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Article
| Open AccessPHA-4/FoxA senses nucleolar stress to regulate lipid accumulation in Caenorhabditis elegans
Nucleolar stress can disrupt ribosome biogenesis and in turn energy metabolism and lipid storage, but how this is regulated is unclear. Here, the authors show in C. elegans that the transcription factor PHA-4/FOXA acts as a sensor for nucleolar stress and can regulate expression of lipogenic genes
- Jieyu Wu
- , Xue Jiang
- & Bin Liang
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Article
| Open AccessInhibitory gain modulation of defense behaviors by zona incerta
Zona incerta (ZI) is an inhibitory subthalamic nucleus with diverse connectivity yet its functional importance has not been extensively studied. Here the authors report that ZI receives mPFC input and can modulate both innate and learned defensive behaviors via its inhibitory projection to the PAG.
- Xiao-lin Chou
- , Xiyue Wang
- & Huizhong Whit Tao
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Article
| Open AccessPhysiological and therapeutic regulation of glucose homeostasis by upper small intestinal PepT1-mediated protein sensing
High protein diets are known to improve metabolic parameters including adiposity and glucose homeostasis. Here the authors demonstrate that preabsorptive upper small intestinal protein-sensing mechanisms mediated by peptide transporter 1 improve glucose homeostasis by inhibiting hepatic glucose production.
- Helen J. Dranse
- , T. M. Zaved Waise
- & Tony K. T. Lam
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Article
| Open AccessVoltage gating of mechanosensitive PIEZO channels
PIEZO proteins form mechanosensitive ion channels. Here the authors present electrophysiological measurements that show that PIEZO channels are also modulated by voltage and can switch to a purely voltage gated mode, which is an evolutionary conserved property of this channel family.
- Mirko Moroni
- , M. Rocio Servin-Vences
- & Gary R. Lewin
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Article
| Open AccessApolipoprotein AI prevents regulatory to follicular helper T cell switching during atherosclerosis
Regulatory T (Treg) cells contribute to the anti-inflammatory response during atherogenesis. Here Gaddis et al. show that Apolipoprotein AI prevents the conversion of Treg cells into pro-atherogenic T follicular helper cells, and thus regulates the immune response during atherogenesis.
- Dalia E. Gaddis
- , Lindsey E. Padgett
- & Catherine C. Hedrick
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Article
| Open AccessAn HDAC9-MALAT1-BRG1 complex mediates smooth muscle dysfunction in thoracic aortic aneurysm
Vascular smooth muscle cell (VSMC) dysfunction is a common feature of thoracic aortic aneurysms (TAAs). Here, Lino Cardenas and colleagues show that the formation of a HDAC9-MALAT1-BRG1 complex promotes VSMC dysfunction in TAA by epigenetically altering the expression of key components of the cytoskeleton in VSMCs.
- Christian L. Lino Cardenas
- , Chase W. Kessinger
- & Mark E. Lindsay
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Article
| Open AccessEarly-life exposure to low-dose oxidants can increase longevity via microbiome remodelling in Drosophila
Low doses of harmful chemicals such as oxidants can have beneficial effects, in some cases mediated by increased expression of stress response genes. In this study, the authors show that low-dose oxidants increase the longevity of Drosophila via a different mechanism, remodelling of the microbiome.
- Fumiaki Obata
- , Clara O. Fons
- & Alex P. Gould
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Article
| Open AccessVisible light reduces C. elegans longevity
The nematode C. elegans is known to alter its behavior in response to UV light. Here, the authors show that visible light triggers photo-oxidative stress and a wider stress response in C. elegans, suggesting that light exposure during routine laboratory handling may influence the outcome of lifespan experiments.
- C. Daniel De Magalhaes Filho
- , Brian Henriquez
- & Andrew Dillin
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Article
| Open AccessThe interdependence of excitation and inhibition for the control of dynamic breathing rhythms
Excitatory neurons in the preBötzinger Complex generate bursting activity responsible for breathing, but these alone cannot generate physiological breathing frequencies. Here the authors show how inhibition regulates refractory properties of excitatory neurons to allow dynamic breathing rhythms.
- Nathan Andrew Baertsch
- , Hans Christopher Baertsch
- & Jan Marino Ramirez
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Article
| Open AccessLkb1 deficiency confers glutamine dependency in polycystic kidney disease
Polycystic kidney disease (PKD) is characterized by the formation of large fluid-filled cysts. Here Flowers and colleagues show that loss of Lkb1, downregulated in PKD, renders kidney cells dependent on glutamine for growth, and suggest that inhibition of glutamine metabolism may prevent cyst development in PKD.
