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Hepatic miR-378 targets p110α and controls glucose and lipid homeostasis by modulating hepatic insulin signalling
PI3K is a central component of the insulin signalling pathway. Here, the authors reveal that miR-378 expression in the liver changes dynamically in response to fasting or refeeding, and show that miR-378 regulates hepatic insulin signalling by targeting the P110a subunit of PI3K.
- Wei Liu
- , Hongchao Cao
- & Hao Ying
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| Open AccessDNA methylation signatures link prenatal famine exposure to growth and metabolism
The long-term effect of prenatal nutrition on gene regulation is largely unknown. Here the authors identify differentially methylated regions in whole blood from individuals exposed to famine early after conception, and show that these epigenetic changes may have adverse metabolic consequences later in life.
- Elmar W. Tobi
- , Jelle J. Goeman
- & Bastiaan T. Heijmans
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| Open AccessTRF2 and lamin A/C interact to facilitate the functional organization of chromosome ends
The shortening of telomeres—a structure that protects chromosome ends—is associated with cellular aging. Here, Wood et al.present evidence that interaction between the telomere-binding protein TRF2 and lamin A/C facilitates the formation of interstitial t-loops and stabilizes telomeres.
- Ashley M. Wood
- , Jannie M. Rendtlew Danielsen
- & Steven T. Kosak
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A glutamatergic reward input from the dorsal raphe to ventral tegmental area dopamine neurons
Glutamatergic neurons project from the dorsal raphe to the ventral tegmental area, two brain areas strongly associated with addictive behaviour, however the functional significance of this connection remains unclear. Qi et al.show that optogenetic activation of this pathway conveys reward in mice.
- Jia Qi
- , Shiliang Zhang
- & Marisela Morales
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S-nitrosothiols regulate nitric oxide production and storage in plants through the nitrogen assimilation pathway
Assimilation of nitrate by plant roots leads to the generation of the signalling molecule, nitric oxide. Here Frungillo et al.show that nitric oxide fine-tunes nitrate homeostasis by feedback regulating nitrate transporters and reductases, while also promoting its own storage.
- Lucas Frungillo
- , Michael J. Skelly
- & Ione Salgado
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| Open AccessCotton cytochrome P450 CYP82D regulates systemic cell death by modulating the octadecanoid pathway
Oxylipin signalling is known to play important roles in plant growth, development and defence against pathogens. Here Sun et al.identify a novel cytochrome P450 in cotton and show that its suppression leads to activation of plant defence responses and alteration of oxylipin metabolism.
- Longqing Sun
- , Longfu Zhu
- & Xianlong Zhang
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Regulation of the NaV1.5 cytoplasmic domain by calmodulin
Voltage-gated sodium channels (Nav) are transmembrane proteins that underlie action potentials in excitable tissues. Here, Gabelli et al. suggest a novel mechanism for the cytoplasmic control of switching from the inactivated to the non-inactivated form of the Nav1.5 channel that involves dimerization.
- Sandra B. Gabelli
- , Agedi Boto
- & L. Mario Amzel
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Functional reconstitution of mitochondrial Fe/S cluster synthesis on Isu1 reveals the involvement of ferredoxin
The action of iron–sulphur proteins has been found in many important biological processes. Here, the authors present a reconstituted in vitrosystem for the characterization of a ferredoxin–ferredoxin reductase pair as an electron transfer chain in the initial step of iron–sulphur protein biogenesis.
- Holger Webert
- , Sven-Andreas Freibert
- & Roland Lill
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Cell type-specific plasticity of striatal projection neurons in parkinsonism and L-DOPA-induced dyskinesia
Parkinson’s disease and L-DOPA-induced dyskinesia are both associated with imbalances in activity between populations of spiny projection neurons. Fieblinger et al.show that homeostatic adaptations in excitability are engaged by these disease states, but synaptic strengths are not scaled accordingly.
- Tim Fieblinger
- , Steven M. Graves
- & D. James Surmeier
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Platelets promote tumour metastasis via interaction between TLR4 and tumour cell-released high-mobility group box1 protein
Factors affecting the fate of disseminating tumour cells in the circulation play a critical role in metastasis. Here the authors show that TLR4 on platelets promotes their adhesion to tumour cells and enhances metastasis.
