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Dependence of fertility on kisspeptin–Gpr54 signaling at the GnRH neuron
The kisspeptin receptor GPR54 is implicated in the maintenance of mammalian fertility. Kirilov et al.study GPR54 mutant mice and identify a subset of neurons in the brain expressing gonadotropin-releasing hormone as the critical site for kisspeptin action.
- Milen Kirilov
- , Jenny Clarkson
- & Allan E. Herbison
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Human copper chaperone for superoxide dismutase 1 mediates its own oxidation-dependent import into mitochondria
The accumulation of superoxide in mitochondria is counteracted by superoxide dismutase 1 and its activating chaperone CCS1. Suzuki et al.show that in human cells, mature CCS1 itself mediates CCS1 import and helps to oxidize CCS1 and SOD1 in the mitochondrial intermembrane space.
- Yutaka Suzuki
- , Muna Ali
- & Jan Riemer
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The carotid body as a putative therapeutic target for the treatment of neurogenic hypertension
Enhanced sympathetic drive from chemoreceptors in the carotid body contributes to hypertension. Here McBryde et al. show that carotid sinus denervation is an effective antihypertensive treatment in rats with neurogenic hypertension even if performed in addition to renal denervation.
- Fiona D. McBryde
- , Ana P. Abdala
- & Julian F. R. Paton
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| Open AccessGenome analysis reveals insights into physiology and longevity of the Brandt’s bat Myotis brandtii
Bats account for 20 per cent of all mammals, these are the only mammals with powered flight, and are among the few animals that echolocate. Here, Seim et al. sequence the genome of the long-lived (>40 years) Brandt’s bat, Myotis brandtiiand provide clues to its evolution, longevity and other traits.
- Inge Seim
- , Xiaodong Fang
- & Vadim N. Gladyshev
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| Open AccessGlycogen shortage during fasting triggers liver–brain–adipose neurocircuitry to facilitate fat utilization
During fasting, animals shift their energy source from carbohydrates to triglycerides. Here, Izumida et al. report that glycogen shortage in the liver activates a liver–brain–adipose-tissue neurocircuit that signals the switch in fuel source from liver glycogen to triglycerides in fat cells.
- Yoshihiko Izumida
- , Naoya Yahagi
- & Hitoshi Shimano
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| Open AccessOrbitofrontal and striatal circuits dynamically encode the shift between goal-directed and habitual actions
Interactions between corticostriatal circuits are implicated in the shifts between habit- and goal-directed actions. Gremel and Costa show that the orbital frontal cortex and the dorsal medial striatum are necessary for goal-directed actions, whereas the dorsal lateral striatum is necessary for habitual actions.
- Christina M. Gremel
- & Rui M. Costa
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| Open AccessPrelamin A causes progeria through cell-extrinsic mechanisms and prevents cancer invasion
Mutations in the metalloproteinase Zmpste24 preclude prelamin A processing and cause premature ageing. Here, de la Rosaet al.create mosaic Zmpste24 mice, revealing that cell-extrinsic effects are essential for accelerated ageing caused by prelamin A accumulation and that prelamin A reduces invasiveness of cancer cells.
- Jorge de la Rosa
- , José M.P. Freije
- & Carlos López-Otín
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Reductive glutamine metabolism is a function of the α-ketoglutarate to citrate ratio in cells
Reductive glutamine metabolism supports cell proliferation under stress conditions such as hypoxia. Here Fendtet al.report that the ratio between the two metabolites α-ketoglutarate and citrate determines whether glutamine is metabolized oxidatively or reductively.
- Sarah-Maria Fendt
- , Eric L. Bell
- & Gregory Stephanopoulos
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| Open AccessBrown fat in a protoendothermic mammal fuels eutherian evolution
Endothermy facilitated mammalian species radiation, but the events leading to sustained thermogenesis are not clear. Here, the authors report functional brown adipose tissue in a protoendothermic mammal, linking nonshivering thermogenesis directly to the roots of eutherian endothermic evolution.
- Rebecca Oelkrug
- , Nadja Goetze
- & Carola W. Meyer
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A stabilizing factor for mitochondrial respiratory supercomplex assembly regulates energy metabolism in muscle
Interactions between mitochondrial respiratory chain complexes control electron transfer and oxidative phosphorylation. Here, the authors find that COX7RP regulates supercomplex assembly, and show that decreasing or increasing COX7RP expression, respectively, reduces and enhances muscular performance in mice.
