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| Open AccessSteviol glycosides enhance pancreatic beta-cell function and taste sensation by potentiation of TRPM5 channel activity
Steviol glycosides are sweet-tasting compounds isolated from a South American shrub and are increasingly used as sweeteners in foods and beverages. Philippaertet al. demonstrate that steviol glycosides potentiate Ca2+-dependent TRPM5 activity and promote glucose-induced insulin secretion and glucose tolerance.
- Koenraad Philippaert
- , Andy Pironet
- & Rudi Vennekens
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Article
| Open AccessEpithelial tension in the second heart field promotes mouse heart tube elongation
Epithelial progenitor cell growth in the second heart field contributes to heart morphogenesis but how this is regulated at the tissue level is unclear. Here, the authors show that cell elongation, polarized actomyosin and nuclear YAP/TAZ drive epithelial growth and correlate with mechanical tension.
- Alexandre Francou
- , Christopher De Bono
- & Robert G. Kelly
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| Open AccessA microfluidic culture model of the human reproductive tract and 28-day menstrual cycle
The female reproductive tract constitutes the ovary, fallopian tubes, uterus, and cervix, but it is challenging to engineer this systemin vitro. Here, the authors develop a microfluidic device (EVATAR) with reproductive tract and peripheral tissues to replicate hormone release of a 28-day menstrual cycle.
- Shuo Xiao
- , Jonathan R. Coppeta
- & Teresa K. Woodruff
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| Open AccessRegulation of hepatic lipogenesis by the zinc finger protein Zbtb20
De novo lipogenesis is tightly controlled by hormonal and nutritional signals and plays an important role in energy homoeostasis. Here, Liu et al. show that zinc finger protein ZBTB20 regulates the expression of key glycolytic and lipogenic genes by modulating ChREBP expression and transcriptional activity.
- Gan Liu
- , Luting Zhou
- & Weiping J. Zhang
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Article
| Open AccessPharmacological inhibition of adipose triglyceride lipase corrects high-fat diet-induced insulin resistance and hepatosteatosis in mice
The enzyme Atgl participates in the breakdown of lipids in adipose tissue. Here the authors show that pharmacological inhibition of Atgl reduces weight gain and improves metabolic health in mice fed a high-fat diet, without causing adverse effects in cardiac muscle associated with genetic depletion ofAtgl.
- Martina Schweiger
- , Matthias Romauch
- & Rudolf Zechner
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| Open AccessAntidromic-rectifying gap junctions amplify chemical transmission at functionally mixed electrical-chemical synapses
Emerging evidence suggests that chemical and electrical synapses interact to regulate the strength of synaptic transmission. Liuet al. report that in a C. elegansescape circuit, functionally mixed electrical-chemical synapses exist between premotor interneurons and downstream motor neurons, and that the electrical synapse amplifies the chemical transmission between the neurons.
- Ping Liu
- , Bojun Chen
- & Zhao-Wen Wang
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| Open AccessSfrp5 identifies murine cardiac progenitors for all myocardial structures except for the right ventricle
It is unclear which progenitors define different regions of the heart. Here, the authors find Secreted frizzled-related protein 5 is expressed in murine progenitor cells for the outflow tract, first heart field, and sinus venosus, but not the right ventricle, and Wnt inhibition prevents progenitor proliferation.
- Masayuki Fujii
- , Akane Sakaguchi
- & Hiroki Kokubo
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| Open AccessTheory of optimal balance predicts and explains the amplitude and decay time of synaptic inhibition
Inhibition and excitation are counterbalanced at synapses, but the conditions that constitute optimal balance are not known. Here the authors show through modelling that the properties of synaptic inhibition are fine-tuned to maintain an optimal balance in which peak excitation reaches precisely to spike threshold.
- Jaekyung K. Kim
- & Christopher D. Fiorillo
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Article
| Open AccessRNA surveillance via nonsense-mediated mRNA decay is crucial for longevity in daf-2/insulin/IGF-1 mutant C. elegans
The decline of DNA and protein quality control contributes to organismal ageing. Here, Sonet al. report that nonsense-mediated mRNA decay, a RNA quality control mechanism, is enhanced in long-lived daf-2 mutant worms and contributes to their longevity by regulating expression of the yars-2/tyrosyl tRNA synthetase.
- Heehwa G. Son
- , Mihwa Seo
- & Seung-Jae V. Lee
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| Open AccessZyxin regulates endothelial von Willebrand factor secretion by reorganizing actin filaments around exocytic granules
The adaptor protein zyxin is known for its mechanosensing function in the maintenance of actin network. Here the authors show that zyxin is key to blood homeostasis and thrombosis by controlling the endothelial release of von Willebrand factor and the formation of actin scaffolds on exocytic granules.