- Le-Xing Yu
- , Lei Yan
- & Hong-Yang Wang
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Identification of the phytosphingosine metabolic pathway leading to odd-numbered fatty acids
Most cellular fatty acids contain even-numbered chains, and the origin of the small fraction of odd-numbered fatty acids remains unclear. Kondo et al.show that odd-numbered fatty acids are generated by metabolism of the long-chain base phytosphingosine in yeast and mammalian cells.
- Natsuki Kondo
- , Yusuke Ohno
- & Akio Kihara
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| Open AccessSuperficial layer pyramidal cells communicate heterogeneously between multiple functional domains of cat primary visual cortex
Pyramidal cells in superficial layers of neocortex form a lateral network of synaptic bouton clusters, but its functional implication remains unclear. Here the authors overlaid activity maps of orientation preference in cat visual cortex with single-cell anatomy and observed projections to multiple functional domains.
- Kevan A. C. Martin
- , Stephan Roth
- & Elisha S. Rusch
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Oestrogen signalling in white adipose progenitor cells inhibits differentiation into brown adipose and smooth muscle cells
Oestrogen has various metabolic and physiological effects. Here the authors show that oestrogen receptor alpha signalling determines lineage commitment of murine adipose progenitor cells, regulating their differentiation into white adipocytes, beige adipocytes or smooth muscle cells.
- Kfir Lapid
- , Ajin Lim
- & Jonathan M. Graff
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| Open AccessInterferon regulatory factor 9 is critical for neointima formation following vascular injury
Blood vessels respond to injury by thickening the supportive smooth muscle layer in a process known as neointima formation. Here the authors describe a novel regulatory pathway of neointima formation that involves a transcription factor, Interferon Regulating Factor 9, and its downstream target, the deacetylase SIRT1.
- Shu-Min Zhang
- , Li-Hua Zhu
- & Hongliang Li
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Integrated control of hepatic lipogenesis versus glucose production requires FoxO transcription factors
The transcription factors FoxoO1 and Srebp-1 control hepatic glucose and lipid production, respectively. Here, Haeusler et al.propose a model that integrates glucose and lipid regulation in the normal and diabetic liver under the unifying control of FoxO transcription factors.
- Rebecca A. Haeusler
- , Kirsten Hartil
- & Domenico Accili
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| Open AccessSKN-1 and Nrf2 couples proline catabolism with lipid metabolism during nutrient deprivation
The coordinated metabolism of cellular nutrients is important to maintain energy homeostasis, particularly if nutrients are scarce. Here, the authors report that the sensor protein SKN-1/Nrf2 links catabolism of the amino acid proline with lipid metabolism in C. elegansand in cultured human cells.
- Shanshan Pang
- , Dana A. Lynn
- & Sean P. Curran
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Regulated spatial organization and sensitivity of cytosolic protein oxidation in Caenorhabditis elegans
Cells respond to redox changes by shifting their protein thiol–disulfide balance. Here, the authors show that this balance is spatially regulated and varies widely across individuals, challenging the concept that glutathione acts as the main cellular redox buffer.
- Catalina Romero-Aristizabal
- , Debora S. Marks
- & Javier Apfeld
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The tumour suppressor LKB1 regulates myelination through mitochondrial metabolism
Myelination of peripheral axons by Schwann cells is essential for proper transmission of nerve signals but the underlying mechanisms are not completely understood. Here the authors show that metabolic changes are required to ensure Schwann cell differentiation and proper myelination, and involve the tumour suppressor Lkb1 in regulating this process.
- Shabnam Pooya
- , Xiaona Liu
- & Biplab Dasgupta
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Hypothalamic S1P/S1PR1 axis controls energy homeostasis
Sphingosine-1-phosphate is a bioactive lipid with various physiological roles. Here, Silva et al. show that sphingosine-1-phosphate signalling in the hypothalamic arcuate nucleus regulates food intake of rodents, and that this process is altered in animal models of obesity and cancer anorexia.
- Vagner R. R. Silva
- , Thayana O. Micheletti
- & Eduardo R. Ropelle
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Dynamic GATA4 enhancers shape the chromatin landscape central to heart development and disease
Transcription factors (TFs) drive spatiotemporal patterns of gene expression that control organ development and disease responses. Here, He et al.show that chromatin occupancy of GATA4 varies between fetal, adult and hypertrophic heart to direct developmental stage- and disease-specific transcriptional programs.