- Ebony M. Flowers
- , Jessica Sudderth
- & Thomas J. Carroll
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Article
| Open AccessPeriosteum contains skeletal stem cells with high bone regenerative potential controlled by Periostin
The periosteum, a tissue lining the bone surface, and the bone marrow are known to contain bone-forming cells. Here the authors show that skeletal stem cells reside in the mouse periosteum, and that periosteal cells have common embryonic origins with bone marrow stromal/stem cells (BMSCs), but are better at bone repair and long-term integration than BMSCs.
- Oriane Duchamp de Lageneste
- , Anaïs Julien
- & Céline Colnot
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Article
| Open AccessAnalysis of cardiomyocyte clonal expansion during mouse heart development and injury
During cardiac tissue formation it is unclear whether newly generated myocytes originate from cardiac progenitor cells or from pre-existing cardiomyocytes. Here, the authors use a stochastic four-colour reporter system (Rainbow) to identify the source of new cardiomyocytes during mouse development.
- Konstantina-Ioanna Sereti
- , Ngoc B. Nguyen
- & Reza Ardehali
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Article
| Open AccessHost defense against oral microbiota by bone-damaging T cells
IL-17-producing T cells are protective against infection, but the authors of this article previously showed that these cells also contribute to inflammatory bone destruction. Here they show in the context of periodontitis that microbiota-driven Th17-mediated bone destruction may actually be a physiological rather than a pathological process, as associated tooth loss prevents dissemination of oral bacteria.
- Masayuki Tsukasaki
- , Noriko Komatsu
- & Hiroshi Takayanagi
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Article
| Open AccessBone marrow lympho-myeloid malfunction in obesity requires precursor cell-autonomous TLR4
Obesity can affect bone marrow cell differentiation and the generation of myeloid and lymphoid cells. Here, the authors show that diet and obesity, as well as low-dose lipopolysaccharide, can alter Toll-like receptor 4 signaling bone marrow cells to skew the myeloid-lymphoid homeostasis in mice.
- Ailing Liu
- , Minhui Chen
- & Lisa Borghesi
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Article
| Open AccessTridimensional visualization reveals direct communication between the embryo and glands critical for implantation
Embryo implantation initiates the interaction of the blastocyst with the uterus and occurs within a specialised crypt formed by uterine epithelial cells. Here, using 3D imaging techniques of wild type and mutant uteri, the authors show that crypt formation occurs with preexisting glands of the uterus, opening communication between glands and the implanting embryo.
- Jia Yuan
- , Wenbo Deng
- & Sudhansu. K. Dey
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Correspondence
| Open AccessCorrespondence: Reply to ‘Compound 17b and formyl peptide receptor biased agonism in relation to cardioprotective effects in ischaemia-reperfusion injury’
- Cheng Xue Qin
- , Lauren T. May
- & Rebecca H. Ritchie
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Article
| Open Accessα-cell glucokinase suppresses glucose-regulated glucagon secretion
Glucagon secretion is promoted during hypoglycemia and inhibited by increased glucose levels. Here, Basco et al. show that glucokinase suppresses glucose-regulated glucagon secretion by modulating the intracellular ATP/ADP ratio and the closure of KATP channels in α-cells.
- Davide Basco
- , Quan Zhang
- & Bernard Thorens
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Article
| Open AccessAhR and SHP regulate phosphatidylcholine and S-adenosylmethionine levels in the one-carbon cycle
Methyl metabolites in the one-carbon cycle, such as phosphatidylcholines and S-adenosylmethionine, play a role in hepatic triglyceride regulation. Here Kim et al. show that AhR and SHP are both involved in the expression of several key enzymes of one-carbon metabolism, with the former regulating them early after feeding and the latter inhibiting AhR at later stages.
- Young-Chae Kim
- , Sunmi Seok
- & Jongsook Kim Kemper
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Article
| Open AccessCardiogenic programming of human pluripotent stem cells by dose-controlled activation of EOMES
The T-box transcription factor eomesodermin (EOMES) acts both in endoderm specification as well as heart development, suggesting context-specific function. Here, the authors show that dose-controlled EOMES induction is sufficient for cardiogenic programming of human pluripotent stem cells.
- Martin J. Pfeiffer
- , Roberto Quaranta
- & Boris Greber
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Article
| Open AccessSubcortical evidence for a contribution of arousal to fMRI studies of brain activity
Resting cortical activity fluctuates, but it is unclear what underlies these variations in activity. Here, the authors show that large-scale fluctuations in fMRI cortical activity are associated with momentary decreases in cortical arousal and opposite activity changes in the basal forebrain and thalamus.
