded DNA in response to replication stress and DNA damage
Cancer develops in Wiskott-Aldrich syndrome (WAS). Here the authors identify a role for WAS-protein (WASp) in the DNA stress-resolution pathway by promoting the function of Replication Protein A at replication forks after DNA damage.
- Seong-Su Han
- , Kuo-Kuang Wen
- & Yatin M. Vyas
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Article
| Open AccessLight-induced charge generation in polymeric nanoparticles restores vision in advanced-stage retinitis pigmentosa rats
Retinal dystrophies such as Retinitis pigmentosa are among the most prevalent causes of inherited incurable legal blindness. Here the authors demonstrate that conjugated polymer nanoparticles reinstate visual functions in aged rats with fully degenerated and rewired retinas.
- S. Francia
- , D. Shmal
- & F. Benfenati
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Review Article
| Open AccessIdentification, discrimination and heterogeneity of fibroblasts
In this review, the authors look at how recent progress in single-cell transcriptomics complement and enrich the classical, largely morphological, portraits of fibroblasts. The detailed molecular information now available provides new insights into fibroblast identity, heterogeneity and function.
- Urban Lendahl
- , Lars Muhl
- & Christer Betsholtz
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Article
| Open AccessVariants in ASPH cause exertional heat illness and are associated with malignant hyperthermia susceptibility
The genetic cause(s) of malignant hyperthermia and exertional heat illness are unknown in approximately 30% of cases. To address this barrier, the authors performed genome sequencing on a large cohort of cases, identifying rare variants in ASPH, a gene encoding junctin, and validating them in animal and cell models.
- Yukari Endo
- , Linda Groom
- & James J. Dowling
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Article
| Open AccessNUP62 localizes to ALS/FTLD pathological assemblies and contributes to TDP-43 insolubility
ALS and FTLD are both characterized by insoluble cytoplasmic depositions of TDP43. Here the authors show that the nucleopore protein NUP62 is mislocalized in C9orf72 and sporadic ALS/FTLD and propose that it interacts with TDP-43 to promote its insolubility.
- Amanda M. Gleixner
- , Brandie Morris Verdone
- & Christopher J. Donnelly
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Article
| Open AccessPersister state-directed transitioning and vulnerability in melanoma
Slow-cycling melanoma persister cells are characterised by a high, reversible expression of H3K4 demethylase KDM5B. Here, the authors use genetic and chemical methods to enforce a permanent high expression of KDM5B and show that these cells transit to a melanocytic differentiated state and undergo cell cycle arrest.
- Heike Chauvistré
- , Batool Shannan
- & Alexander Roesch
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Article
| Open AccessThe genomic landscape of cholangiocarcinoma reveals the disruption of post-transcriptional modifiers
Cholangiocarcinoma is a heterogenous group of cancers, with large genetic variation seen within subtypes. Here, the authors find 12 significantly mutated genes and 5 focal CNA regions were found in perihilar cholangiocarcinoma, and identified METTL14 to have a potential tumour suppressive role.
- Yaodong Zhang
- , Zijian Ma
- & Xiangcheng Li
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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 AccessDepletion of skeletal muscle satellite cells attenuates pathology in muscular dystrophy
Boyer et al. created genetic mouse models of muscular dystrophy in which satellite cells were selectively depleted. The depletion of satellite cells at select times was protective. Myofibers no longer had plasma membrane instability leading to tissue wasting in the muscular dystrophies.
- Justin G. Boyer
- , Jiuzhou Huo
- & Jeffery D. Molkentin
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Article
| Open AccessAnoctamin 1 controls bone resorption by coupling Cl− channel activation with RANKL-RANK signaling transduction
Osteoclast over-activation leads to bone loss and chloride homeostasis is important for osteoclast function. Here, the authors show that Anoctamin 1 controls bone resorption by coupling Cl− channel activation with RANKL-RANK signaling transduction.
- Weijia Sun
- , Shuai Guo
- & Yingxian Li
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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 AccessNeuroligin-mediated neurodevelopmental defects are induced by mitochondrial dysfunction and prevented by lutein in C. elegans
Mitochondrial deficiency causes rare incurable disorders. Here, the authors use C. elegans to study these diseases and find that the natural compound lutein prevents neurodevelopmental deficits, thus pointing to a possible therapeutic target for the human diseases.