- Aibin He
- , Fei Gu
- & William T. Pu
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SIRT6 represses LINE1 retrotransposons by ribosylating KAP1 but this repression fails with stress and age
Retrotransposons are repetitive sequences in the genome that can amplify themselves and whose activity has been linked to age-related pathologies. Here, Van Meter et al.report that the histone deacetylase SIRT6 represses activity of the L1 retrotransposon by ribosylating the nuclear corepressor protein, KAP1.
- Michael Van Meter
- , Mehr Kashyap
- & Vera Gorbunova
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| Open AccessGlucose substitution prolongs maintenance of energy homeostasis and lifespan of telomere dysfunctional mice
Shortened telomeres and reduced mitochondrial biogenesis are cellular hallmarks of ageing. Here, Missios et al.show that old mice with telomere dysfunction have an increased energetic demand that cannot be met unless mice are fed a glucose-rich diet, which improves energy metabolism and extends lifespan.
- Pavlos Missios
- , Yuan Zhou
- & K. Lenhard Rudolph
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Metabolic properties in stroked rats revealed by relaxation-enhanced magnetic resonance spectroscopy at ultrahigh fields
1H magnetic resonance can detect endogenous metabolites at physiological concentrations but its application in animal models is challenged by low sensitivity. Here the authors focus ultrahigh magnetic fields on metabolites whose spectral signatures are selectively excited, and achieve microarchitectural insight of rat brains after a stroke.
- Noam Shemesh
- , Jens T. Rosenberg
- & Lucio Frydman
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Lifespan maturation and degeneration of human brain white matter
White matter in the human brain is known to change its properties during an individual's lifespan. Here, Yeatman et al. use quantitative imaging measurements of the living human brain to model changes in white mater structure based on tissue development and decline between the ages of 7–85 years.
- Jason D. Yeatman
- , Brian A. Wandell
- & Aviv A. Mezer
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Steroid hormone signalling links reproduction to lifespan in dietary-restricted Caenorhabditis elegans
Dietary restriction increases the lifespan of many species, but often at the cost of reduced fertility. Here, Thondamal et al. show that the dietary restriction-mediated increase in lifespan in Caenorhabditis elegansdepends on the production of a steroid hormone and its inhibition of germline plasticity.
- Manjunatha Thondamal
- , Michael Witting
- & Hugo Aguilaniu
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Insights into mitochondrial fatty acid synthesis from the structure of heterotetrameric 3-ketoacyl-ACP reductase/3R-hydroxyacyl-CoA dehydrogenase
3-Ketoacyl-ACP reductase is required for mitochondrial fatty acid synthesis. Venkatesan et al.present structures of this enzyme, show that the β-subunit is involved in fatty acid synthesis and propose a role for the α-subunit in routing unsaturated fatty acids into β-oxidation.
- Rajaram Venkatesan
- , Shiv K. Sah-Teli
- & Zhijun Chen
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Megakaryocyte-specific Profilin1-deficiency alters microtubule stability and causes a Wiskott–Aldrich syndrome-like platelet defect
Patients with mutations in the gene encoding the cytoskeleton regulator WAS have platelet defects. Here the authors show that the WAS-binding protein, Profilin1, is essential for platelet formation in mice, and that its deficiency reproduces the bleeding disorder of patients with WAS mutations.
- Markus Bender
- , Simon Stritt
- & Bernhard Nieswandt
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MicroRNA-378 controls classical brown fat expansion to counteract obesity
Brown fat tissue contributes to organismal energy expenditure due to its thermogenic capacity. Here, the authors identify miR-378 as a specific regulator of brown fat tissue expansion, and suggest that physiological crosstalk between adipose tissue depots leads to a reduction in white fat mass.
- Dongning Pan
- , Chunxiao Mao
- & Yong-Xu Wang
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| Open AccessReversible changes in pancreatic islet structure and function produced by elevated blood glucose
In patients with diabetes, insulin release from pancreatic β-cells is reduced due to altered islet structure and function. Here, Brereton et al. show that elevated blood glucose underlies these changes and is sufficient to reversibly alter β-cell identity in a mouse model of β-cell dysfunction.