- Xiaofan Han
- , Pin Li
- & Jincai Luo
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Article
| Open AccessAmotl1 mediates sequestration of the Hippo effector Yap1 downstream of Fat4 to restrict heart growth
Growth of the mammalian heart is controlled by Hippo signalling but how this is regulated is unclear. Here, the authors show that Fat4 (an atypical cadherin) acts upstream of Hippo signalling and Fat4 mutant mice have thicker myocardium, which is mediated by the scaffold Amot1 and transcription factor Yap1.
- Chiara V. Ragni
- , Nicolas Diguet
- & Sigolène M Meilhac
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| Open AccessHyperactivation of Nrf2 in early tubular development induces nephrogenic diabetes insipidus
Nrf2 regulates oxidative and electrophilic stress responses by modulating the expression of enzymes involved in detoxification pathways. Here Suzukiet al. show that Nrf2 activation in early tubular development promotes nephrogenic diabetes insipidus by regulating aquaporin 2 expression and trafficking and water permeability.
- Takafumi Suzuki
- , Shiori Seki
- & Masayuki Yamamoto
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| Open AccessCellular senescence mediates fibrotic pulmonary disease
Removal of senescent cells rejuvenates lungs of aged mice. Here the authors show that elimination of senescent cells using either genetic or pharmacological means improves lung function and physical health in a mouse model of idiopathic pulmonary fibrosis (IPF), suggesting potential therapy for treatment of human IPF.
- Marissa J. Schafer
- , Thomas A. White
- & Nathan K. LeBrasseur
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| Open AccessSex differences in microglial CX3CR1 signalling determine obesity susceptibility in mice
Unlike males, female mice are resistant to hypothalamic inflammation and weight gain when fed a high-fat diet. Here, the authors reveal sex-specific regulation of hypothalamic microglial activation through CX3CR1 signalling, providing a potential mechanism for differential susceptibility to diet-induced obesity.
- Mauricio D. Dorfman
- , Jordan E. Krull
- & Joshua P. Thaler
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| Open AccessCircadian deep sequencing reveals stress-response genes that adopt robust rhythmic expression during aging
Disruption of circadian rhythms leads to reduced healthspan, but the mechanisms by which the normal clock protects aging organisms are not known. Here, the authors show that a subset of genes becomes more rhythmically expressed in older flies, and these are enriched for response to oxidative stress.
- Rachael C. Kuintzle
- , Eileen S. Chow
- & David A Hendrix
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| Open AccessImpact of genetic background and experimental reproducibility on identifying chemical compounds with robust longevity effects
Irreproducibility of biological findings is a major challenge for drug development. Here the authors examine the lifespans of 22 worm strains in three different laboratories and the effects of ten known chemicals to assess reproducibility in the face of variations in genetic background, chemical treatment and lab environment.
- Mark Lucanic
- , W. Todd Plummer
- & Patrick C. Phillips
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| Open AccessA connexin30 mutation rescues hearing and reveals roles for gap junctions in cochlear amplification and micromechanics
A point mutation in the gap-junction protein connexin 30 stops early onset age-related hearing loss. Here, the authors show that gap junctions contribute to cochlear micromechanics and that cochlear amplification is likely controlled by extracellular potentials in vicinity of the cochlear sensory cells.
- Victoria A. Lukashkina
- , Snezana Levic
- & Ian J. Russell
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Article
| Open AccessProtein disulfide isomerase secretion following vascular injury initiates a regulatory pathway for thrombus formation
What keeps blood from clotting in homeostasis is a puzzle. Here, the authors suggest that lack of the enzyme disulfide isomerase (PDI) in the blood is key, and show that PDI is secreted only after vascular injury to act on substrates that include vitronectin, affecting its binding to αVβ3 and αIIbβ3 integrins and enabling thrombus formation.
- Sheryl R. Bowley
- , Chao Fang
- & Bruce Furie
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| Open AccessHormetic heat stress and HSF-1 induce autophagy to improve survival and proteostasis in C. elegans
Mild heat stress has beneficial effects on organismal health and survival. Here, Kumstaet al. show that a mild heat shock and HSF-1 overexpression induce autophagy in multiple tissues of C. elegansand autophagy-related genes are essential for both heat shock-induced and HSF-1–mediated stress resistance and longevity.