- Silvia Maglioni
- , Alfonso Schiavi
- & Natascia Ventura
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Article
| Open AccessStress-induced protein disaggregation in the endoplasmic reticulum catalysed by BiP
Aggregation of misfolded proteins underlie dementias. Here, the authors show that stressed cells activate an innate mechanism to resolve aggregates of defective proteins in the endoplasmic reticulum, where a third of cellular proteins are produced.
- Eduardo Pinho Melo
- , Tasuku Konno
- & Edward Avezov
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Article
| Open AccessSimultaneous stabilization of actin cytoskeleton in multiple nephron-specific cells protects the kidney from diverse injury
A common cellular manifestation for diverse kidney diseases is dysregulated actin cytoskeleton in distinct cell types that include glomerular podocytes and tubular epithelial cells. Here, authors pharmacologically activate dynamin and this results in polymerization and crosslinking of actin filaments to establish the structural integrity of these cells, thus ameliorating disease phenotypes.
- Kamalika Mukherjee
- , Changkyu Gu
- & Sanja Sever
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Article
| Open AccessCFTR mRNAs with nonsense codons are degraded by the SMG6-mediated endonucleolytic decay pathway
Currently, there is no therapy for patients with cystic fibrosis caused by nonsense mutations. Here the authors show that CFTR mRNAs with nonsense codons are predominantly degraded by the SMG6-mediated branch of the NMD pathway, providing potential therapeutic strategies for the devastating disease.
- Edward J. Sanderlin
- , Melissa M. Keenan
- & Lulu Huang
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Article
| Open AccessHeterozygous frameshift variants in HNRNPA2B1 cause early-onset oculopharyngeal muscular dystrophy
Missense variants in RNA-binding proteins underlie many diseases. Here the authors report an oculopharyngeal muscular dystrophy caused by heterozygous frameshift mutations in HNRNPA2B1 that alter its nucleocytoplasmic transport dynamics and result in cytoplasmic accumulation of hnRNPA2 protein.
- Hong Joo Kim
- , Payam Mohassel
- & J. Paul Taylor
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Article
| Open AccessMapping SP-C co-chaperone binding sites reveals molecular consequences of disease-causing mutations on protein maturation
Interstitial Lung Disease (ILD)-associated mutations in surfactant protein C (SP-C) render the protein prone to aggregation. Here, the authors reveal their impact on protein maturation, provide insights into recognition of aggregation prone regions by chaperones, and address the autosomal dominant nature of ILD mutants.
- Kristine F. R. Pobre-Piza
- , Melissa J. Mann
- & Linda M. Hendershot
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Article
| Open AccessOpposite physiological and pathological mTORC1-mediated roles of the CB1 receptor in regulating renal tubular function
Renal proximal tubules modulate whole-body homeostasis by sensing various nutrients. Here the authors describe the existence and importance of a unique CB1/mTORC1/GLUT2 signaling axis in regulating nutrient homeostasis in healthy and diseased kidney.
- Liad Hinden
- , Majdoleen Ahmad
- & Joseph Tam
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Article
| Open AccessUltrastructural insight into SARS-CoV-2 entry and budding in human airway epithelium
Human airway epithelium infected with SARS-CoV-2 shows viral entry occurring at the apical plasma membrane, excluding cilia. Here, the visualization of viral fusion at the cell surface and budding profiles within infected cells through high-resolution electron microscopy and tomography provide new insight into the infection process.
- Andreia L. Pinto
- , Ranjit K. Rai
- & Thomas Burgoyne
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Article
| Open AccessZebrafish imaging reveals TP53 mutation switching oncogene-induced senescence from suppressor to driver in primary tumorigenesis
It is unclear how a single oncogenic cell primes tumorigenesis. Here the authors visualised this behaviour using a zebrafish larval skin as a model and show that RasG12V oncogenic cell is eliminated through oncogene-senescence while a gain of function mutation in p53 alters this behaviour from tumour suppressive to tumour promoting.
