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Thrombin-dependent intravascular leukocyte trafficking regulated by fibrin and the platelet receptors GPIb and PAR4
Thrombin is a key proinflammatory protease regulating leukocyte trafficking at sites of vascular injury. Here the authors show that balanced thrombin interactions with platelet proteins PAR4, GPIbα and fibrin plays a major role in regulating this process.
- Zane S. Kaplan
- , Alessandro Zarpellon
- & Shaun P. Jackson
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| Open AccessBile diversion to the distal small intestine has comparable metabolic benefits to bariatric surgery
Gastric bypass surgery is one of the most effective interventions to achieve durable weight loss. Here, Flynnet al. show that, in mice, bile diversion to the small intestine results in beneficial and sustained metabolic improvements similar to Roux-en-Y gastric bypass surgery.
- Charles Robb Flynn
- , Vance L. Albaugh
- & Naji N. Abumrad
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PDGFRβ signalling regulates local inflammation and synergizes with hypercholesterolaemia to promote atherosclerosis
Platelet-derived growth factor (PDGF) signaling in vascular smooth muscle cells (VSMCs) promotes atherogenesis. Here, the authors show that mutant mice with increased PDGF activity in VSMCs have augmented STAT1-dependent chemokine signals resulting in artery wall inflammation and formation of advanced plaque morphologies clinically relevant in humans.
- Chaoyong He
- , Shayna C. Medley
- & Lorin E. Olson
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E2F1-dependent miR-421 regulates mitochondrial fragmentation and myocardial infarction by targeting Pink1
Inhibition of mitochondrial fragmentation can block or delay cell death. Here the authors show that the signalling axis E2F1-miR-421-Pink1 represents a major regulator of mitochondrial fission and cardiomyocyte death, identifying potential therapeutic targets for treatment of heart failure.
- Kun Wang
- , Lu-Yu Zhou
- & Pei-Feng Li
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| Open AccessTransient brain activity disentangles fMRI resting-state dynamics in terms of spatially and temporally overlapping networks
Growing evidence from neuroimaging studies suggests that the brain is dynamically organized into functionally connected networks. Here, the authors develop a new technique for decomposing spontaneous activity into temporally overlapping building blocks that assemble standard functional networks.
- Fikret Işik Karahanoğlu
- & Dimitri Van De Ville
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| Open AccessParallel circuits control temperature preference in Drosophila during ageing
The capacity for thermoregulation deteriorates with age, particularly in cold environments. Here the authors demonstrate inDrosophilathat age-related changes in cold avoidance result from a shift in the relative contribution of two parallel mushroom body circuits that are modulated by dopamine.
- Hsiang-Wen Shih
- , Chia-Lin Wu
- & Ann-Shyn Chiang
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GABA depolarizes immature neurons and inhibits network activity in the neonatal neocortex in vivo
GABA depolarizes immature neurons in the central nervous system, yet the mode of GABA action in the developing brain is unknown. Here the authors demonstrate thatin vivoGABA acts as a depolarizing neurotransmitter imposing inhibitory control on network activity in the mouse postnatal day 3–4 neocortex.
- Knut Kirmse
- , Michael Kummer
- & Knut Holthoff
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Arginylation regulates purine nucleotide biosynthesis by enhancing the activity of phosphoribosyl pyrophosphate synthase
The phosphoribosyl pyrophosphate synthase PRPS2 catalyses the first step ofde novo purine nucleotide biosynthesis, and has recently been shown to couple protein and nucleotide metabolism. Zhang et al. demonstrate that PRPS2 activity is regulated by tRNA-dependent post-translational addition of arginine.
- Fangliang Zhang
- , Devang M. Patel
- & Anna Kashina
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Article
| Open AccessObesity-induced DNA hypermethylation of the adiponectin gene mediates insulin resistance
The hormone adiponectin is produced by fat cells and has positive metabolic effects. Here, Kim et al.show that DNA methyltransferase 1 (DNMT1) represses adiponectin expression through hypermethylation of its promoter, and that inflammatory cytokines enhance DNMT1 activity in obese mice and humans.
- A. Young Kim
- , Yoon Jeong Park
- & Jae Bum Kim
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Farnesoid X receptor inhibits glucagon-like peptide-1 production by enteroendocrine L cells
Bile acids exert metabolic effects by modulating FXR receptor activity. Here, Trabelsi et al.show that FXR negatively regulates production of the incretin GLP-1 in enteroendocrine L-cells by reducing glycolysis and that inhibition of FXR improves glucose metabolism by increasing GLP-1 in obese mice.
- Mohamed-Sami Trabelsi
- , Mehdi Daoudi
- & Sophie Lestavel
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| Open AccessPPL2ab neurons restore sexual responses in aged Drosophila males through dopamine
We currently lack a detailed understanding of the neurobiological basis for the decline of male sexual desire with age. Here the authors demonstrate that restoring impaired dopaminergic signalling in a specific cluster of neurons in the Drosophilabrain increases sexual behaviour in ageing male flies.