- Xiao Liu
- , Jacco A. de Zwart
- & Jeff H. Duyn
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Article
| Open AccessAstrocytes modulate brainstem respiratory rhythm-generating circuits and determine exercise capacity
Circuits of the preBötzinger complex generate rhythms needed for breathing. Here, the authors provide evidence, using a combination of chemogenetic approaches and approaches to inhibit vesicular release, that astrocytes play a role in regulating respiratory rate.
- Shahriar Sheikhbahaei
- , Egor A. Turovsky
- & Alexander V. Gourine
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Article
| Open AccessHypoxia and hypoxia inducible factor-1α are required for normal endometrial repair during menstruation
About a quarter of pre-menopausal women will suffer from heavy menstrual bleeding in their lives. Here, Maybin and colleagues show hypoxia and subsequent activation of HIF-1α during menses are required for normal endometrial repair, and identify pharmacological stabilisation of HIF-1α as a potential therapeutic strategy for this debilitating condition.
- Jacqueline A. Maybin
- , Alison A. Murray
- & Hilary O. D. Critchley
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Article
| Open AccessFibroblast growth factor 21 increases insulin sensitivity through specific expansion of subcutaneous fat
FGF21 has a number of beneficial metabolic effects. Here, Li et al. show that FGF21 promotes the healthy expansion of subcutaneous white adipose tissue, promoting the healthy expansion of fat tissue as a regulatory mechanism to maintain systemic insulin sensitivity during nutrient excess.
- Huating Li
- , Guangyu Wu
- & Weiping Jia
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Article
| Open AccessTGR5 signalling promotes mitochondrial fission and beige remodelling of white adipose tissue
White adipose tissue can undergo a process of beiging and acquire functional characteristics similar to brown adipose tissue, including the ability to dissipate energy via uncoupled respiration. Here, Velazquez-Villegas et al. show that activation of the bile acid membrane receptor, TGR5, leads to white adipocyte beiging by promoting mitochondrial fission.
- Laura A. Velazquez-Villegas
- , Alessia Perino
- & Kristina Schoonjans
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Article
| Open AccessThe lncRNA GATA6-AS epigenetically regulates endothelial gene expression via interaction with LOXL2
LncRNAs influence endothelial cell function via a number of mechanisms. Here the authors show that the lncRNA GATA6-AS regulates endothelial gene expression through interaction with the nuclear deaminase LOXL2, with functional consequences on endothelial-mesenchymal transition and angiogenesis.
- Philipp Neumann
- , Nicolas Jaé
- & Stefanie Dimmeler
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Article
| Open AccessCopper sulfide nanoparticles as a photothermal switch for TRPV1 signaling to attenuate atherosclerosis
Capsaicin prevents atherosclerotic plaque formation by activating TRPV1 cation channels, but its toxicity precludes its use in clinical settings. Here, Tang and colleagues use copper sulfide nanoparticles as a photothermal switch to locally and temporally activate TRPV1 in vascular smooth muscle cells and reduce plaque formation without apparent toxicity.
- Wen Gao
- , Yuhui Sun
- & Bo Tang
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Article
| Open Access20-HETE promotes glucose-stimulated insulin secretion in an autocrine manner through FFAR1
FFAR1 receptor is highly expressed in beta cells and its activation has been suggested as therapy against type-2 diabetes. Here, Tunaru et al. show that 20-hydroxyeicosatetraenoic acid, produced within the islets upon glucose stimulation, acts in an autocrine manner to stimulate insulin secretion via FFAR1 activation.
- Sorin Tunaru
- , Remy Bonnavion
- & Stefan Offermanns
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Article
| Open AccessSequential forward and reverse transport of the Na+ Ca2+ exchanger generates Ca2+ oscillations within mitochondria
Mitochondrial Ca2+ homoeostasis is tightly regulated and export of Ca2+ is mediated by an Na+Ca2+ exchanger. Here authors show that in depolarised mitochondria the exchanger initially operates in reverse mode, transporting cytosolic Ca2+ into the matrix before it reverts to its forward mode state.
- Krishna Samanta
- , Gary R. Mirams
- & Anant B. Parekh
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Article
| Open AccessMicrobiota derived short chain fatty acids promote histone crotonylation in the colon through histone deacetylases
Histone post-translational modifications are known key regulators of gene expression. Here, the authors characterize histone crotonylation at histone H3 lysine 18 in intestinal epithelia and find that it is a highly dynamic cell cycle regulated mark under the regulation of the HDAC deacetylases.