- Yukinari Haraoka
- , Yuki Akieda
- & Tohru Ishitani
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Article
| Open AccessWTAP-mediated m6A modification of lncRNA NORAD promotes intervertebral disc degeneration
Intervertebral disc degeneration (IVDD) is the leading cause of low back pain and Nucleus pulposus cell senescence contributes a lot to its progression. Here, the authors reveal WTAP-mediated m6A modification of lncRNA NORAD promotes IVDD.
- Gaocai Li
- , Liang Ma
- & Cao Yang
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Article
| Open AccessLoss of the Bardet-Biedl protein Bbs1 alters photoreceptor outer segment protein and lipid composition
Primary cilia are key sensory organelles whose dysfunction leads to ciliopathy disorders such as Bardet-Biedl syndrome (BBS). Here they identify a role for Bbs1 in lipid homeostasis of photoreceptor outer segments in zebrafish, which may contribute to vision loss in patients with Bardet-Biedl syndrome.
- Markus Masek
- , Christelle Etard
- & Ruxandra Bachmann-Gagescu
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Article
| Open AccessSirtuin-1 sensitive lysine-136 acetylation drives phase separation and pathological aggregation of TDP-43
TDP-43 is a nucleic acid binding protein, whose insoluble aggregates are neuropathological hallmarks of specific subsets of patients with amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Post-translational modifications and acetylation of TDP-43 impact its interaction with RNA, its localization in the cells, and are linked to disease. Using antibodies generated against TDP-43 lysine acetylation sites, sirtuin-1 was found to potently deacetylate amber suppressed [acK136]TDP-43 and reduce its aggregation propensity. Thus, distinct lysine acetylations modulate nuclear import, RNA binding as well as phase separation and aggregation of TDP-43, suggesting regulatory mechanisms for TDP-43 pathogenesis.
- Jorge Garcia Morato
- , Friederike Hans
- & Philipp J. Kahle
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Article
| Open AccessATAD3A oligomerization promotes neuropathology and cognitive deficits in Alzheimer’s disease models
Disturbance in lipid metabolism is one of the major pathological events in Alzheimer’s disease (AD). Here, the authors identify ATAD3A oligomerization as a key mechanism causing impaired cholesterol metabolism and neuropathology in AD models.
- Yuanyuan Zhao
- , Di Hu
- & Xin Qi
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Article
| Open AccessAP-4-mediated axonal transport controls endocannabinoid production in neurons
Davies et al. identify a putative mechanism underlying the childhood neurological disorder AP-4 deficiency syndrome. In the absence of AP-4, an enzyme that makes 2-AG is not transported to the axon, leading to axonal growth defects, which can be rescued by inhibition of 2-AG breakdown.
- Alexandra K. Davies
- , Julian E. Alecu
- & Georg H. H. Borner
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Article
| Open AccessHeterogeneous repolarization creates ventricular tachycardia circuits in healed myocardial infarction scar
Ventricular arrhythmias after heart attack are a leading cause of death. Here the authors show, in a porcine model, that KCNE3 and KCNE4 upregulation and a unique pattern of repolarization heterogeneity in the scar facilitate reentrant ventricular tachycardia.
- Kamilla Kelemen
- , Ian D. Greener
- & J. Kevin Donahue
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Article
| Open AccessEndogenous formaldehyde scavenges cellular glutathione resulting in redox disruption and cytotoxicity
Formaldehyde (FA) is known to exert cytotoxicity through DNA damage. Here, the authors show that FA also triggers cellular redox imbalance by reacting with glutathione (GSH), and that FA cytotoxicity is prevented by GSH synthesis and by ADH5, an enzyme that metabolizes FA-GSH products.
- Carla Umansky
- , Agustín E. Morellato
- & Lucas B. Pontel
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Article
| Open AccessA disease-linked lncRNA mutation in RNase MRP inhibits ribosome synthesis
Mutations in the non-coding RNA RMRP cause primary immunodeficiency. Robertson et al show that a disease-associated mutation in RMRP impairs pre-ribosomal RNA processing and reduces ribosome abundance, establishing this disorder as a ribosomopathy.