- Shu-Yun Kuo
- , Chia-Lin Wu
- & Tsai-Feng Fu
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Cidea improves the metabolic profile through expansion of adipose tissue
Unlike rodents, humans produce the protein Cidea in white adipose tissue, where it associates with lipid droplets. Here the authors generate mice that express human Cidea in fat tissues to show Cidea exerts beneficial metabolic effects by regulating the expansion of visceral fat in response to a high-fat diet.
- Gustavo Abreu-Vieira
- , Alexander W. Fischer
- & Natasa Petrovic
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A metabolic stress-inducible miR-34a-HNF4α pathway regulates lipid and lipoprotein metabolism
The nuclear hormone receptor HNF4α is important for liver function. Here, Xu et al.show that miR-34a regulates expression of HNF4α and is increased under conditions of metabolic stress, suggesting miR-34a promotes the development of non-alcoholic fatty liver disease.
- Yang Xu
- , Munaf Zalzala
- & Yanqiao Zhang
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Article
| Open AccessKDEL receptor 1 regulates T-cell homeostasis via PP1 that is a key phosphatase for ISR
KDEL receptors are known to be involved in retrotransporting chaperones to the endoplasmic reticulum from the Golgi complex. Here the authors unravel a role of KDEL receptor 1 in regulating integrated stress responses in naïve T cells through its association with protein phosphatase 1.
- Daisuke Kamimura
- , Kokichi Katsunuma
- & Masaaki Murakami
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| Open AccessDJ-1 links muscle ROS production with metabolic reprogramming and systemic energy homeostasis in mice
The protein DJ-1 is known to have antioxidant effects in cells. Here, the authors reveal that DJ-1 has a role in coupling mitochondrial respiration in skeletal muscles of mice, and show that absence of DJ-1 increases energy expenditure and protects mice from diet-induced obesity.
- Sally Yu Shi
- , Shun-Yan Lu
- & Minna Woo
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Genome-wide association study identifies novel genetic variants contributing to variation in blood metabolite levels
Metabolites are important indicators of the physiological state of the body and potential biomarkers for disease. Here, Draisma et al. use a genome-wide association study to identify novel single-nucleotide polymorphisms associated with blood metabolite levels in genes of pharmaceutical importance.
- Harmen H. M. Draisma
- , René Pool
- & Dorret I. Boomsma
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| Open AccessCircadian control of bile acid synthesis by a KLF15-Fgf15 axis
Bile acids are important for the absorption of nutrients. Here the authors provide a molecular explanation for the oscillatory release of bile acids, showing that diurnal expression of the transcription factor KLF15 regulates FGF15 secretion from enterocytes, which then inhibits bile acid synthesis in the liver.
- Shuxin Han
- , Rongli Zhang
- & Mukesh K. Jain
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| Open AccessAMPK activation promotes lipid droplet dispersion on detyrosinated microtubules to increase mitochondrial fatty acid oxidation
Lipid droplets (LDs) supply fatty acids to cellular processes and move bidirectionally on microtubules. Here the authors show that nutrient starvation causes dispersal of mitochondria and LD to the periphery of the cell along detyrosinated microtubules and increases LD–mitochondria interactions in an AMPK-dependent manner.
- Albert Herms
- , Marta Bosch
- & Albert Pol
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| Open AccessStimulation of soluble guanylyl cyclase protects against obesity by recruiting brown adipose tissue
The enzyme soluble guanylyl cyclase (sGC) regulates differentiation of brown fat. Here, Hoffman et al.show that a small molecule sGC stimulator increases brown fat activity and browning of white fat, thereby inducing energy expenditure, weight loss and partial protection from diet-induced obesity in mice.
- Linda S. Hoffmann
- , Jennifer Etzrodt
- & Alexander Pfeifer
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| Open AccessDrosophila glucome screening identifies Ck1alpha as a regulator of mammalian glucose metabolism
Diabetes is associated with aberrations in glucose metabolism. Here the authors perform a genomic screen in fruit flies to identify new regulators of fly glucose metabolism, and show that mice lacking the murine homologue of one of their hits, the protein kinase CK1alpha, in the adipose lineage develop diabetes.
- Rupali Ugrankar
- , Eric Berglund
- & Jonathan M. Graff
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| Open AccessExposure to a youthful circulation rejuvenates bone repair through modulation of β-catenin
The reparative capacity of tissues decreases with age. Here, Baht et al. perform parabiosis experiments and provide evidence for the existence of a soluble factor produced by young, but not old, haematopoietic cells that is capable of improving fracture repair in old mice.
- Gurpreet S. Baht
- , David Silkstone
- & Benjamin A. Alman
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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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Article
| 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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Article
| 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