- Rachel Fellows
- , Jérémy Denizot
- & Patrick Varga-Weisz
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Article
| Open AccessProfiling the lymphoid-resident T cell pool reveals modulation by age and microbiota
Non-circulating, tissue-resident T cells have been reported for non-lymphoid organs, but their characterization and regulation in secondary lymphoid organs (SLO) are still lacking. Here the authors show that age and microbiota both exert SLO-specific effects for the various tissue-resident T cell subsets.
- Aurélie Durand
- , Alexandra Audemard-Verger
- & Bruno Lucas
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Article
| Open AccessMetabolic rate evolves rapidly and in parallel with the pace of life history
The ‘pace of life’ depends on both metabolic rate and life history traits; however, whether these evolve similarly in response to the environment is not clear. Here, Auer et al. show parallel evolution of metabolic rate and a suite of life history traits in response to predator environment in Trinidadian guppies.
- Sonya K. Auer
- , Cynthia A. Dick
- & David N. Reznick
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Article
| Open AccessHomocysteine directly interacts and activates the angiotensin II type I receptor to aggravate vascular injury
High homocysteine plasma levels are associated with cardiovascular diseases. Here, Li and colleagues find that homocysteine aggravates vascular injury by direct binding to the angiotensin II type 1 receptor (AT1R), identifying AT1R inhibition as a potential strategy to counteract the deleterious vascular effects of hyperhomocysteinemia.
- Tuoyi Li
- , Bing Yu
- & Wei Kong
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Article
| Open AccessDiabetes impairs wound healing by Dnmt1-dependent dysregulation of hematopoietic stem cells differentiation towards macrophages
Type 2 diabetes is associated with impaired wound healing, which can lead to limb loss. Here, the authors show that in Type 2 diabetic mouse models, Dnmt1 is upregulated in hematopoietic stem cells, leading to impaired differentiation towards macrophages, reduced macrophage infiltration in the wound and skewed M1/M2 polarization.
- Jinglian Yan
- , Guodong Tie
- & Louis M. Messina
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Article
| Open AccessSmall-molecule TFEB pathway agonists that ameliorate metabolic syndrome in mice and extend C. elegans lifespan
Activation of autophagy, via the transcription factor TFEB, is a promising strategy to treat metabolic diseases. Here, the authors report three novel classes of small molecules that promote TFEB nuclear translocation, and provide evidence for the therapeutic efficacy of these compounds in mice and worms.
- Chensu Wang
- , Hanspeter Niederstrasser
- & Michael A. White
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Article
| Open AccessThe podoplanin-CLEC-2 axis inhibits inflammation in sepsis
Sepsis is a life-threatening condition where exaggerated inflammatory responses lead to severe tissue damage. Here, Rayes and colleagues show that the interaction between podoplanin and its receptor CLEC-2 on platelets plays a critical role in limiting inflammation during sepsis.
- Julie Rayes
- , Siân Lax
- & Steve P. Watson
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Article
| Open AccessHydralazine induces stress resistance and extends C. elegans lifespan by activating the NRF2/SKN-1 signalling pathway
Hydralazine is an FDA approved drug for the treatment of hypertension. Here, Dehghan et al. report that hydralazine triggers the cellular oxidative stress response by activating NRF2/SKN-1 signaling and extends C. elegans healthy lifespan, suggesting hydralazine may have potential to treat age-associated diseases more broadly.
- Esmaeil Dehghan
- , Yiqiang Zhang
- & Hamid Mirzaei
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Article
| Open AccessEvidence for causal top-down frontal contributions to predictive processes in speech perception
The role of frontal lobes in speech perception is controversial. Here, the authors show that neurodegeneration of frontal speech regions delays prediction reconciliation in temporal cortex and results in inflexible prior expectations, indicating that fronto-temporal interactions determine predictive processes in speech.
- Thomas E. Cope
- , E. Sohoglu
- & James B. Rowe
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Article
| Open AccessSYK kinase mediates brown fat differentiation and activation
Spleen protein tyrosine kinase (Syk) has so far been mainly studied in haematopoietic and immune cells. Here, the authors show that Syk also has a role in brown adipose tissue, where it regulates the formation of brown adipocytes and their thermogenic activation in response to β-adrenergic stimulation.
- Marko Knoll
- , Sally Winther
- & Harvey F. Lodish
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Article
| Open AccessGli1 identifies osteogenic progenitors for bone formation and fracture repair
Skeletal progenitors in postnatal mice are highly heterogeneous. Using lineage tracing and RNA-seq the authors show that Gli1+ cells give rise to all osteoblasts in mice, including those required for healing of bone fractures.