- Kazuhiro Ikeda
- , Sachiko Shiba
- & Satoshi Inoue
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Large fibre size in skeletal muscle is metabolically advantageous
Energy demand in muscle is largely due to maintaining the membrane potential of muscle fibres. Jimenez et al.study the metabolic cost of maintaining the membrane potential of muscle fibres across different species of crustaceans and fishes, and find that larger fibres are metabolically cheaper to maintain.
- Ana Gabriela Jimenez
- , Richard M. Dillaman
- & Stephen T. Kinsey
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Fibroblast growth factor 21 protects against cardiac hypertrophy in mice
Fibroblast growth factor 21 (FGF21) regulates energy metabolism in peripheral tissues. Here Planavila and colleagues show that FGF21 also acts directly on cardiomyocytes, thereby protecting mice against cardiac hypertrophy.
- A. Planavila
- , I. Redondo
- & F. Villarroya
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A common functional promoter variant links CNR1 gene expression to HDL cholesterol level
Haplotypes in CNR1, the gene encoding the cannabinoid receptor CB1, are known to influence HDL cholesterol levels. Here Feng and colleagues identify rs806371 as a novel regulatory element reducing CNR1 gene expression and as the causal allele driving the association between CNR1 and HDL cholesterol levels in humans.
- Q. Feng
- , K.C. Vickers
- & R.A. Wilke
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| Open AccessHaemodynamically dependent valvulogenesis of zebrafish heart is mediated by flow-dependent expression of miR-21
microRNAs rapidly regulate gene expression and are implicated in cardiogenesis and angiogenesis. Banjo and colleagues show that the microRNA mir-21 is activated by the physical forces generated by blood flow, and that this regulates the development of heart valves in zebrafish.
- Toshihiro Banjo
- , Janin Grajcarek
- & Toshihiko Ogura
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| Open AccessThe orphan receptor Gpr83 regulates systemic energy metabolism via ghrelin-dependent and ghrelin-independent mechanisms
The murine G protein-coupled receptor 83 (Gpr83) is expressed widely in the brain, but its physiological role is largely unknown. Here Müller et al.show that Gpr83 regulates systemic energy metabolism in part by modulating ghrelin signalling in the arcuate nucleus of the hypothalamus.
- Timo D. Müller
- , Anne Müller
- & Matthias H. Tschöp
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Constitutively active Foxo3 in oocytes preserves ovarian reserve in mice
The number of primordial follicles, which constitute the ovarian reserve, decreases with age. By overexpressing a constitutively active version of the transcription factor FOXO3, the authors increase the ovarian reserve and fertility in aging female mice.
- Emanuele Pelosi
- , Shakib Omari
- & Chris Ottolenghi
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| Open AccessThe gut microbiota suppresses insulin-mediated fat accumulation via the short-chain fatty acid receptor GPR43
The gut microbiota produces metabolites such as short-chain fatty acids (SCFAs), which can influence the development of obesity. Here Kimura et al.show that SCFAs act via the receptor GPR43, which acts as a sensor for excessive dietary energy and controls body energy utilization as well as metabolic homoeostasis.
- Ikuo Kimura
- , Kentaro Ozawa
- & Gozoh Tsujimoto
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| Open AccessSelect interneuron clusters determine female sexual receptivity in Drosophila
The protein spinster is implicated in Drosophilacourtship behaviour. Sakurai and colleagues identify two clusters of spinster-expressing interneurons, and show that these cells are required for female receptivity to male advances.
- Akira Sakurai
- , Masayuki Koganezawa
- & Daisuke Yamamoto
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Control of lung vascular permeability and endotoxin-induced pulmonary oedema by changes in extracellular matrix mechanics
Vascular permeability is increased by inflammation and in disorders such as acute respiratory distress syndrome. Mammoto et al. show that lung vascular permeability is controlled by the stiffness of the extracellular matrix and identify lysyl oxidase as a regulator of vascular leakage in pulmonary oedema in mice.
- Akiko Mammoto
- , Tadanori Mammoto
- & Donald E. Ingber
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| Open AccessMolecular mechanics of mineralized collagen fibrils in bone
Bone is a natural composite of collagen and hydroxyapatite but, surprising, little is known about its characteristics at the molecular scale. Nair et al. conduct molecular-scale simulations of mineralized collagen networks to better understand how bone achieves superior mechanical properties to its constituents.