- Nic Robertson
- , Vadim Shchepachev
- & David Tollervey
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Article
| Open AccessDepletion of mitochondrial methionine adenosyltransferase α1 triggers mitochondrial dysfunction in alcohol-associated liver disease
Lower activity of MATα1, which catalyzes the synthesis of the methyl donor S-adenosylmethionine, and mitochondrial dysfunction occur in alcohol-associated liver disease (ALD). Here the authors report that the peptidyl-prolyl cis/trans isomerase PIN1 mediates a selective depletion of MATα1 in the mitochondria, which contributes to mitochondrial dysfunction and fat accumulation, in mouse models of ALD.
- Lucía Barbier-Torres
- , Ben Murray
- & Shelly C. Lu
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Article
| Open AccessDivalent metal cations stimulate skeleton interoception for new bone formation in mouse injury models
Mechanisms underlying bone formation induced by divalent metal cations remain largely unknown. Here the authors show that these cations can activate the skeleton interoceptive circuit through the immune-neural axis to initiate new bone formation.
- Wei Qiao
- , Dayu Pan
- & Xu Cao
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Article
| Open AccessAberrant upregulation of the glycolytic enzyme PFKFB3 in CLN7 neuronal ceroid lipofuscinosis
CLN7 neuronal ceroid lipofuscinosis is an inherited lysosomal storage disease typically with childhood onset of neurodegenerative symptoms. Here the authors report that in a mouse model of CLN7 disease neuronal reactive oxygen species and the activity of glycolytic enzyme PFKFB3 are increased, while PFKFB3 inhibition ameliorates hallmarks of pathology.
- Irene Lopez-Fabuel
- , Marina Garcia-Macia
- & Juan P. Bolaños
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Article
| Open AccessCharacterization of the COPD alveolar niche using single-cell RNA sequencing
Chronic obstructive pulmonary disease is a leading cause of death worldwide, while our understanding of cell-specific mechanisms underlying its pathobiology remains incomplete. Here the authors perform scRNA-seq of human lung tissue to identify transcriptional changes in alveolar niche cells associated with the disease.
- Maor Sauler
- , John E. McDonough
- & Ivan O. Rosas
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Article
| Open AccessEnrichment of the exocytosis protein STX4 in skeletal muscle remediates peripheral insulin resistance and alters mitochondrial dynamics via Drp1
STX4 is a regulator of the glucose transporter GLUT4 vesicle fusion at the plasma membrane in skeletal muscle. Here, the authors show that skeletal muscle-specific STX4 enrichment reverses established insulin resistance and improves mitochondrial function in the context of diabetogenic stress.
- Karla E. Merz
- , Jinhee Hwang
- & Debbie C. Thurmond
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Article
| Open AccessRetinal pigment epithelium-specific CLIC4 mutant is a mouse model of dry age-related macular degeneration
Age-related macular degeneration (AMD) is a leading cause of blindness and is characterised by the accumulation of lipid deposits, called drusen. Here, the authors show that mice lacking chloride intracellular channel 4 in retinal pigment epithelium have defective lipid processing in the eye and pathological features mirroring human AMD, including drusen formation.
- Jen-Zen Chuang
- , Nan Yang
- & Ching-Hwa Sung
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Article
| Open AccessLung emphysema and impaired macrophage elastase clearance in mucolipin 3 deficient mice
Excess macrophage elastase MMP-12 is a major driver of chronic obstructive pulmonary disease. Here the authors show that the endolysosomal ion channel TRPML3 is a regulator of the cellular reuptake of MMP-12, thus neutralizing harmful MMP-12 in the lung.
- Barbara Spix
- , Elisabeth S. Butz
- & Christian Grimm
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Article
| Open AccessGenomic loci mispositioning in Tmem120a knockout mice yields latent lipodystrophy
Little is known how spatial genome organization is directed in fat; however, key proadipogenic genes reposition from the nuclear envelope (NE) to the interior during adipogenesis. Here the authors show that deletion of NE protein Tmem120a in adipocytes disrupts fat genome organization, which results in suppression of lipid metabolism pathways and induces myogenic gene expression.
- Rafal Czapiewski
- , Dzmitry G. Batrakou
- & Eric C. Schirmer
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Article
| Open AccessMatrix mechanics regulates epithelial defence against cancer by tuning dynamic localization of filamin
Epithelial cells have the ability to competitively remove potentially cancerous cells from the tissue. Here the authors discover that pathological stiffening of extracellular matrix leads to the loss of this basic epithelial defence against cancer.