- Yu Shi
- , Guangxu He
- & Fanxin Long
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Article
| Open AccessBrain insulin resistance impairs hippocampal synaptic plasticity and memory by increasing GluA1 palmitoylation through FoxO3a
Metabolic diseases have been associated with cognitive impairment. Here, the authors show that brain insulin resistance induced by high-fat diet leads to increased palmitoylation of AMPA receptors and thus changes in hippocampal plasticity, learning and memory.
- Matteo Spinelli
- , Salvatore Fusco
- & Claudio Grassi
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Article
| Open AccessRhythmic potassium transport regulates the circadian clock in human red blood cells
Circadian rhythms usually rely on cyclic variations in gene expression. Red blood cells, however, display circadian rhythms while being devoid of nuclear DNA. Here, Henslee and colleagues show that circadian rhythms in isolated human red blood cells are dependent on rhythmic transport of K+ ions.
- Erin A. Henslee
- , Priya Crosby
- & Fatima H. Labeed
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Article
| Open AccessNeuronal signals regulate obesity induced β-cell proliferation by FoxM1 dependent mechanism
Neuronal signals, in particular those transmitted via the vagal nerve, regulate both β-cell function and proliferation. Here, Yamamoto et al. show that the forkhead box M1 pathway is required for vagal signal-mediated induction of β-cell proliferation during obesity.
- Junpei Yamamoto
- , Junta Imai
- & Hideki Katagiri
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Article
| Open AccessORAI channels are critical for receptor-mediated endocytosis of albumin
Patients with diabetic nephropathy suffer from impaired albumin reabsorption by proximal tubular epithelial cells. Here authors use diabetic and transgenic mouse models and in vitro models to show the cause for this lies in the down regulation and internalization of the ion channels, ORAI1-3.
- Bo Zeng
- , Gui-Lan Chen
- & Shang-Zhong Xu
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Article
| Open AccessOpposite effects of Activin type 2 receptor ligands on cardiomyocyte proliferation during development and repair
Zebrafish can regenerate damaged myocardial tissue but it is unclear how this is regulated. Here, the authors show that two TGF-β family members, Mstnb and Inhbaa, have opposite effects in regeneration, with mstnb overexpression or inhbaa loss-of-function causing cardiac scarring after injury.
- Deepika Dogra
- , Suchit Ahuja
- & Sven Reischauer
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Article
| Open AccessThe chromatin remodeling factor ISW-1 integrates organismal responses against nuclear and mitochondrial stress
Changes in chromatin structure have been linked to organismal ageing. Here the authors show that altered histone expression and mitochondrial stress during C. elegans development result in chromatin changes and a cytosolic stress response that affects organismal longevity, and depends on HSF-1 and the chromatin remodeller, ISW-1.
- Olli Matilainen
- , Maroun S. Bou Sleiman
- & Johan Auwerx
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Article
| Open AccessVps34 PI 3-kinase inactivation enhances insulin sensitivity through reprogramming of mitochondrial metabolism
Vps34 is a lipid kinase conserved from yeast to humans and involved in in intracellular vesicular trafficking and autophagy. Here Bilanges et al. show that inhibition of this kinase in mice improves glucose tolerance and diet-induced steatosis by modulating mitochondrial respiration and metabolism.
- Benoit Bilanges
- , Samira Alliouachene
- & Bart Vanhaesebroeck
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Article
| Open AccessRods progressively escape saturation to drive visual responses in daylight conditions
Rod photoreceptors are thought to be saturated under bright light. Here, the authors describe the physiological parameters that mediate response saturation of rod photoreceptors in mouse retina, and show that rods can drive visual responses in photopic conditions.
- Alexandra Tikidji-Hamburyan
- , Katja Reinhard
- & Thomas A. Münch
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Article
| Open AccessAnalyses of gut microbiota and plasma bile acids enable stratification of patients for antidiabetic treatment
The authors examine the effects of antidiabetic medication on the gut microbiome and bile acid composition and show that these data can be used to stratify treatment regimens for type 2 diabetes.
- Yanyun Gu
- , Xiaokai Wang
- & Weiqing Wang
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Article
| Open AccessGABAA receptor dependent synaptic inhibition rapidly tunes KCC2 activity via the Cl−-sensitive WNK1 kinase
GABAergic transmission regulates the K+-Cl− co-transporter KCC2. Here the authors demonstrate that inhibitory transmission, via GABAA receptor and WNK signaling, regulates KCC2 expression in the membrane of hippocampal neurons.
- Martin Heubl
- , Jinwei Zhang
- & Sabine Lévi