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FoxO1 integrates direct and indirect effects of insulin on hepatic glucose production and glucose utilization
Insulin and the transcription factor FoxO1 are key regulators of glucose metabolism. Using mice that lack insulin receptor and FoxO1 in the liver, O-Sullivan et al.show that extrahepatic effects of insulin are sufficient to maintain glucose homeostasis when hepatic FoxO1 is disrupted.
- InSug O-Sullivan
- , Wenwei Zhang
- & Terry G. Unterman
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| Open AccessAblation of the p16INK4a tumour suppressor reverses ageing phenotypes of klotho mice
The protein p16INK4a promotes senescence in tissue stem cells and thereby contributes to organismal ageing. Here the authors reveal that p16INK4a also downregulates expression of a-klotho, thereby revealing an additional ageing-promoting function of 16INK4athat is independent from its role in senescence.
- Seidai Sato
- , Yuka Kawamata
- & Eiji Hara
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| Open AccessFGF1 and FGF19 reverse diabetes by suppression of the hypothalamic–pituitary–adrenal axis
Fibroblast growth factor (FGF) family proteins have anti-diabetic effects, but how they work is currently unclear. Here the authors show that injections of FGF1 or FGF19 into the brain of diabetic rats alter glucose and lipid homeostasis by suppressing activity of the hypothalamic-pituitary-adrenal signalling axis.
- Rachel J. Perry
- , Sangwon Lee
- & Gerald I. Shulman
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| Open AccessA REDD1/TXNIP pro-oxidant complex regulates ATG4B activity to control stress-induced autophagy and sustain exercise capacity
Stress-induced macroautophagy is initiated by the induction of reactive oxygen species (ROS). Here Qiao et al.show that the mTOR inhibitor REDD1 in a complex with pro-oxidant protein TXNIP induces ROS formation, leading to ATG4B suppression and autophagy activation in a largely mTOR-independent manner.
- Shuxi Qiao
- , Michael Dennis
- & Leif W. Ellisen
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In vivo model with targeted cAMP biosensor reveals changes in receptor–microdomain communication in cardiac disease
cAMP is a second messenger that acts in distinct intracellular locations regulating diverse cellular functions. Here the authors design a FRET-based cAMP biosensor and use it to measure in vivodynamics of cAMP concentration changes in the sarcoplasmatic reticulum of mouse cardiomyocytes in health and disease.
- Julia U. Sprenger
- , Ruwan K. Perera
- & Viacheslav O. Nikolaev
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| Open AccessBoth respiration and photosynthesis determine the scaling of plankton metabolism in the oligotrophic ocean
Whether the oligotrophic ocean is net heterotrophic or net autotrophic has been a matter of debate for many years. Here Serret et al. show that, rather than being one or the other, the oligotrophic ocean is functionally diverse, with different metabolic states in different gyres.
- Pablo Serret
- , Carol Robinson
- & Rob Thomas
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Direct neuronal glucose uptake heralds activity-dependent increases in cerebral metabolism
The brain is a highly active organ that relies almost exclusively on glucose as its energy source, but whether glucose is directly taken up by neurons or whether it is converted to lactate by astrocytes before neuronal uptake is still unclear. Here the authors perform in vivoimaging in awake mice and show evidence in support of the direct uptake of glucose by neurons.
- Iben Lundgaard
- , Baoman Li
- & Maiken Nedergaard
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| Open AccessTracing the evolutionary origins of insect renal function
The evolution of neuropeptide signalling in insects is poorly understood. Here the authors map renal tissue architecture in the major insect Orders, and show that while the ancient neuropeptide families are involved in signalling in nearly all species, there is functional variation in the cell types that mediate the signal.
- Kenneth A. Halberg
- , Selim Terhzaz
- & Julian A. T. Dow
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| Open AccessIncreased prevalence of EPAS1 variant in cattle with high-altitude pulmonary hypertension
Pulmonary hypertension and congestive right heart failure afflict some cattle living at high altitude in an autosomal dominant pattern, yet no responsible genes have been identified. Here Newman et al.use whole-exome sequencing to identify variants in the hypoxia inducible factor gene, EPAS1.
- John H. Newman
- , Timothy N. Holt
- & Rizwan Hamid
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Honokiol blocks and reverses cardiac hypertrophy in mice by activating mitochondrial Sirt3
The chemical honokiol is found in the bark of magnolia trees, which are used for traditional medicine in Asian countries. Here, Pillai et al, show honokiol protects the heart from hypertrophic remodelling in mice, and even reverses established cardiac hypertrophy, by activating the deacetylase Sirt3.