- Shilpa P. Pothapragada
- , Praver Gupta
- & Tamal Das
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Article
| Open AccessMAPK4 promotes triple negative breast cancer growth and reduces tumor sensitivity to PI3K blockade
PI3K inhibitors have limited efficacy in triple negative breast cancer (TNBC). Here, the authors show that MAPK4 activates AKT independent of PI3K and thus promotes tumour growth in a subset of TNBC and that MAPK4 inhibition sensitizes to PI3K blockade in these tumours.’
- Wei Wang
- , Dong Han
- & Feng Yang
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Article
| Open AccessTartrate-resistant acid phosphatase 5 promotes pulmonary fibrosis by modulating β-catenin signaling
Idiopathic pulmonary fibrosis is a fatal lung disease with limited treatment options. Here the authors show that tartrate-resistant acid phosphatase 5 (Acp5) promotes lung fibrosis by enhancing beta-catenin signaling and that inhibition of Acp5 can reverse stablished pulmonary fibrosis.
- Yinan Hu
- , Qi Wang
- & Yi Wang
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Article
| Open AccessEZH2 depletion potentiates MYC degradation inhibiting neuroblastoma and small cell carcinoma tumor formation
While inhibition of the EZH2 methyltransferase activity has been used for targeting EZH2, its role in cancer progression remains unclear. Here, the authors use neuroblastoma and small cell lung carcinoma model systems and reveal the crosstalk between EZH2 and MYC(N) in the regulation of tumour formation.
- Liyuan Wang
- , Chan Chen
- & Guoliang Qing
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Article
| Open AccessThe m6A methyltransferase METTL3 regulates muscle maintenance and growth in mice
Muscle undergoes hypertrophy and atrophy in response to physiological stimuli or in pathological conditions, which is partially controlled through altered gene expression. Here the authors report that m6A methyltransferase METTL3 and mRNA m6A post-transcriptional modifications as a mechanism that regulates muscle hypertrophy and atrophy via myostatin signalling in mice.
- Jennifer M. Petrosino
- , Scott A. Hinger
- & Federica Accornero
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Article
| Open AccessAGPAT2 interaction with CDP-diacylglycerol synthases promotes the flux of fatty acids through the CDP-diacylglycerol pathway
AGPATs (1-acylglycerol-3-phosphate O-acyltransferases) catalyze the acylation of lysophosphatidic acid to form phosphatidic acid (PA), a key step in the synthesis of all glycerolipids. Here, the authors show that AGPAT2 and CDP-DAG synthases (CDS1 and CDS2) form functional complexes that promote further conversion of PA along the CDP-DAG pathway of phospholipid synthesis.
- Hoi Yin Mak
- , Qian Ouyang
- & Hongyuan Yang
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Article
| Open AccessNogoA-expressing astrocytes limit peripheral macrophage infiltration after ischemic brain injury in primates
Astrocytes are important players in ischemic stroke. Here, the authors use single nuclei transcriptomics to characterise marmoset astrocytes following brain injury. At functional level, they show that NogoAexpressing astrocytes limit macrophage infiltration.
- Anthony G. Boghdadi
- , Joshua Spurrier
- & James A. Bourne
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Article
| Open AccessEpigenetic interaction between UTX and DNMT1 regulates diet-induced myogenic remodeling in brown fat
Brown adipocytes contribute to energy balance, and adipocyte development and brown adipocyte thermogenesis are in part regulated by epigenetic modifications. Here the authors report that the histone demethylase Utx maintains brown adipocyte identity via demethylation of PRDM16, which in turn represses myogenic remodelling via DNMT1-mediated Myod1 promoter hypermethylation in mice.
- Fenfen Li
- , Jia Jing
- & Bingzhong Xue
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Review Article
| Open AccessEmerging technologies and infection models in cellular microbiology
Cellular microbiology is a field that combines the study of infection and cell biology. In this review, we highlight emerging technologies and infection models that recently transformed our understanding of the infected cell and may inspire future medicine.
- Ana Teresa López-Jiménez
- & Serge Mostowy