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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
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LSD1 promotes oxidative metabolism of white adipose tissue
Brown adipocytes are rich in mitochondria and influence whole-body energy balance. Here, Duteil et al. show that the lysine-specific demethylase 1 (LSD1) controls mitochondrial biogenesis and the formation of brown-like adipocytes, and that LSD1 overexpression in white fat reduces weight gain of mice on a high-fat diet.
- Delphine Duteil
- , Eric Metzger
- & Roland Schüle
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MRTF-A controls vessel growth and maturation by increasing the expression of CCN1 and CCN2
Myocardin-related transcription factors (MRTFs) increase muscle growth and regeneration. Here, Hinkel et al. show that MRTFs also promote microvessel growth and maturation in chronic ischaemic disease of the heart or peripheral muscle by increasing the expression of the pro-angiongenic factors, CCN1 and CCN2.
- Rabea Hinkel
- , Teresa Trenkwalder
- & Christian Kupatt
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Orbitofrontal neurons infer the value and identity of predicted outcomes
Orbitofrontal cortex neuronal activity is thought to represent expected outcomes based on inferred states. Here, the authors show definitively that orbitofrontal cortex activity represents features of expected outcomes through inferred rather than experienced information, which is not dependent on the outcome value.
- Thomas A. Stalnaker
- , Nisha K. Cooch
- & Geoffrey Schoenbaum
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Cathepsin K-mediated notch1 activation contributes to neovascularization in response to hypoxia
The cathepsin family of proteases cleaves intracellular as well as extracellular proteins. Here the authors implicate cathepsin K in ischaemia-induced neovascularization by showing that cathepsin K increases the levels of cleaved Notch1 and downstream Notch signalling in endothelial cells.
- Haiying Jiang
- , Xian Wu Cheng
- & Masafumi Kuzuya
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| Open AccessTRPV2 is critical for the maintenance of cardiac structure and function in mice
The TRPV2 calcium channel can be activated by mechanical stretch and may act as a mechanoreceptor in tissues. Here the authors deplete the TRPV2 calcium channel from the hearts of adult mice, showing that TRPV2 is important for the maintenance of cardiac structure and function.
- Yuki Katanosaka
- , Keiichiro Iwasaki
- & Keiji Naruse
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| Open AccessSeparating NADH and NADPH fluorescence in live cells and tissues using FLIM
NAD and NADP play fundamentally different roles in cellular metabolism, and yet these pyridine nucleotides cannot be distinguished spectroscopically in living cells. Blacker et al.demonstrate that fluorescence lifetime imaging can be used to quantify NADPH/NADH balance in cultured cells and in the mammalian cochlea.
- Thomas S. Blacker
- , Zoe F. Mann
- & Michael R. Duchen
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MitoNEET-mediated effects on browning of white adipose tissue
Mice overexpressing the mitochondrial protein MitoNEET in white adipose tissue (WAT) are very fat but metabolically healthy. Here the authors study the physiological consequences of MitoNEET overexpression in WAT, showing that this triggers an initial browning and that the subsequently expanded WAT is less fibrotic.
- Christine M. Kusminski
- , Jiyoung Park
- & Philipp E. Scherer
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Epidermal cells help coordinate leukocyte migration during inflammation through fatty acid-fuelled matrix metalloproteinase production
Metabolic regulation is emerging as an important component of immune response control and may be implicated in the development of inflammatory diseases. Here, the authors show that inflammatory leukocyte recruitment depends on mitochondrial metabolism in epidermal cells in zebrafish.
- Christopher J. Hall
- , Rachel H. Boyle
- & Philip S. Crosier
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Modulation of dopamine release in the striatum by physiologically relevant levels of nicotine
Nicotine exposure from cigarette smoke modulates dopamine release in the brain, which is implicated in nicotine addiction, but how it does this is unclear. Here, in mouse brain slices, the authors show that nicotine inhibits cholinergic- but not dopaminergic-dependent dopamine release.
- Li Wang
- , Shujiang Shang
- & Zhuan Zhou
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| Open AccessLow abundance of the matrix arm of complex I in mitochondria predicts longevity in mice
Mitochondria are involved in ageing but exactly how they are involved is controversial. Here the authors show that optimal assembly of mitochondrial complex I predicts longevity in mice, whereas partial complex I assembly increases the production of reactive oxygen species.
- Satomi Miwa
- , Howsun Jow
- & Thomas von Zglinicki
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A Krüppel-like factor downstream of the E3 ligase WWP-1 mediates dietary-restriction-induced longevity in Caenorhabditis elegans
The ubiquitin ligase WWP-1 mediates the lifespan-increasing effect of dietary restriction (DR) in worms. Here the authors show that WWP-1 mono-ubiquitinylates the transcription factor Klf-1 in cultured cells and demonstrate that WWP-1 acts upstream of Klf-1 to regulate DR-induced longevity in worms.
