Review Article
|
Open Access
Featured
-
-
Article
| Open AccessSox17 is required for endothelial regeneration following inflammation-induced vascular injury
Endothelial cell regeneration is essential for blood vessels to recover from inflammation-induced injury. Here Liu et al. show that the transcription factor Sox17 is required for endothelial regeneration following endotoxemia, and that delivery of a transgene expressing Sox17 to lung endothelial cells enhances recovery after injury.
- Menglin Liu
- , Lianghui Zhang
- & Asrar B. Malik
-
Article
| Open AccessA fat-tissue sensor couples growth to oxygen availability by remotely controlling insulin secretion
The mechanisms by which organisms adapt their growth according to the availability of oxygen are incompletely understood. Here the authors identify the Drosophila fat body as a tissue regulating growth in response to oxygen sensing via a mechanism involving Hph inhibition, HIF1-a activation and insulin secretion.
- Michael J. Texada
- , Anne F. Jørgensen
- & Kim F. Rewitz
-
Article
| Open AccessThe cyclooxygenase-1/mPGES-1/endothelial prostaglandin EP4 receptor pathway constrains myocardial ischemia-reperfusion injury
The use of nonsteroidal anti-inflammatory drugs inhibiting COX-1/2 is associated with an increased risk of heart failure. Here the authors show that mPGES-1, a therapeutic target downstream of COX enzymes, protects from cardiac ischemia/reperfusion injury, limiting leukocyte-endothelial interactions and preserving microvascular perfusion partly via the endothelial EP4 receptor.
- Liyuan Zhu
- , Chuansheng Xu
- & Miao Wang
-
Article
| Open AccessGut microbiome-derived phenyl sulfate contributes to albuminuria in diabetic kidney disease
Diabetes is a major cause of kidney disease. Here Kikuchi et al. show that phenol sulfate, a gut microbiota-derived metabolite, is increased in diabetic kidney disease and contributes to the pathology by promoting kidney injury, suggesting phenyl sulfate could be used a marker and therapeutic target for the treatment of diabetic kidney disease.
- Koichi Kikuchi
- , Daisuke Saigusa
- & Takaaki Abe
-
Article
| Open AccessNeural substrates, dynamics and thresholds of galvanic vestibular stimulation in the behaving primate
Galvanic vestibular stimulation (GVS) uses transmastoid electrical currents to activate the vestibular system in humans without head movement. Here, the authors apply GVS to monkeys and record the activity of vestibular afferents to both GVS and motion to reveal the neural substrate underlying GVS evoked perceptual, ocular and postural responses.
- Annie Kwan
- , Patrick A. Forbes
- & Kathleen E. Cullen
-
Article
| Open AccessZFP30 promotes adipogenesis through the KAP1-mediated activation of a retrotransposon-derived Pparg2 enhancer
Although Krüppel-associated box zinc finger proteins (KZFPs) were found to mostly repress transposable elements, recent studies found that KFZPs also play other roles in cells. Here, the authors provide evidence that the KZFP ZFP30 promotes adipogenesis by targeting and activating a retrotransposon-derived Pparg2 enhancer in cooperation with co-regulator KRAB-associated protein 1 (KAP1).
- Wanze Chen
- , Petra C. Schwalie
- & Bart Deplancke
-
Article
| Open AccessA conserved CCM complex promotes apoptosis non-autonomously by regulating zinc homeostasis
Cerebral Cavernous Malformations (CCM) are often caused by mutations in CCM1/KRIT1. Here, Chapman et al. elegantly show that the CCM complex promotes apoptosis by regulating zinc homeostasis and storage via a conserved mechanism that likely generates the pathological defects observed in CCM.
- Eric M. Chapman
- , Benjamin Lant
- & W. Brent Derry
-
Article
| Open AccessTherapeutic role of miR-19a/19b in cardiac regeneration and protection from myocardial infarction
The miR-17-92 cluster has been shown to regulate cardiomyocyte proliferation in vitro and in genetic mutation and overexpression models. Here the authors show that the cluster member miR-19a/19b regulates cardiomyocyte proliferation in vivo, and that delivery of miR-19a/19b to the heart leads to both short-term and long-term protective responses to myocardial infarction.