- Vinodkumar B. Pillai
- , Sadhana Samant
- & Mahesh P. Gupta
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| Open AccessRegulation of systemic energy homeostasis by serotonin in adipose tissues
The neurotransmitter serotonin has both central and peripheral effects. Here, the authors show that adipocyte-derived serotonin regulates organismal energy homeostasis in mice by acting on adipocyte serotonin receptors on fat cells, which regulates lipolysis and thermogenesis in white and brown fat tissue.
- Chang-Myung Oh
- , Jun Namkung
- & Hail Kim
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| Open AccessControlled induction of DNA double-strand breaks in the mouse liver induces features of tissue ageing
Accumulation of DNA damage is a hallmark of cellular ageing but cause and effect are unclear. Here White et al.induce clean DNA double-strand breaks in the liver of mice using a modified restriction enzyme and demonstrate that DNA damage alone is sufficient to recapitulate some aspects of tissue ageing.
- Ryan R. White
- , Brandon Milholland
- & Jan Vijg
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Rio1 promotes rDNA stability and downregulates RNA polymerase I to ensure rDNA segregation
The protein kinase Rio1 is known to promote 40S ribosome formation in the cytoplasm. Using budding yeast, the authors here show that Rio1 also acts in the nucleus, downregulates rDNA transcription by Pol I, and activates the processing of its transcripts to ensure rDNA stability and segregation.
- Maria G. Iacovella
- , Cristina Golfieri
- & Peter De Wulf
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| Open AccessFlavin-containing monooxygenase 3 as a potential player in diabetes-associated atherosclerosis
The hepatic enzyme FMO3 has been linked to atherosclerosis. Here the authors show that FMO3 is upregulated in various models of diabetes and link FMO3 with key transcriptional regulators of hepatic glucose and cholesterol synthesis, thus proposing a mechanistic connection between diabetes and atherosclerosis.
- Ji Miao
- , Alisha V. Ling
- & Sudha B. Biddinger
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Metabolic learning and memory formation by the brain influence systemic metabolic homeostasis
Flies can remember the caloric content of food. Here, the authors show that flies have a learned preference for normal caloric food, but this metabolic learning or memory is lost after forced consumption of a high-caloric diet, and identify key neuronal genes required for the formation of such memories.
- Yumin Zhang
- , Gang Liu
- & Dongsheng Cai
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| Open AccessSymportin 1 chaperones 5S RNP assembly during ribosome biogenesis by occupying an essential rRNA-binding site
Biogenesis of the 80S ribosome involves more than 200 pre-ribosomal factors, which ensure the sequential assembly of ribosomal proteins and RNAs. Here the authors show that the nuclear transport adaptor Syo1 shields the 5S RNP-docking site on RpL11 before incorporation into the pre-60S through molecular mimicry.
- Fabiola R. Calviño
- , Satyavati Kharde
- & Irmgard Sinning
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| Open AccessA muscle-liver-fat signalling axis is essential for central control of adaptive adipose remodelling
Skeletal muscle proteolysis can affect organismal energy homeostasis. Here, the authors provide molecular insight into this process by showing that muscle-derived alanine acts as a signal that triggers FGF21 secretion from the liver, which then regulates lipolysis and browning of white fat tissue.
- Noriaki Shimizu
- , Takako Maruyama
- & Hirotoshi Tanaka
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Immune complexes regulate bone metabolism through FcRγ signalling
Bone and the immune system are functionally intertwined. This study shows that osteoclastogenesis is modulated by the intensity of Fcγ receptor signalling, which is shaped by the balance between the positive and negative Fcγ receptors expressed on osteoclasts and the availability of their ligands, immune complexes.
- Takako Negishi-Koga
- , Hans-Jürgen Gober
- & Hiroshi Takayanagi
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Suppressor of Deltex mediates Pez degradation and modulates Drosophila midgut homeostasis
The protein tyrosine phosphatase Pez controls intestinal stem cell proliferation in Drosophila by inhibiting the Hippo pathway transcription factor Yorkie. Wang et al. reveal that Pez protein stability is regulated by interactions with the E3 ubiquitin ligase Suppressor of Deltex.
- Chao Wang
- , Wenxiang Zhang
- & Lei Zhang
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| Open AccessPD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation
Activation of T cells results in metabolic reprogramming to favour glycolysis. Here, Patsoukis et al. show that the surface receptor PD-1 inhibits glycolysis and increases the metabolism of lipids, providing a potential mechanism for the blockade of T effector functions but also for the longevity accompanying T cell exhaustion.
