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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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Article
| 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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Article
| 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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Article
| 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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Article
| 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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Article
| 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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Article
| 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
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Hepatic IRE1α regulates fasting-induced metabolic adaptive programs through the XBP1s–PPARα axis signalling
The IRE1α-XBP1 signalling pathway is part of the ER stress response but has also been linked to glucose and lipid metabolism. Here the authors show that IRE1α in the liver acts as a nutrient-sensor, regulating the metabolic adaptation to fasting and a ketogenic diet by inducing PPARα expression.
- Mengle Shao
- , Bo Shan
- & Yong Liu
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Ablation of TrkB signalling in CCK neurons results in hypercortisolism and obesity
Glucocorticoid levels in the body are controlled by an intricate feedback system acting on the hypothalamus. Here the authors provide molecular insight into this process, identifying TrkB signalling in cholecystokinin-GABAergic neurons as a key component of hypothalamic glucocorticoid signalling.
- Mirjam Geibel
- , Sylvia Badurek
- & Liliana Minichiello
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3D multifunctional integumentary membranes for spatiotemporal cardiac measurements and stimulation across the entire epicardium
Tools for cardiac physiological mapping are important for basic and clinical cardiac research. Here the authors use 3D printing to create a thin, elastic silicone sheath that fits tightly around the entire epicardium and contains sensors to measure a variety of physiological parameters of the beating heart ex vivo.
- Lizhi Xu
- , Sarah R. Gutbrod
- & John A. Rogers
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| Open AccessIRF8 suppresses pathological cardiac remodelling by inhibiting calcineurin signalling
The transcription factor interferon regulatory factor 8 (IRF8) is known to regulate differentiation and function of immune cells. Here the authors show that IRF8 is upregulated in the hypertrophic heart in humans and mice, where it suppresses cardiac remodelling by inhibiting calcineurin signalling.
- Ding-Sheng Jiang
- , Xiang Wei
- & Hongliang Li
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Genome-wide RNAi ionomics screen reveals new genes and regulation of human trace element metabolism
The composition of trace elements in human cells (the ionome) is an important component of metabolism. Here, the authors carry out a high-throughput, genome-wide analysis of the human ionome and identify cellular regulators of important trace elements such as selenium, copper and iron.
- Mikalai Malinouski
- , Nesrin M. Hasan
- & Vadim N. Gladyshev
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Neonatal testosterone suppresses a neuroendocrine pulse generator required for reproduction
The milk-ejection reflex in mammals requires the coordinated bursting of oxytocin neurons in the hypothalamus. Here, Israel et al.show that the rhythmic bursting behaviour displayed by these neurons is active in both male and female neonatal rats, but is inactivated in males after the first week of life.
- Jean-Marc Israel
- , Jean-Marie Cabelguen
- & Philippe Ciofi
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Article
| Open AccessCritical roles of nardilysin in the maintenance of body temperature homoeostasis
The precise regulation of mammalian body temperature is important for survival. Here the authors show that the peptidase nardilysin represses the transcription factor PGC-1α, and identify nardilysin as a regulator of basal body temperature, cold-induced thermogenesis and body insulation.
- Yoshinori Hiraoka
- , Tatsuhiko Matsuoka
- & Eiichiro Nishi
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Global metabolic network reorganization by adaptive mutations allows fast growth of Escherichia coli on glycerol
Organisms can adapt to environmental change but how this affects metabolism is unclear. Here, the authors provide a detailed analysis of the effects of individual adaptive mutations on the metabolic network in E. coli, and find evidence of metabolic reprogramming during laboratory evolution on glycerol.
- Kian-Kai Cheng
- , Baek-Seok Lee
- & Martin Robert
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Kctd10 regulates heart morphogenesis by repressing the transcriptional activity of Tbx5a in zebrafish
T-box transcription factors such as Tbx5 have essential roles during cardiac development. Here the authors show that a member of the potassium channel tetramerization domain-containing family, Kctd10 is required for zebrafish heart development and represses the transcriptional activity of Tbx5.