- Feng Gao
- , Masaharu Kataoka
- & Da-Zhi Wang
-
Article
| Open AccessHepatic arginase 2 (Arg2) is sufficient to convey the therapeutic metabolic effects of fasting
Fasting is known for its beneficial effects on obesity and diabetes-related health complications. Here Zhang et al. show that fasting induces expression of arginase-2 (Arg2) in the liver, and that hepatic Arg2, by suppressing the expression of the regulator of G-protein signalling 16, recapitulates the positive effects of fasting in obesity and diabetes.
- Yiming Zhang
- , Cassandra B. Higgins
- & Brian J. DeBosch
-
Article
| Open AccessTMCO1-mediated Ca2+ leak underlies osteoblast functions via CaMKII signaling
TMCO1 is a recently described endoplasmic reticular Ca2+ channel. Here, the authors show it is important for osteoblast function and bone formation in mice, and identify a novel pathway linking local increases in Ca2+ at the ER surface with the posttranslational modification of RUNX2.
- Jianwei Li
- , Caizhi Liu
- & Yingxian Li
-
Article
| Open AccessThe class 3 PI3K coordinates autophagy and mitochondrial lipid catabolism by controlling nuclear receptor PPARα
Peroxisome Proliferator Activated Receptor alpha (PPARα) drives fatty acid catabolism. Here, the authors show that in liver of autophagy deficient class 3 phosphoinositide 3-kinase mutant mice PPARα transcriptional repressors fail to degrade in lysosomes and accumulate leading to PPARα inhibition and blunted transcriptional responses during fasting.
- Anton Iershov
- , Ivan Nemazanyy
- & Ganna Panasyuk
-
Article
| Open AccessN-terminal syndecan-2 domain selectively enhances 6-O heparan sulfate chains sulfation and promotes VEGFA165-dependent neovascularization
Proteoglycans are glycosylated proteins that play a number of structural and signalling functions. Here, Corti, Wang et al. show that the N-terminal sequence of proteoglycan Syndecan-2 selectively increases 6-O sulfation of its heparan sulfate chains, and that this promotes formation of a ternary Sdc2/VEGFA/VEGFR2 complex leading to increased angiogenesis.
- Federico Corti
- , Yingdi Wang
- & Michael Simons
-
Article
| Open AccessEnhanced β-adrenergic signalling underlies an age-dependent beneficial metabolic effect of PI3K p110α inactivation in adipose tissue
Insulin/IGF-1 signalling plays an important role in the regulation of metabolism and ageing. Here the authors show that inactivation of the pathway component PI3K p110α in the adipose tissue of mice produces a beneficial metabolic effect by enhancing β-adrenergic signalling thus energy expenditure.
- Caroline Araiz
- , Anqi Yan
- & Lazaros C. Foukas
-
Article
| Open AccessSterol regulatory element binding protein 1 couples mechanical cues and lipid metabolism
SREBP transcription factors activate lipid synthesis and generate raw materials to lipidate various proteins. Here, the authors show that a stiff cellular environment causes RhoA lipidation and acto-myosin contraction, which inhibits SREBP1 and connects the extracellular matrix to lipid metabolism.
- Rebecca Bertolio
- , Francesco Napoletano
- & Giannino Del Sal
-
Article
| Open AccessBreeders that receive help age more slowly in a cooperatively breeding bird
Sociality explains substantial variation in ageing across species, but less is known about this relationship within species. Here, the authors show that female dominant Seychelles warblers with helpers at the nest have higher late-life survival and lower telomere attrition and the probability of having helpers increases with age.
- Martijn Hammers
- , Sjouke A. Kingma
- & David S. Richardson
-
Article
| Open AccessNeutrophil activation and NETosis are the major drivers of thrombosis in heparin-induced thrombocytopenia
The pathogenesis of heparin-induced thrombocytopenia and thrombosis (HIT) is mediated by heparin-reactive autoantibodies binding to platelets (thrombocytes). Here the authors show neutrophil activation and NETosis are elevated in patients with HIT, and are essential for thrombosis in HIT mouse models.