- Nikolaos Patsoukis
- , Kankana Bardhan
- & Vassiliki A. Boussiotis
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Dietary methionine can sustain cytosolic redox homeostasis in the mouse liver
NADPH acts as a reducing currency in mammalian cells and is thought to be required to maintain redox homeostasis. Here the authors discover an alternative NADPH-independent pathway, based on the conversion of methionine into cysteine, which is capable of sustaining redox homeostasis in the mouse liver.
- Sofi Eriksson
- , Justin R. Prigge
- & Edward E. Schmidt
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| Open AccessRGS1 regulates myeloid cell accumulation in atherosclerosis and aortic aneurysm rupture through altered chemokine signalling
Vascular inflammation plays a key role in pathogenesis of major vascular diseases. Here the authors show that Regulator of G-Protein Signaling-1 (RGS1) controls macrophage function in the development of vascular inflammation that underlies atherosclerosis and abdominal aortic aneurysms in mice and humans.
- Jyoti Patel
- , Eileen McNeill
- & Keith M. Channon
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| Open AccessAdipose tissue NAPE-PLD controls fat mass development by altering the browning process and gut microbiota
Endocannabinoids are bioactive lipid molecules produced in the body. Here, Geurts et al. create mice lacking the endocannabinoid-producing enzyme NAPE-PLD in adipocytes and report defects in adipose-induced browning, which are mediated by alterations in the gut microbiome.
- Lucie Geurts
- , Amandine Everard
- & Patrice D. Cani
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The insulin and IGF1 receptor kinase domains are functional dimers in the activated state
In contrast to most receptor tyrosine kinases, the insulin and insulin-like growth factor-1 receptors are preformed, disulfide-linked dimers. Here the authors show that, after the two kinase domains of IR and IGF1R undergo autophosphorylation, they form a specific dimer to phosphorylate downstream substrates.
- M. Zulema Cabail
- , Shiqing Li
- & W. Todd Miller
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| Open AccessBrown fat activation reduces hypercholesterolaemia and protects from atherosclerosis development
Brown adipose tissue (BAT) produces heat by burning lipid triglycerides. Here, Berbée et al. show that pharmacological BAT activation protects hyperlipidemic mice from atherosclerosis, provided mice retain the metabolic capacity to clear cholesterol-enriched lipoprotein remnants by the liver.
- Jimmy F. P. Berbée
- , Mariëtte R Boon
- & Patrick C.N. Rensen
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| Open AccessDefective podocyte insulin signalling through p85-XBP1 promotes ATF6-dependent maladaptive ER-stress response in diabetic nephropathy
Diabetic kidney disease is associated with ER stress in podocytes. Here the authors use various genetically modified mouse models to study ER-stress-related signalling pathways and propose a mechanistic framework that links insulin signalling with ER stress in podocytes of diabetic mice.
- Thati Madhusudhan
- , Hongjie Wang
- & Berend Isermann
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| Open AccessDysregulation of transition metal ion homeostasis is the molecular basis for cadmium toxicity in Streptococcus pneumoniae
The molecular basis for the high toxicity of cadmium is unclear. Here, Begg et al. use the bacterium Streptococcus pneumoniaeas a model system, and show that cadmium uptake increases sensitivity to oxidative stress by reducing intracellular concentrations of manganese and zinc through different mechanisms.
- Stephanie L. Begg
- , Bart A. Eijkelkamp
- & Christopher A. McDevitt
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The cholesterol transporter ABCG1 links cholesterol homeostasis and tumour immunity
ABCG1 transporter pumps cholesterol out of the cell. Here, the authors show that ABCG1-deficient mice have reduced tumour growth due to a switch of the tumour-associated macrophages from a tumour-promoting to tumour-suppressing phenotype, and are protected from the pro-tumorigenic effects of a Western-like diet.
- Duygu Sag
- , Caglar Cekic
- & Catherine C. Hedrick
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Nutritional stress induces exchange of cell material and energetic coupling between bacterial species
Bacterial communities adapt to changing environments by modulating patterns of nutrient flow between species. Benomar et al. show that under nutrient stress, the sulfate-reducing bacterium Desulfovibrio vulgaris can exchange cytoplasmic material with Clostridium acetobutylicum, altering metabolic flux.