- Caroline Kumsta
- , Jessica T. Chang
- & Malene Hansen
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Article
| Open AccessLow-frequency theta oscillations in the human hippocampus during real-world and virtual navigation
Rhythmic oscillations in theta frequency range (7–9 Hz) are observed in rodents during navigation. Here the authors demonstrate robust similar theta rhythmicity in human hippocampus during both real and virtual movements.
- Véronique D. Bohbot
- , Milagros S. Copara
- & Arne D. Ekstrom
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Article
| Open AccessProtective role of fructokinase blockade in the pathogenesis of acute kidney injury in mice
The polyol pathway, which converts glucose into sorbitol and fructose, is active in chronic conditions like hepatic steatosis and chronic kidney disease. Here, Andres-Hernandoet al. show that fructose production promotes renal injury and fructokinase inhibition protects against kidney damage during ischaemic acute kidney disease.
- Ana Andres-Hernando
- , Nanxing Li
- & Miguel A. Lanaspa
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| Open AccessHuman skeletal muscle plasmalemma alters its structure to change its Ca2+-handling following heavy-load resistance exercise
Heavy-load eccentric exercise causes an increase in cytoplasmic Ca2+ that can damage muscles. Here the authors show that the t-tubule system remodels into vacuoles that can sequester calcium from the cytoplasm and are not responsive to store-operated Ca2+ entry, thereby potentially protecting muscles against elevated [Ca2+].
- Tanya R. Cully
- , Robyn M. Murphy
- & Bradley S. Launikonis
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| Open AccessTheta and beta synchrony coordinate frontal eye fields and anterior cingulate cortex during sensorimotor mapping
Frontal eye fields (FEF) and anterior cingulate cortex (ACC) are coactivated during cognitive tasks, but the precise format of their interaction is not known. Here the authors show that phase coupling between ACC -FEF in theta and beta frequency bands better predicts behavioural performance.
- Sahand Babapoor-Farrokhran
- , Martin Vinck
- & Stefan Everling
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| Open AccessSmall-molecule-biased formyl peptide receptor agonist compound 17b protects against myocardial ischaemia-reperfusion injury in mice
G Protein-Coupled Receptors (GPCRs) can adopt different conformations, each linked to distinct cellular outcomes. Here the authors show that compound 17b, a novel agonist of the GPCR family member FPR, robustly activates cardioprotective but not detrimental FPR signalling, showing beneficial therapeutic effect in a mouse model of cardiac infarction.
- Cheng Xue Qin
- , Lauren T. May
- & Rebecca H. Ritchie
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Article
| Open AccessFAK signalling controls insulin sensitivity through regulation of adipocyte survival
The kinase FAK is important for integrin signalling and promotes cell survival. Here, the authors demonstrate FAK regulates adipocyte survival, and is particularly important for maintaining insulin sensitivity during adipose tissue expansion in the context of a calorie-rich diet.
- Cynthia T. Luk
- , Sally Yu Shi
- & Minna Woo
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| Open AccessDietary fatty acid metabolism of brown adipose tissue in cold-acclimated men
Brown adipose tissue (BAT) takes up and burns fatty acids for thermogenesis in mice. Here the authors use PET to show that, in humans, cold stimulation increases BAT dietary fatty acid uptake from plasma and oxidative metabolism, although, unlike mice, human BAT takes up less fatty acids than other metabolic tissues.
- Denis P. Blondin
- , Hans C. Tingelstad
- & André C. Carpentier
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| Open AccessA tachykinin-like neuroendocrine signalling axis couples central serotonin action and nutrient sensing with peripheral lipid metabolism
Serotonin is a potent stimulator of fat loss and energy expenditure in several species, includingC. elegans. Here, Palamiuc et al. identify the neuropeptide, FP-7, and its receptor in the intestine, NRP-22 as mediators of serotonergic body fat loss in worms.
- Lavinia Palamiuc
- , Tallie Noble
- & Supriya Srinivasan
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| Open AccessBCAS2 is involved in alternative mRNA splicing in spermatogonia and the transition to meiosis
Breast cancer amplified sequence 2 (BCAS2) is involved in pre-mRNA splicing but its physiological role is unclear. Here, the authors find BCAS2 enriched in mice spermatogonia in the testes, and BCAS2 deletion in germ cells alters alternative splicing of spermatogenesis-related genes, causing male infertility.
- Wenbo Liu
- , Fengchao Wang
- & Lei Li
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| Open AccessCaloric restriction improves health and survival of rhesus monkeys
Caloric restriction (CR) delays ageing of model organisms, but whether it works in nonhuman primates has been controversial. Here, the authors pool and reanalyse data from two long-running CR primate studies, concluding that moderate CR indeed improves health and survival of rhesus monkeys.