- José Perdomo
- , Halina H. L. Leung
- & Beng H. Chong
-
Article
| Open AccessOptogenetic stimulation of Gs-signaling in the heart with high spatio-temporal precision
Studying adrenergic signalling in the heart requires perfusion with receptor agonists, which lacks cell specificity and spatiotemporal control. Here the authors use the light sensitive G-coupled receptor JellyOp to optogenetically control Gs-signaling in cardiomyocytes and intact hearts with high spatiotemporal precision.
- Philipp Makowka
- , Tobias Bruegmann
- & Philipp Sasse
-
Article
| Open AccessContractile forces in platelet aggregates under microfluidic shear gradients reflect platelet inhibition and bleeding risk
Platelet aggregates generate contractile forces that contribute to their cohesion and adhesion. Here, Ting et al. develop a microfluidic device to measure contractile forces generated by platelet aggregates, and find it can detect the response of platelets to pharmacological agents and predict bleeding risk in trauma patients.
- Lucas H. Ting
- , Shirin Feghhi
- & Nathan J. Sniadecki
-
Article
| Open AccessGenome-wide association study identifies genetic loci for self-reported habitual sleep duration supported by accelerometer-derived estimates
Sleep is essential for homeostasis and insufficient or excessive sleep are associated with adverse outcomes. Here, the authors perform GWAS for self-reported habitual sleep duration in adults, supported by accelerometer-derived measures, and identify genetic correlation with psychiatric and metabolic traits
- Hassan S. Dashti
- , Samuel E. Jones
- & Richa Saxena
-
Article
| Open AccessAssessing the causal association of glycine with risk of cardio-metabolic diseases
Epidemiological studies have associated circulating levels of the amino acid glycine with cardiometabolic outcomes. Here, in a genome-wide meta-analysis of 80,003 individuals, Wittemans et al. identify 22 novel genetic loci for glycine and find a causal relationship with coronary heart disease using MR.
- Laura B. L. Wittemans
- , Luca A. Lotta
- & Claudia Langenberg
-
Article
| Open AccessDeep brain activities can be detected with magnetoencephalography
Magnetoencephalography (MEG) is a non-invasive method of measuring neural activity but the hippocampus and amygdala are difficult to measure with MEG because of their deep localization. Here, the authors show with simultaneous MEG and invasive recordings that hippocampus and amygdala activity can be retrieved from the surface.
- Francesca Pizzo
- , N. Roehri
- & C. G. Bénar
-
Article
| Open AccessAn atlas of the aging lung mapped by single cell transcriptomics and deep tissue proteomics
Aging impacts lung functionality and makes it more susceptible to chronic diseases. Combining proteomics and single cell transcriptomics, the authors chart molecular and cellular changes in the aging mouse lung, discover aging hallmarks, and predict the cellular sources of regulated proteins.
- Ilias Angelidis
- , Lukas M. Simon
- & Herbert B. Schiller
-
Article
| Open AccessIntradermal delivery of modified mRNA encoding VEGF-A in patients with type 2 diabetes
Chemically modified mRNA is a new approach for therapeutic protein expression that could be applied to angiogenesis. Here the authors show in a phase 1 clinical trial that a modified mRNA encoding VEGF-A is well tolerated in patients with type 2 diabetes.
- Li-Ming Gan
- , Maria Lagerström-Fermér
- & Regina Fritsche-Danielson
-
Article
| Open AccessThe flavonoid 4,4′-dimethoxychalcone promotes autophagy-dependent longevity across species
Although ageing is the most important risk factor for chronic ailments, effective interventions remain rare. Here, the authors identify the flavonoid 4,4’-dimethoxychalcone and demonstrate that it extends lifespan and promotes health in multiple organisms by inducing autophagy.