- Xiangjun Tong
- , Yao Zu
- & Bo Zhang
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Article
| Open AccessHypothalamic inhibition of socio-sexual behaviour by increasing neuroestrogen synthesis
The conversion of testosterone into oestrogen in the brain is implicated in male aggressive behaviour. Ubuka et al.show that gonadotropin-inhibitory hormone inhibits male aggression by increasing oestrogen synthesis in the brain beyond its optimum concentration for the expression of aggressive behaviour.
- Takayoshi Ubuka
- , Shogo Haraguchi
- & Kazuyoshi Tsutsui
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Article
| Open AccessA paracrine network regulates the cross-talk between human lung stem cells and the stroma
The human lung contains Lgr6-positive progenitor cells, which have the potential to generate multiple epithelial lineages in cell explant studies. Here, the authors present a role of p38a MAPK signalling in regulating the cross-talk between this lung progenitor cell population and the stromal and endothelial cells comprising their niche microenvironment.
- E. Josue Ruiz
- , Feride Oeztuerk-Winder
- & Juan-Jose Ventura
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Mitochondrial reactive oxygen species regulate the strength of inhibitory GABA-mediated synaptic transmission
Cellular energy metabolism is essential for sustaining neuronal signalling in the brain. Acardi et al.show that mitochondrial reactive oxygen species, which are by-products of cellular metabolism, selectively strengthen inhibitory transmission by recruiting a subpopulation of GABAA receptors.
- Michael V. Accardi
- , Bryan A. Daniels
- & Derek Bowie
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Genome-scale metabolic modelling of hepatocytes reveals serine deficiency in patients with non-alcoholic fatty liver disease
Alterations in hepatocyte metabolism can lead to disorders such as non-alcoholic steatohepatitis (NASH). Here the authors create a comprehensive model of hepatocyte metabolism and use it to identify metabolic pathways altered in disease, revealing that serine levels are reduced in patients with NASH.
- Adil Mardinoglu
- , Rasmus Agren
- & Jens Nielsen
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Predicting network functions with nested patterns
Identifying functionally important features of complex biological networks is computationally challenging. Ganter et al.develop a probabilistic framework that uses recurrent metabolite patterns to predict the properties and existence of reactions within a genome-scale metabolic network.
- Mathias Ganter
- , Hans-Michael Kaltenbach
- & Jörg Stelling
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Gap junction signalling is a stress-regulated component of adrenal neuroendocrine stimulus-secretion coupling in vivo
Findings from ex vivo studies suggest that gap junctional coupling contributes to hormone release in neuroendocrine/endocrine tissues. Here, the authors provide in vivo evidence that direct communication between adrenal chromaffin cells viagap junctions contributes to catecholamine secretion.
- Michel G. Desarménien
- , Carole Jourdan
- & Nathalie C. Guérineau
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| Open AccessA failure in energy metabolism and antioxidant uptake precede symptoms of Huntington’s disease in mice
Defective ascorbic acid flux is a sign of metabolic failure associated with Huntington’s disease. Here, Acuña et al.show that reduction in ascorbic acid flux from astrocytes precedes the symptoms of Huntington’s disease in mice and impairs ascorbic acid uptake in neurons.
- Aníbal I. Acuña
- , Magdalena Esparza
- & Maite A. Castro
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Essential regulation of cell bioenergetics in Trypanosoma brucei by the mitochondrial calcium uniporter
The mitochondrial calcium uniporter supports oxidative phosphorylation in mammals; however, it is also present in blood-stage trypanosomes, which lack a functional respiratory chain. Huang et al. show that the mitochondrial calcium uniporter is essential for blood-stage survival and metabolism in Trypanosoma brucei.
- Guozhong Huang
- , Anibal E. Vercesi
- & Roberto Docampo
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Highly efficient methane biocatalysis revealed in a methanotrophic bacterium
Methane is a promising renewable carbon source for chemical synthesis, yet methane bio-gas is currently underutilised as a feedstock. Here the authors examine the metabolic processes of methanotrophic bacteria to assess their use for conversion of methane to value-added chemical products.
- M. G. Kalyuzhnaya
- , S. Yang
- & M. E. Lidstrom