- Julie A. Mattison
- , Ricki J. Colman
- & Rozalyn M. Anderson
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| Open AccessCD8+ T cells stimulate Na-Cl co-transporter NCC in distal convoluted tubules leading to salt-sensitive hypertension
T cells contribute to development of high blood pressure but their role in salt-sensitive hypertension is less clear. Liuet al. show that CD8+ T cells upregulate and activate Na-Cl co-transporter NCC in distal convoluted tubules via direct cell-cell contact and ROS-Src activation, leading to Na+retention and salt-sensitive hypertension.
- Yunmeng Liu
- , Tonya M. Rafferty
- & Shengyu Mu
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Article
| Open AccessRegional adaptation defines sensitivity to future ocean acidification
Global warming is expected to lead to shifts in species' geographic ranges to track preferred temperatures. Here, the authors show that populations of the common periwinkle vary in their sensitivity to ocean acidification, another major global change driver, which could further restrict range shifts caused by warming.
- Piero Calosi
- , Sedercor Melatunan
- & Simon D. Rundle
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| Open AccessA somatic piRNA pathway in the Drosophila fat body ensures metabolic homeostasis and normal lifespan
The Piwi-interacting RNA (piRNA) pathway is known to suppress transposable elements in gonadal tissues. Here the authors provide evidence for a functional piRNA pathway in the somatic cells of theDrosophilafat body with roles in metabolism, immunological function and overall health.
- Brian C. Jones
- , Jason G. Wood
- & Stephen L. Helfand
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| Open AccessTwo pathways regulate cortical granule translocation to prevent polyspermy in mouse oocytes
Mammalian eggs release cortical granules to avoid being fertilized by more than a single sperm as polyspermy results in nonviable embryos. Here, the authors describe the mechanism driving translocation of the granules to the cortex in the mouse egg and show this process is essential to prevent polyspermy.
- Liam P. Cheeseman
- , Jérôme Boulanger
- & Melina Schuh
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| Open AccessDendritic excitation–inhibition balance shapes cerebellar output during motor behaviour
Here, the authors combinein vivopatch-clamp recordings and optogenetics to show that balanced dendritic excitation and inhibition provides a sensitive ‘push-pull’ mechanism that generates the bidirectional modulation of Purkinje cell SSp output necessary for normal locomotor behaviour.
- Marta Jelitai
- , Paolo Puggioni
- & Ian Duguid
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| Open AccessAgeing and brain white matter structure in 3,513 UK Biobank participants
Part of understanding ageing involves knowing how the brain’s connecting pathways change in healthy aging. Here, authors provide a detailed characterisation of data from 3513 UK Biobank participants, and show that the microstructure of these pathways becomes more similar with age.
- Simon R. Cox
- , Stuart J. Ritchie
- & Ian J. Deary
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| Open AccessOsteoblasts secrete Cxcl9 to regulate angiogenesis in bone
Bone development and vascularization are coupled events that share many molecular mechanisms. Here the authors identify osteoblast-secreted Cxcl9 as an inhibitory regulator of angiogenesis and osteogenesis, and show that mTORC1 signaling and STAT1 are critical upstream mediators of the cytokine expression.
- Bin Huang
- , Wenhao Wang
- & Xiaochun Bai
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| Open AccessTaotie neurons regulate appetite in Drosophila
Feeding control requires the integration and coordination of motivational, sensory and motor circuits in the brain. Here, the authors discover a set of neurons that regulate feeding inDrosophilaby promoting insulin release, and whose activity reflects physiological hunger and satiety states of flies.
- Yin Peng Zhan
- , Li Liu
- & Yan Zhu
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| Open AccessBlood flow controls bone vascular function and osteogenesis
Formation of new blood vessels and bone is coupled. Here the authors show that blood flow represents a key regulator of angiogenesis and endothelial Notch signalling in the bone, and that reactivation of Notch signalling in the endothelium of aged mice rejuvenates the bone.
- Saravana K. Ramasamy
- , Anjali P. Kusumbe
- & Ralf H. Adams
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| Open AccessParvalbumin- and vasoactive intestinal polypeptide-expressing neocortical interneurons impose differential inhibition on Martinotti cells
Martinotti cells disinhibit excitatory cells in the brain cortex and play an important role in information flow. Here the authors study the role of parvalbumin and vasoactive intestinal polypeptide interneurons on the inhibition of Martinotti cells in the mouse somatosensory cortex.