- Saida Benomar
- , David Ranava
- & Marie-Thérèse Giudici-Orticoni
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| Open AccessAntagonistic interplay between hypocretin and leptin in the lateral hypothalamus regulates stress responses
The hypothalamic-pituitary-adrenal axis coordinates behavioral and physiological responses to stress but the mechanisms are poorly understood. Here, the authors show that neurons that produce hypocretin/orexin in the lateral hypothalamic area regulate corticosterone release and a variety of behaviors related to the stress response.
- Patricia Bonnavion
- , Alexander C. Jackson
- & Luis de Lecea
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TMC-1 attenuates C. elegans development and sexual behaviour in a chemically defined food environment
The tmc-1 gene encodes for a sodium channel that has been linked to chemosensation in C. elegans. Here the authors show that in a non-optimal nutrient environment, tmc-1mediates physiological worm responses such as developmental retardation and inhibited sexual behaviour.
- Liusuo Zhang
- , Daisy G. Gualberto
- & L. Rene Garcia
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NEDD4 controls intestinal stem cell homeostasis by regulating the Hippo signalling pathway
The Hippo pathway plays a role in regulating organ size and stem cell renewal but the regulatory mechanisms that fine-tune this pathway are not well understood. Here the authors report on the role of NEDD4 as a negative regulator of the Hippo signalling components, WW45 and LATS kinase, and in controlling cell proliferation and intestinal stem cell homeostasis.
- Sung Jun Bae
- , Myungjin Kim
- & Jae Hong Seol
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Mutation within the hinge region of the transcription factor Nr2f2 attenuates salt-sensitive hypertension
Transcription factor Nr2f2 is linked to high blood pressure in humans and animals. Using hypertensive rats that have been genetically modified to express a mutant Nr2f2 that binds stronger to transcription factor Fog2, the authors show that the interaction between these two proteins is critical for blood pressure regulation.
- Sivarajan Kumarasamy
- , Harshal Waghulde
- & Bina Joe
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| Open AccessA rapid bioluminescence assay for measuring myeloperoxidase activity in human plasma
Levels of the enzyme myeloperoxidase in the blood are considered a biomarker for the severity of cardiovascular disease. Here the authors report a rapid and inexpensive method for measuring myeloperoxidase activity in human plasma by luminescence, after adsorption of the enzyme to a polymer surface.
- Reece J. Goiffon
- , Sara C. Martinez
- & David Piwnica-Worms
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MnSOD upregulation sustains the Warburg effect via mitochondrial ROS and AMPK-dependent signalling in cancer
Tumour cells sustain high levels of glycolysis even in presence of oxygen, which is known as the Warburg effect. Here the authors show that MnSOD contributes to the Warburg effect by increasing the levels of H2O2released from mitochondria, which sustains glycolysis by activating AMPK.
- Peter C. Hart
- , Mao Mao
- & Marcelo G. Bonini
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| Open AccessThe sperm of aging male bustards retards their offspring’s development
Sperm from aging males may decline in quality, but it is unclear how aging affects the ability of males to produce successful offspring. Here, the authors show that paternal aging of captive long-lived houbara bustards reduces both the likelihood that eggs hatch and the rate at which chicks grow.
- Brian T. Preston
- , Michel Saint Jalme
- & Gabriele Sorci
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| Open AccessFumarate induces redox-dependent senescence by modifying glutathione metabolism
Fumarate hydratase (FH) mutations are associated with renal cancer. Here, Zheng et al. use metabolomic and analytical chemistry approaches to reveal that fumarate accumulated due to FH loss covalently modifies intracellular glutathione, leading to oxidative stress and senescence.
- Liang Zheng
- , Simone Cardaci
- & Eyal Gottlieb
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The 40-residue insertion in Vibrio cholerae FadR facilitates binding of an additional fatty acyl-CoA ligand
FadR is a regulator of fatty acid metabolism in bacteria, and contains a binding site for acyl-CoA. Here, Shi et al. present a structure of V. cholerae FadR and show that a unique C-terminal extension comprises a second acyl-CoA binding site, perhaps rendering V. choleraeFadR a more efficient regulator.
- Wei Shi
- , Gabriela Kovacikova
- & F. Jon Kull
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The mitochondrial uniporter controls fight or flight heart rate increases
Animals react to threats by increasing their heart rate. Wu et al. show that mitochondrial calcium uptake via a highly selective ion channel, the mitochondrial calcium uniporter, stimulates metabolism in cardiac pacemaker cells and is essential for physiological pulse acceleration but not resting heart rate.