- Didac Carmona-Gutierrez
- , Andreas Zimmermann
- & Frank Madeo
-
Article
| Open AccessLack of androgen receptor SUMOylation results in male infertility due to epididymal dysfunction
SUMOylation is known to regulate androgen receptor (AR) activity in cultured cells. Here, using SUMOylation-deficient AR knock-in mice, the authors demonstrate that SUMOylation is required for AR-related gene expression specifically in the epididymal tissues, but not the testis.
- Fu-Ping Zhang
- , Marjo Malinen
- & Jorma J. Palvimo
-
Article
| Open AccessInhibition of upper small intestinal mTOR lowers plasma glucose levels by inhibiting glucose production
The mechanistic target of rapamycin (TOR) functions as an energy sensor and contributes to the control of glucose homeostasis. Here, the authors show that mTOR in the upper small intestine regulates hepatic glucose production and is required for the glucose lowering effect of metformin.
- T. M. Zaved Waise
- , Mozhgan Rasti
- & Tony K. T. Lam
-
Article
| Open AccessGrowth hormone regulates neuroendocrine responses to weight loss via AgRP neurons
Reduction in food intake elicits neuroendocrine adaptations to counterregulate the negative energy balance, e.g. via reduction in leptin levels. Here, the authors identify an additional starvation signal, growth hormone (GH). Blocking GH receptor attenuates the fall of whole body energy expenditure during food deprivation in mice.
- Isadora C. Furigo
- , Pryscila D. S. Teixeira
- & J. Donato Jr
-
Article
| Open AccessPost-translational regulation of lipogenesis via AMPK-dependent phosphorylation of insulin-induced gene
Insulin-related gene (Insig) negatively regulates hepatic fatty acid synthesis, a process involved in development of non-alcoholic fatty liver disease (NAFLD). Here, the authors show that AMPK activation by metformin promotes Insig phosphorylation, stabilizing it and inhibiting lipogenic gene expression. This is protective against steatosis in diabetic mice.
- Yamei Han
- , Zhimin Hu
- & Yu Li
-
Article
| Open AccessGeneration of pluripotent stem cell-derived mouse kidneys in Sall1-targeted anephric rats
The use of pluripotent-stem cell derived organs for transplantation would be promising, if organs can be grown in a suitable host. Here, the authors use interspecific blastocyst complementation to generate a mouse pluripotent stem cell-derived kidney in anephric Sall1 mutant rats.
- Teppei Goto
- , Hiromasa Hara
- & Masumi Hirabayashi
-
Article
| Open AccessPatterned human microvascular grafts enable rapid vascularization and increase perfusion in infarcted rat hearts
Heart grafts need good vascularization to survive. Here, the authors engineer perfusable constructs of human embryonic stem cell-derived endothelial cells seeded in collagen matrix in patterned microchannels that form anastomosed vessels in vitro and have increased coronary vascular perfusion on transplantation in rats.
- Meredith A. Redd
- , Nicole Zeinstra
- & Ying Zheng
-
Article
| Open AccessDehydration and insulinopenia are necessary and sufficient for euglycemic ketoacidosis in SGLT2 inhibitor-treated rats
The use of sodium-glucose transport protein 2 (SGLT2) inhibitors for the treatment of diabetes has been associated with euglycemic ketoacidosis and increased glucose production and glucagon secretion. Here Perry et al. show that these effects rely on both insulinopenia and dehydration, and thus suggest ways to manage the side effects associated with the use of SGLT2 inhibitors.
- Rachel J. Perry
- , Aviva Rabin-Court
- & Gerald I. Shulman
-
Article
| Open AccessGenome-wide gene-based analyses of weight loss interventions identify a potential role for NKX6.3 in metabolism
Individuals show large variability in their capacity to lose weight and maintain this weight. Here, the authors perform GWAS in two weight loss intervention cohorts and identify two genetic loci associated with weight loss that are taken forward for Bayesian fine-mapping and functional assessment in flies.
- Armand Valsesia
- , Qiao-Ping Wang
- & Jörg Hager
-
Article
| Open AccessThe cholesterol biosynthesis pathway regulates IL-10 expression in human Th1 cells
Metabolic pathways are increasingly recognized as crucial determinants of T cell function. Here the authors show that the balance between IFNγ and IL-10 production in human CD4 T cells is modulated by the cholesterol biosynthetic pathway.