- Arun K. Nair
- , Alfonso Gautieri
- & Markus J. Buehler
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| Open AccessVE-PTP regulates VEGFR2 activity in stalk cells to establish endothelial cell polarity and lumen formation
Vascular endothelial growth factor is implicated in blood vessel development. In zebrafish, Hayashi et al. find that blood vessel development is dependent on the suppression of vascular endothelial growth factor by the phosphatase VE-PTP, which is recruited by activation of the angiopoietin receptor Tie2.
- Makoto Hayashi
- , Arindam Majumdar
- & Lena Claesson-Welsh
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α-SNAP inhibits AMPK signaling to reduce mitochondrial biogenesis and dephosphorylates Thr172 in AMPKα in vitro
The energy-sensing kinase AMPK is regulated by phosphorylation, however, the identity of AMPK phosphatases remains uncertain. Here the authors show that α-SNAP, a protein previously known for its role in membrane fusion, can dephosphorylate AMPK despite lacking a recognizable phosphatase domain.
- Lifu Wang
- & David L. Brautigan
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Human hypocretin and melanin-concentrating hormone levels are linked to emotion and social interaction
The emotional state of humans depends on the temporal concentration of neurochemicals. Blouin et al. measure temporal changes in two neuropeptides, hypocretin and melanin-concentrating hormone, and find that hypocretin but not melanin-concentrating hormone is linked to positive emotions and social interaction.
- Ashley M. Blouin
- , Itzhak Fried
- & Jerome M. Siegel
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Haemogenic endocardium contributes to transient definitive haematopoiesis
Cardiac and endocardial/endothelial cells arise from progenitor cells expressing multiple haematopoietic transcription factors. Nakano and colleagues find that Nkx2–5-positive endocardial cells serve as a de novosource for definitive haematopoietic progenitors during mammalian embryogenesis.
- Haruko Nakano
- , Xiaoqian Liu
- & Atsushi Nakano
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De novo lipogenesis in human fat and liver is linked to ChREBP-β and metabolic health
Changes in the biosynthesis of fatty acids can influence tissue insulin sensitivity and the development of metabolic diseases. Eissing and colleagues show that de novolipogenesis in liver and adipose tissue is linked to metabolic health in humans and can be modulated by bariatric surgery.
- Leah Eissing
- , Thomas Scherer
- & Ludger Scheja
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Human haemodynamic frequency harmonics regulate the inflammatory phenotype of vascular endothelial cells
Natural variations in blood flow haemodynamics are associated with localized inflammation and atherosclerosis. Here the authors show that individual harmonics present within this complex signal have distinct impacts on the inflammatory phenotype in endothelial cells.
- Ryan E. Feaver
- , Bradley D. Gelfand
- & Brett R. Blackman
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Parasympathetic stimulation improves epithelial organ regeneration
Irradiation treatment for cancer therapy often causes irreparable damage to adult organs. Knox and colleagues study irradiated mouse submandibular salivary glands and find that restoring parasympathetic nerve function with the neurotrophic factor neurturin improves regeneration.
- Sarah M. Knox
- , Isabelle M. A. Lombaert
- & Matthew P. Hoffman
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A novel pathway for the production of hydrogen sulfide from D-cysteine in mammalian cells
Hydrogen sulphide is a signalling molecule with cytoprotective activity in mammals. Here, Kimura and colleagues identify a new biosynthetic pathway for the production of hydrogen sulphide from D-cysteine, which is shown to protect mouse kidneys from oxidative stress after ischaemia/reperfusion injury.
- Norihiro Shibuya
- , Shin Koike
- & Hideo Kimura
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A genetically female brain is required for a regular reproductive cycle in chicken brain chimeras
Sexual dimorphism describes physical differences between males and females of the same species and is partly shaped by the action of hormones. Maekawa and colleagues construct mixed-sex chicken brain chimeras and find that the female reproductive cycle is largely destroyed in female chimeras with male brains.
- Fumihiko Maekawa
- , Miyano Sakurai
- & Hiroko Ohki-Hamazaki
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Splicing factor SRSF3 is crucial for hepatocyte differentiation and metabolic function
Splicing factors, such as the protein SRSF3, regulate mRNA metabolism but are hard to study in vivobecause genetic kockouts are usually lethal. Here, Sen and colleagues create mice with a hepatocyte-specific knockout of Srsf3 and demonstrate its role in hepatocyte differentiation and liver function.