- Melissa F. Brereton
- , Michaela Iberl
- & Frances M. Ashcroft
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Cardiac arrhythmia induced by genetic silencing of ‘funny’ (f) channels is rescued by GIRK4 inactivation
The ‘funny’ current (If) is important for the generation and regulation of the heart’s automaticity. Here the authors show that If silencing through genetic modification of the f-channel component HCN4 causes heart arrhythmia by altering Ca2+handling in pacemaker myocytes.
- Pietro Mesirca
- , Jacqueline Alig
- & Matteo E. Mangoni
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A metabolic view on menopause and ageing
Changes in serum metabolites can indicate the development of disease. Here, the authors measure serum metabolite and lipoprotein levels in a large cohort of Northern Europeans, creating metabolic fingerprints for various age groups and, specifically, for women at the onset of menopause.
- Kirsi Auro
- , Anni Joensuu
- & Markus Perola
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| Open AccessHGK/MAP4K4 deficiency induces TRAF2 stabilization and Th17 differentiation leading to insulin resistance
HGK kinase is involved in signalling in many cell types but its function in T cells remains unclear. Here, using T-cell-specific HGK knockout mice, the authors show that HGK prevents the development of systemic inflammation and insulin resistance by inhibiting production of the proinflammatory cytokines IL-6 and IL-17.
- Huai-Chia Chuang
- , Wayne H. -H. Sheu
- & Tse-Hua Tan
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Conformable amplified lead zirconate titanate sensors with enhanced piezoelectric response for cutaneous pressure monitoring
The development of more sensitive tools for physiological monitoring presents obvious advantages in health-care and diagnostic assessment. Here, the authors present a thin, skin-like sensor that uses enhanced responses in lead zirconate titanate for monitoring arterial pressure waves.
- Canan Dagdeviren
- , Yewang Su
- & John A. Rogers
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| Open AccessThe LKB1-salt-inducible kinase pathway functions as a key gluconeogenic suppressor in the liver
The liver is an important regulator of glucose homeostasis. Here, the authors provide insight into the molecular signalling pathways controlling hepatic gluconeogenesis by showing that SIK protein kinases suppress gluconeogenesis, and that glucagon—but not insulin—regulates phosphorylation of SIK2.
- Kashyap Patel
- , Marc Foretz
- & Kei Sakamoto
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| Open AccessMyocardium-derived angiopoietin-1 is essential for coronary vein formation in the developing heart
The secreted ligand Angiopoietin-1 is essential for embryonic blood vessel development and adult vascular homeostasis. Here the authors show, using conditional knockout mice, that myocardium-derived Angiopoietin-1 is required for the formation of coronary veins, but not arteries.
- Yoh Arita
- , Yoshikazu Nakaoka
- & Issei Komuro
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PINK1 deficiency sustains cell proliferation by reprogramming glucose metabolism through HIF1
Loss of function of the kinase PINK1 is associated with familial early-onset Parkinson’s disease and impaired clearance of damaged mitochondria. Here the authors show that the resulting oxidative stress activates the hypoxia regulator HIF1α, resulting in increased glycolysis and cell proliferation.
- Raquel Requejo-Aguilar
- , Irene Lopez-Fabuel
- & Juan P. Bolaños
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| Open AccessIdentification of platelet function defects by multi-parameter assessment of thrombus formation
Platelets from patients with bleeding disorders often display altered adherence to surface proteins. In this study, de Witt et al.design a flow chamber for the systematic interrogation of platelets attaching to 52 adhesive surfaces, which may be helpful for the diagnosis of platelet disorders.
- Susanne M. de Witt
- , Frauke Swieringa
- & Judith M.E.M. Cosemans
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| Open AccessH2S and NO cooperatively regulate vascular tone by activating a neuroendocrine HNO–TRPA1–CGRP signalling pathway
Nitric oxide (NO) and hydrogen sulphide (H2S) are two gaseous signalling molecules produced in tissues. Here the authors propose that NO and H2S react with each other to form nitroxyl (HNO), which activates the TRPA1 channel in nerve cells and triggers the release of the vasoactive peptide CGRP.
- Mirjam Eberhardt
- , Maria Dux
- & Milos R. Filipovic
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PKM2 regulates the Warburg effect and promotes HMGB1 release in sepsis
The role of metabolic reprogramming in the regulation of innate inflammatory response remains incompletely understood. Here, the authors show that pyruvate kinase M2-mediated aerobic glycolysis contributes to inflammatory response, and that inhibition of this pathway protects mice from lethal endotoxemia and sepsis.