- F. Walker
- , M. Möck
- & M. Witte
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Article
| Open AccessWnt5a induces renal AQP2 expression by activating calcineurin signalling pathway
The water channel AQP2 mediates the concentration of urine in the kidney. Here Ando et al. show that Wnt5 promotes collecting duct permeability by regulating AQP2 expression and localization through activation of the calmodulin/calcineurin signalling pathway.
- Fumiaki Ando
- , Eisei Sohara
- & Shinichi Uchida
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Article
| Open AccessHyperglycaemia induces metabolic dysfunction and glycogen accumulation in pancreatic β-cells
Diabetes is characterized by prolonged hyperglycaemia and tissue damage in pancreatic islets. Here, Brereton et al. show that chronic high glucose levels lead to glycogen accumulation in β-cells, associated with reduced autophagy, impaired metabolism, insulin granule depletion and apoptosis.
- Melissa F. Brereton
- , Maria Rohm
- & Frances M. Ashcroft
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| Open AccessThe Robo4 cytoplasmic domain is dispensable for vascular permeability and neovascularization
Robo4 is a transmembrane protein that regulates vascular permeability. Zhang et al. now reveal the mechanism of Robo4 action and show that Robo4 and UncB are required for VEGF-mediated regulation of vascular barrier by suppressing VEGF-induced phosphorylation of its receptor Vegfr2 on Y949.
- Feng Zhang
- , Claudia Prahst
- & Anne Eichmann
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Article
| Open AccessMacrophage-dependent IL-1β production induces cardiac arrhythmias in diabetic mice
Ventricular arrhythmia is a leading cause of death in patients with diabetes. Here the authors show that inflammasome activation and ILK-1β production in cardiac macrophages cause arrhythmia in diabetic mice, which can be successfully treated using agonists to IL-1β receptor or NLRP3 inhibitors.
- Gustavo Monnerat
- , Micaela L. Alarcón
- & Emiliano Medei
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| Open AccessInhibition of glycine transporter-1 in the dorsal vagal complex improves metabolic homeostasis in diabetes and obesity
Glycine sensing in the dorsal vagal complex (DVC) regulates hepatic glucose production in rodents. Here the authors show that pharmacological and molecular inhibition of glycine reuptake in the DVC potentiates NMDA receptors, and improves metabolic homeostasis in animal models of obesity and diabetes.
- Jessica T. Y. Yue
- , Mona A. Abraham
- & Tony K. T. Lam
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| Open AccessA single heterochronic blood exchange reveals rapid inhibition of multiple tissues by old blood
Joining the circulatory system of an old with a young animal has been shown to rejuvenate old tissues. Here the authors describe a comparatively simple blood infusion system that allows for the controlled exchange of blood between two animals, and study the effects of a single exchange on various tissues.
- Justin Rebo
- , Melod Mehdipour
- & Irina M. Conboy
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| Open AccessThe lipid sensor GPR120 promotes brown fat activation and FGF21 release from adipocytes
GPR120 is a G-protein-coupled receptor that binds polyunsaturated fatty acids. Here, the authors show that GPR120 is upregulated in brown fat in cold-exposed mice, and mediates thermogenic activation of brown fat via a mechanism that, at least in part, depends on the release of the adipokine FGF21.
- Tania Quesada-López
- , Rubén Cereijo
- & Francesc Villarroya
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| Open AccessDirected transport of neutrophil-derived extracellular vesicles enables platelet-mediated innate immune response
Interaction between platelets and neutrophils promotes neutrophil activation. Here the authors show that neutrophils initiate the cross-talk with platelets by shuttling arachidonic acid via extracellular vesicles, which platelets convert to thromboxane A2that then elicits neutrophil activation.
- Jan Rossaint
- , Katharina Kühne
- & Alexander Zarbock
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Article
| Open AccessAkkermansia muciniphila mediates negative effects of IFNγ on glucose metabolism
Mice deficient in the pro-inflammatory cytokine IFNγ have improved glucose tolerance. Here, the authors show that this effect depends on the gut microbeAkkermansia muciniphila, whose abundance increases in the absence IFNγ, and which is known to have beneficial effects on host metabolism.
- Renee L. Greer
- , Xiaoxi Dong
- & Natalia Shulzhenko
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| Open AccessSocial support reduces stress hormone levels in wild chimpanzees across stressful events and everyday affiliations
The stress-reducing effects of social bonds have been hypothesized to accrue either during stressful events or across daily affiliations. Here, Wittiget al. show that the presence of social partners reduces levels of stress hormones in wild chimpanzees beyond stressful contexts, supporting the latter hypothesis.
- Roman M. Wittig
- , Catherine Crockford
- & Klaus Zuberbühler