- Supriya Sen
- , Hassan Jumaa
- & Nicholas J. G. Webster
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Activity of the mitochondrial calcium uniporter varies greatly between tissues
The flow of calcium into the mitochondrial matrix is mediated by the mitochondrial calcium uniporter. Fieniet al. apply patch-clamp techniques to mitoplasts isolated from different mouse and Drosophilatissues and find that the mitochondrial calcium uniporter activity varies depending on the tissue studied.
- Francesca Fieni
- , Sung Bae Lee
- & Yuriy Kirichok
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ASK3 responds to osmotic stress and regulates blood pressure by suppressing WNK1-SPAK/OSR1 signaling in the kidney
Cells must be able to sense and respond to changes in osmotic pressure, which can be lethal. Here, Naguro and colleagues reveal a role for the protein kinase ASK3 in sensing osmotic stress in the mouse kidney and show that ASK3 contributes to the regulation of blood pressure.
- Isao Naguro
- , Tsuyoshi Umeda
- & Hidenori Ichijo
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Preotic neural crest cells contribute to coronary artery smooth muscle involving endothelin signalling
Endothelin-1 regulates cardiovascular development by acting on neural crest cells. Here endothelin-1-deficient mice are studied, revealing that preotic neural crest cells differentiate into coronary artery smooth muscle cells through endothelin-1-dependent mechanisms.
- Yuichiro Arima
- , Sachiko Miyagawa-Tomita
- & Hiroki Kurihara
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| Open AccessExhaustion of nucleus pulposus progenitor cells with ageing and degeneration of the intervertebral disc
Back pain and sciatica are often caused by intervertebral disc degeneration. Sakai and colleagues identify a subset of nucleus pulposus progenitor cells from the intervertebral disc and show that loss of these progenitor cells correlates with ageing and intervertebral disc degeneration.
- Daisuke Sakai
- , Yoshihiko Nakamura
- & Joji Mochida
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Receptor tyrosine kinase ErbB2 translocates into mitochondria and regulates cellular metabolism
ErbB2 is a receptor tyrosine kinase that localizes to the plasma membrane. Dinget al. now show that ErbB2 also localizes to mitochondria, where it regulates mitochondrial respiratory function and resistance to cancer chemotherapy.
- Yan Ding
- , Zixing Liu
- & Ming Tan
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Cardioprotection by Klotho through downregulation of TRPC6 channels in the mouse heart
Mice that cannot produce the hormone Klotho show various aging-related phenotypes. Here, Xie and colleagues reveal that Klotho protects the heart of mice from stress-induced remodelling by inhibiting exocytosis of the TRPC6 ion channel in cardiomyocytes.
- Jian Xie
- , Seung-Kuy Cha
- & Chou-Long Huang
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| Open AccessThe miRNA-212/132 family regulates both cardiac hypertrophy and cardiomyocyte autophagy
Heart failure is often a consequence of pathological growth of cardiomyocytes or cardiac hypertrophy. Here Ucar and colleagues report that the microRNAs miR-132 and miR-212 promote cardiac hypertrophy and inhibit autophagy in cardiomyocytes by downregulating the transcription factor FoxO3.
- Ahmet Ucar
- , Shashi K. Gupta
- & Thomas Thum
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| Open AccessEscherichia coli noncoding RNAs can affect gene expression and physiology of Caenorhabditis elegans
It is known that differences in the bacterial food ofCaenorhabditis elegans can alter their behaviour. In this study, bacteria expressing two different noncoding RNAs alter the chemosensory and longevity of C. elegans, suggesting a role in modulating C. elegansphysiology.
- Huijie Liu
- , Xueren Wang
- & Ge Shan
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Real-time in vivo imaging of the beating mouse heart at microscopic resolution
Microscopic imaging techniques have a high spatio-temporal resolution but, in living animals, are hampered by cardiac and respiratory motion. This paper describes a microscopic setup that allows fluorescent confocal imaging of the beating mouse heart over a period of several hours.