- Esperanza Perucha
- , Rossella Melchiotti
- & Andrew P. Cope
-
Article
| Open AccessIntestinal epithelial N-acylphosphatidylethanolamine phospholipase D links dietary fat to metabolic adaptations in obesity and steatosis
Obesity is associated with altered N-acylethanolamine levels (NAE). Here the authors show that deletion of the gene encoding N-acylphosphatidylethanolamine phospholipase D, a key enzyme for NAE synthesis, in intestinal cells of mice leads to the development of obesity and hepatic steatosis via a mechanism involving the gut-brain axis.
- Amandine Everard
- , Hubert Plovier
- & Patrice D. Cani
-
Article
| Open AccessCKIP-1 limits foam cell formation and inhibits atherosclerosis by promoting degradation of Oct-1 by REGγ
In atherosclerotic plaques, transformation of macrophages into foam cells is a key step in initiating the inflammatory response. Here Fan et al. show that casein kinase 2-interacting protein-1 (CKIP-1) limits foam cell formation and atherosclerosis by preventing expression of the scavenger receptor LOX-1 through REGγ-mediated degradation of Oct-1.
- Jiao Fan
- , Lifeng Liu
- & Lingqiang Zhang
-
Article
| Open AccessGenome-wide association study of body fat distribution identifies adiposity loci and sex-specific genetic effects
Obesity and the distribution of fat within the body are risk factors for cardiometabolic diseases. Here, Rask-Andersen et al. perform GWAS for bio-electrical impedance measurements in UK Biobank participants and identify 29 novel independent loci for fat distribution and a high degree of sex-heterogeneity.
- Mathias Rask-Andersen
- , Torgny Karlsson
- & Åsa Johansson
-
Article
| Open AccessRegulation of substrate utilization and adiposity by Agrp neurons
Agouti-related peptide (AgRP) producing neurons regulate food intake and metabolic processes in peripheral organs. Here, the authors show that hypothalamic AgRP neurons alter whole body substrate utilization to favour carbohydrate usage and lipid storage.
- João Paulo Cavalcanti-de-Albuquerque
- , Jeremy Bober
- & Marcelo O. Dietrich
-
Article
| Open AccessProstaglandin E2 mediates sensory nerve regulation of bone homeostasis
Bone is innervated, and its turnover is affected by sympathetic nerve activity. Here, the authors show that prostaglandin E2, secreted by osteoblasts, activates the EP4 receptor on sensory nerves, inhibiting sympathetic nerve activity and modulating bone formation in mice.
- Hao Chen
- , Bo Hu
- & Xu Cao
-
Article
| Open AccessPharmacologic ATF6 activation confers global protection in widespread disease models by reprograming cellular proteostasis
Imbalanced proteostasis is associated with diverse diseases, including ischemia/reperfusion injury in the heart. Here the authors show that the ATF6 arm of the unfolded protein response can be pharmacologically activated with a small molecule in vivo, providing protection from ischemia/reperfusion injury in the heart, the brain, and the kidney.
- Erik A. Blackwood
- , Khalid Azizi
- & Christopher C. Glembotski
-
Article
| Open AccessInsulin inhibits glucagon release by SGLT2-induced stimulation of somatostatin secretion
Impaired glucagon secretion in patients with diabetes causes hypoglycemia. Here the authors show that therapeutic concentrations of insulin inhibit alpha-cell glucagon secretion by stimulating delta-cell insulin receptor and the release of somatostatin. Blocking somatostatin secretion or action ameliorates this effect.
- Elisa Vergari
- , Jakob G. Knudsen
- & Patrik Rorsman
-
Article
| Open AccessEstrogen signaling in arcuate Kiss1 neurons suppresses a sex-dependent female circuit promoting dense strong bones
Estrogen promotes negative energy balance and preserves skeletal physiology. Here the authors show that loss of estrogen signalling after ablating estrogen receptor alpha (ERa) in specific hypothalamic neuronal populations leads to a marked sex-dependent increase in bone mass in female mice.