- Yuejin Wu
- , Tyler P. Rasmussen
- & Mark E. Anderson
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Increased atrial arrhythmia susceptibility induced by intense endurance exercise in mice requires TNFα
Endurance exercise is associated with an increased risk of atrial fibrillation. Here, the authors show the adipokine TNFα is a crucial mediator of exercise-induced atrial fibrillation and irreversible atrial remodelling characterized by fibrosis and inflammation.
- Roozbeh Aschar-Sobbi
- , Farzad Izaddoustdar
- & Peter H. Backx
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Exercise at depth alters bradycardia and incidence of cardiac anomalies in deep-diving marine mammals
Deep-sea diving mammals routinely undergo extreme physiological challenges not experienced by their terrestrial counterparts. Using high-resolution electrocardiographic recorders fitted to seals and dolphins, Williams et al. report an increased frequency of cardiac arrhythmias at greater exercise intensity and dive depth.
- Terrie M. Williams
- , Lee A. Fuiman
- & Randall W. Davis
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| Open AccessA subcutaneous adipose tissue–liver signalling axis controls hepatic gluconeogenesis
The drug amlexanox is known to improve obesity-related metabolic dysfunction in mice. Here the authors show that this effect is mediated by interleukin-6 secreted from subcutaneous adipocytes, which then inhibits gluconeogenesis in the liver by phosphorylating the hepatic transcription factor Stat3.
- Shannon M. Reilly
- , Maryam Ahmadian
- & Alan R. Saltiel
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| Open AccessInsulin resistance and white adipose tissue inflammation are uncoupled in energetically challenged Fsp27-deficient mice
Fsp27 mediates ‘fusion’ of lipid droplets in mouse adipose tissue. Here, the authors investigate the physiological consequences of loss of Fsp27 in three different mouse models of ‘energetic overload’, and observe hepatic steatosis and insulin resistance but reduced adipose tissue inflammation.
- Linkang Zhou
- , Shi-Young Park
- & Peng Li
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A non-conserved miRNA regulates lysosomal function and impacts on a human lysosomal storage disorder
Multiple sulfatase deficiency is a lysosomal storage disorder arising from mutations in the sulfatase modifying factor 1 (SUMF1) gene. Here Frankel et al. show that targeting a microRNA, miR-95, can increase residual SUMF1 expression and restore sulfatase activity in patient cells.
- Lisa B. Frankel
- , Chiara Di Malta
- & Anders H. Lund
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Telomerase expression confers cardioprotection in the adult mouse heart after acute myocardial infarction
Short telomeres are risk factors for age-associated diseases such as cardiopathies. Here the authors show that cardiac reactivation of telomerase, the telomere-elongating enzyme whose expression is normally silenced postnatally, mitigates the consequences of myocardial infarction in adult mice.
- Christian Bär
- , Bruno Bernardes de Jesus
- & Maria A. Blasco
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| Open AccessFunctionally reciprocal mutations of the prolactin signalling pathway define hairy and slick cattle
The hormone prolactin is a known modulator of mammalian lactation and hair growth. Here, the authors describe two dominant mutations in bovine prolactin and its receptor, demonstrating antagonistic effects on these traits and highlighting a role for this pathway in sweat gland function and thermoregulation.
- Mathew D. Littlejohn
- , Kristen M. Henty
- & Stephen R. Davis
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| Open AccessThe switching role of β-adrenergic receptor signalling in cell survival or death decision of cardiomyocytes
The contribution of signal strength on cell fate decisions is often not reflected in signalling networks. By combining mathematical simulation and biochemical experiments in cultured adult cardiomyocytes, Shin et al. show that the concentration of a β-adrenergic receptor agonist affects the expression of Bcl-2, influencing the balance between cell survival and death.
- Sung-Young Shin
- , Taeyong Kim
- & Do Han Kim
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Somatic mutations in arachidonic acid metabolism pathway genes enhance oral cancer post-treatment disease-free survival
Chemical inhibitors of the tumour-progression promoting arachidonic acid metabolism pathway prolong post-treatment survival of cancer patients. Here the authors analyse sequence variation in oral cancer patients and show that loss-of-function mutations in this pathway prolong survival.
- Nidhan K. Biswas
- , Subrata Das
- & Partha P. Majumder
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| Open AccessSerotonergic neurons respond to nutrients and regulate the timing of steroid hormone biosynthesis in Drosophila
Steroidal hormones play a major role in the transition from juvenile-to-adult stages of development. Here, Shimada-Niwa and Niwa show that production of one such hormone in the prothoracic gland of Drosophila melanogaster, is regulated by a subset of serotonergic neurons innervating the prothoracic gland.
- Yuko Shimada-Niwa
- & Ryusuke Niwa