- Sungon Lee
- , Claudio Vinegoni
- & Ralph Weissleder
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Rotational dynamics of cargos at pauses during axonal transport
Vesicle trafficking in the cell is likely to involve a tug-of-war between motor proteins of opposing directionality. Guet al. use high-speed single-particle tracking in neurons to uncover rotation of paused cargo vesicles, providing insight into the changing forces as the vesicles change direction.
- Yan Gu
- , Wei Sun
- & Ning Fang
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| Open AccessIn silico method for modelling metabolism and gene product expression at genome scale
To describe the biochemical composition of an organism multiple data sets must be combined and this information can then be used forin silico analysis. By combining metabolism and transcription data, Lerman et al. discovered new regulons and improved the gene annotation for the simple organism Thermotoga maritima.
- Joshua A. Lerman
- , Daniel R. Hyduke
- & Bernhard O. Palsson
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| Open AccessNeuronal influence on peripheral circadian oscillators in pupal Drosophila prothoracic glands
In the fruit flyDrosophila, changes in expression of circadian clock genes are believed to control eclosion. Morioka and colleagues show that transcriptional oscillations of the clock gene, period, in prothoracic gland cells are amplified by photic inputs from the central nervous system.
- Eri Morioka
- , Akira Matsumoto
- & Masayuki Ikeda
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Impaired thermogenesis and adipose tissue development in mice with fat-specific disruption of insulin and IGF-1 signalling
Insulin and insulin-like growth factor 1 signalling pathways have overlapping effects on adipose tissue and glucose homeostasis. Boucheret al.created fat-specific double knockouts of these pathways and demonstrated their crucial role for adipocyte development, metabolism and thermogenesis in mice.
- Jeremie Boucher
- , Marcelo A. Mori
- & C. Ronald Kahn
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| Open AccessThe translation inhibitor pateamine A prevents cachexia-induced muscle wasting in mice
Cachexia, or muscle-wasting syndrome, is often observed in patients with cancer or sepsis, and no specific treatment of cachexia is currently available. In this study, Di Marcoet al.show that low doses of pateamine A, an inhibitor of translation initiation, prevent cachexia in a mouse model of the disease.
- Sergio Di Marco
- , Anne Cammas
- & Imed Eddine Gallouzi
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Differentiation of multipotent vascular stem cells contributes to vascular diseases
De-differentiation and proliferation of vascular smooth muscle cells is thought to have a dominant role in vascular remodelling. Here, Tanget al. identify a new type of multipotent vascular stem cell in the blood vessel wall that contributes to this process, thereby challenging the established hypothesis.
- Zhenyu Tang
- , Aijun Wang
- & Song Li
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| Open AccessThe Eutherian Armcx genes regulate mitochondrial trafficking in neurons and interact with Miro and Trak2
Mitochondrial dynamics and trafficking are important for providing energy for neuron function. In this study, the Armadillo repeat containing proteins clustered on the X chromosome are shown to be highly expressed in the nervous system and have a role in mitochondrial dynamics.
- Guillermo López-Doménech
- , Román Serrat
- & Eduardo Soriano
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Involvement of urinary bladder Connexin43 and the circadian clock in coordination of diurnal micturition rhythm
Humans and rodents normally store more urine in the bladder when fast asleep than when awake. In this study, the production of the gap junction protein connexin43, a regulator of bladder capacity, is shown to oscillate in mouse urinary bladder muscle in synchrony with the circadian clock.
- Hiromitsu Negoro
- , Akihiro Kanematsu
- & Osamu Ogawa
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miR-484 regulates mitochondrial network through targeting Fis1
Abnormal mitochondrial fission leads to apoptosis and disease. Li and colleagues reveal the mechanism with which the transcription factor Foxo3a suppresses Fis1-mediated mitochondrial fission and apoptosis in cardiomyocytes and adrenocortical cancer cells, which involves miR-484 inhibition of Fis1 translation.
- Kun Wang
- , Bo Long
- & Pei-Feng Li
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| Open Accessγ-Glutamylcysteine detoxifies reactive oxygen species by acting as glutathione peroxidase-1 cofactor
Glutathione's key role as a modulator of reactive oxygen species levels has recently been challenged. Quintana-Cabreraet al. now provide in vivoevidence supporting an antioxidant and neuroprotective function for γ-glutamylcysteine, which replaces glutathione by acting as glutathione peroxidase-1 cofactor.
- Ruben Quintana-Cabrera
- , Seila Fernandez-Fernandez
- & Juan P. Bolaños