- Candice B. Herber
- , William C. Krause
- & Holly A. Ingraham
-
Article
| Open AccessLin28 and let-7 regulate the timing of cessation of murine nephrogenesis
Nephrogenesis ceases after postnatal day 2 in the mouse or after the 36th week of gestation in humans, but how this is regulated is unclear. Here, the authors identify a role for the RNA-binding protein Lin28 and suppression of let-7 microRNA in regulating the duration of nephrogenesis.
- Alena V. Yermalovich
- , Jihan K. Osborne
- & George Q. Daley
-
Article
| Open AccessCa2+-activated Cl− channel TMEM16A/ANO1 identified in zebrafish skeletal muscle is crucial for action potential acceleration
The Ca2+-activated Cl- channel TMEM16A/Anoctamin 1 (ANO1) mediates secretion and intestinal motility in gastrointestinal epithelia and smooth muscle cells. Here, the authors show a role for ANO1 in zebrafish skeletal muscle which is activated by SR Ca2+ release during excitation-contraction coupling.
- Anamika Dayal
- , Shu Fun J. Ng
- & Manfred Grabner
-
Article
| Open AccessThe mitochondrial type IB topoisomerase drives mitochondrial translation and carcinogenesis
TOP1MT is a topoisomerase that is localised to mitochondria. Here, the authors show that TOP1MT has a tumor promoting role in hepatocellular carcinoma by supporting mitochondrial translation and that its deficiency limits tumorigenicity.
- S. A. Baechler
- , V. M. Factor
- & Y. Pommier
-
Article
| Open AccessLongevity defined as top 10% survivors and beyond is transmitted as a quantitative genetic trait
While human lifespan is only moderately heritable, “getting old” runs in families. Here, van den Berg et al. study mortality data from three-generation cohorts to define a threshold for longevity and find that individuals have an increasing survival advantage with each additional relative in the top 10% survivors of their birth cohort.
- Niels van den Berg
- , Mar Rodríguez-Girondo
- & P. Eline Slagboom
-
Article
| Open AccessTrans-ethnic kidney function association study reveals putative causal genes and effects on kidney-specific disease aetiologies
Estimated glomerular filtration rate (eGFR) is a measure of kidney function used to define chronic kidney disease. Here, Morris et al. perform trans-ethnic genome-wide meta-analyses for eGFR in 312,468 individuals and identify novel loci and downstream putative causal genes.
- Andrew P. Morris
- , Thu H. Le
- & Nora Franceschini
-
Article
| Open AccessVagus-macrophage-hepatocyte link promotes post-injury liver regeneration and whole-body survival through hepatic FoxM1 activation
The mechanisms underlying the regenerative capacity of the liver are not fully understood. Here, the authors show that the acute regenerative response to liver injury in mice is regulated by the communication involving the vagus nerve, macrophages, and hepatocytes, leading to hepatic FoxM1 activation and promotion of overall survival.
- Tomohito Izumi
- , Junta Imai
- & Hideki Katagiri
-
Article
| Open AccessBioconjugation strategy for cell surface labelling with gold nanostructures designed for highly localized pH measurement
Understanding the pH changes at cell surfaces is important for understanding the mechanisms of different physiological processes. Here, the authors report on the development of a cell membrane anchored gold nanoparticle for surface enhanced Raman spectroscopy determination of pH.
- Leonardo Puppulin
- , Shigekuni Hosogi
- & Yoshinori Marunaka
-
Article
| Open AccessA phenotypic Caenorhabditis elegans screen identifies a selective suppressor of antipsychotic-induced hyperphagia
The molecular pathway(s) driving antipsychotics (AP) induced hyperphagia remains unclear. A novel C. elegans system is used here to screen for FDA approved drugs that selectively suppresses this response, unraveling potential molecular mediators influencing AP induced hyperphagia in mouse models.
- Anabel Perez-Gomez
- , Maria Carretero
- & Michael Petrascheck