- Liangchun Yang
- , Min Xie
- & Daolin Tang
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Learning-induced and stathmin-dependent changes in microtubule stability are critical for memory and disrupted in ageing
The microtubule-associated protein stathmin is implicated in cognitive processing but it is unclear how. Here, the authors show that stathmin regulates microtubule stability and dendritic transport of specific AMPA receptor subunits, and that this regulation is impaired in aged mice.
- Shusaku Uchida
- , Guillaume Martel
- & Gleb P. Shumyatsky
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Genome-wide analysis in Drosophila reveals age-specific effects of SNPs on fitness traits
Senescence is the decline in physiological function associated with age, and the genetic basis of this phenomenon is poorly understood. Here, the authors identify genetic variants in Drosophilathat affect reproduction and lifespan in an age-specific manner, and provide support for the mutation accumulation theory of aging.
- Mary F. Durham
- , Michael M. Magwire
- & Jeff Leips
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The stem cell factor/Kit signalling pathway regulates mitochondrial function and energy expenditure
Stem cell factor (SCF) and its receptor, Kit, have known roles in regulating cell growth and survival. Here, Huang et al. reveal a new function of SCF/Kit signalling, showing that it increases energy expenditure and mitochondrial function in brown adipose tissue by promoting expression of PGC-1a.
- Zan Huang
- , Hai-Bin Ruan
- & Xiang Gao
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Structural and functional differences in medial prefrontal cortex underlie distractibility and suppression deficits in ageing
Brain-imaging studies have shown that compared with younger adults, older adults experience an increase in distractibility during working memory tasks. Here, the authors show that the increase in distractibility is in part due to reduced integrity and connectivity of the medial prefrontal cortex in older adults.
- James Z. Chadick
- , Theodore P. Zanto
- & Adam Gazzaley
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Review Article |
Systemic regulation of mammalian ageing and longevity by brain sirtuins
Sirtuins have been implicated in the ageing process in a variety of organisms, but their role in mammalian ageing remains somewhat controversial. Here the authors discuss sirtuin proteins in the brain, providing an overview of their physiological functions as well as their implication in mammalian ageing.
- Akiko Satoh
- & Shin-ichiro Imai
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Hepatoprotective role of Sestrin2 against chronic ER stress
When exposed to chronic endoplasmic reticulum (ER) stress, cells downregulate protein synthesis by inhibiting mTOR signalling. Park et al.identify Sestrin2 as a transcriptional target of the ER stress pathway and an important mediator of this protective response in the liver.
- Hwan-Woo Park
- , Haeli Park
- & Jun Hee Lee
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Diminished hERG K+ channel activity facilitates strong human labour contractions but is dysregulated in obese women
Uterine muscle contracts rhythmically during labour but the underlying electrophysiological mechanisms are not fully understood. The authors of this study show that hERG1 potassium channels reduce human uterine contractions in pregnancy and are suppressed during labour in lean but not in obese women.
- Helena C. Parkington
- , Janet Stevenson
- & Roger Smith
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Haemodynamic and extracellular matrix cues regulate the mechanical phenotype and stiffness of aortic endothelial cells
Endothelial cells at the inner surface of blood vessels are exposed to mechanical forces as a result of blood flow. Here the authors show that the interaction of extracellular matrix proteins with adhesion molecules on the endothelial cell surface determines cellular stiffness and sensitivity to mechanical forces.
- Caitlin Collins
- , Lukas D. Osborne
- & Ellie Tzima
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Dysregulation of hydrogen sulphide metabolism impairs oviductal transport of embryos
Enzymes required for the production of hydrogen sulphide (H2S) are expressed in mammalian reproductive tracts. Here, the authors show that production of H2S regulates contraction in excised human fallopian tube samples and is required for transport of the embryo through the fallopian tube in mice.
- Nannan Ning
- , Jianchun Zhu
- & Jingxin Li
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Oxytocin is an age-specific circulating hormone that is necessary for muscle maintenance and regeneration
The age-related decline in the regenerative capacity of muscle can be reversed in mice by exposure to young circulation. Elabd et al.identify the hormone, oxytocin, as a potential mediator of this effect, showing that its plasma levels decline with age and that administration of oxytocin to aged mice improves muscle regeneration.
- Christian Elabd
- , Wendy Cousin
- & Irina M. Conboy