- Andrea C. Carrano
- , Andrew Dillin
- & Tony Hunter
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| Open AccessThe short-chain fatty acid acetate reduces appetite via a central homeostatic mechanism
The consumption of fermentable carbohydrates, or fibre, is associated with weight loss. Here the authors show that the metabolite acetate, created by fermentation of fibre in the mouse colon, is taken up into the brain where it induces appetite-suppressing neuronal activity in the hypothalamus.
- Gary Frost
- , Michelle L. Sleeth
- & Jimmy D. Bell
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| Open AccessGATA-dependent regulatory switches establish atrioventricular canal specificity during heart development
The atrioventricular canal partitions the developing vertebrate heart. Here, the authors show that the cardiac transcription factor Gata4 together with histone modification enzymes and localized co-factors binds atrioventricular canal-specific enhancers, thereby repressing gene activity in the cardiac chambers.
- Sonia Stefanovic
- , Phil Barnett
- & Vincent M. Christoffels
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Alternative splicing regulates vesicular trafficking genes in cardiomyocytes during postnatal heart development
Alternative splicing is a process during gene expression that increases the diversity of proteins encoded by a single gene. Here, the authors perform RNA-sequencing on cardiac cells from mice and show that extensive changes in gene expression and alternative splicing occur during the first month after birth.
- Jimena Giudice
- , Zheng Xia
- & Thomas A. Cooper
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Glycolytic genes are targets of the nuclear receptor Ad4BP/SF-1
The transcription factor NR5A1 has so far mainly been known for regulating the biosynthesis of steroids. Here the authors discover that NR5A1 also has a role in energy metabolism, demonstrating that NR5A1 regulates several key enzymes involved in the breakdown of glucose.
- Takashi Baba
- , Hiroyuki Otake
- & Ken-Ichirou Morohashi
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| Open AccessD-Glucosamine supplementation extends life span of nematodes and of ageing mice
D-Glucosamine is a dietary supplement widely used for the treatment of osteoarthritis. Here Weimer et al. show that D-glucosamine extends the life span of Caenorhabditis elegans and of mice by mimicking the molecular effects of a diet low in carbohydrates.
- Sandra Weimer
- , Josephine Priebs
- & Michael Ristow
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Methionine restriction extends lifespan of Drosophila melanogaster under conditions of low amino-acid status
Dietary restriction of the amino acid methionine extends the lifespan of rodents. Here the authors systematically test diets with varying amino-acid content and show that methionine restriction extends the lifespan of yeast and flies only when the content of other amino acids in the diet is also low.
- Byung Cheon Lee
- , Alaattin Kaya
- & Vadim N. Gladyshev
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CARL lncRNA inhibits anoxia-induced mitochondrial fission and apoptosis in cardiomyocytes by impairing miR-539-dependent PHB2 downregulation
The prohibitin complex promotes cell survival by regulating mitochondrial morphogenesis. Wang et al.identify a long non-coding RNA that regulates this complex in cardiomyocytes by acting as a sponge to downregulate a prohibitin-targetting miRNA, protecting cells from apoptosis in anoxic conditions.
- Kun Wang
- , Bo Long
- & Pei-Feng Li
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Article
| Open AccessWhisker barrel cortex delta oscillations and gamma power in the awake mouse are linked to respiration
Oscillatory neuronal activity in the mammalian neocortex is implicated in cognitive processes but its generation is poorly understood. In this study, the authors show that delta band oscillatory activity in mice phase-locks with respiratory activity and that this is mediated by activity in the olfactory bulb.
- J. Ito
- , S. Roy
- & D.H. Heck
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| Open AccessAcidosis overrides oxygen deprivation to maintain mitochondrial function and cell survival
In hypoxic conditions, cells depend on anaerobic respiration, which results in extracellular acidosis. Khacho et al.find that acidosis serves a protective function, enhancing mitochondrial respiratory capacity and sustaining ATP synthesis despite limited oxygen availability, by both promoting mitochondrial fusion and inhibiting fission.
- Mireille Khacho
- , Michelle Tarabay
- & Ruth S. Slack
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Morphological and functional remodelling of the neuromuscular junction by skeletal muscle PGC-1α
The peroxisome proliferator activated receptor γ co-activator 1α (PGC-1α) is implicated in regulating the morphology and function of the neuromuscular junction. Here, Arnold et al.show that PGC-1α promotes the remodeling of pre- and postsynaptic neuromuscular junction sites, even in the absence of physical activity.
- Anne-Sophie Arnold
- , Jonathan Gill
- & Christoph Handschin
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Metabolic efficiency underpins performance trade-offs in growth of Arabidopsis thaliana
Resources are finite for living organisms; therefore, compromises are required when partitioning resources to different tasks. Here, the authors use the Pareto concept to show how a trade-off is achieved in terms of the performance and metabolic efficiency in a panel of 97 Arabidopsis thalianaaccessions.
- Sabrina Kleessen
- , Roosa Laitinen
- & Zoran Nikoloski