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| Open AccessGDF11 slows excitatory neuronal senescence and brain ageing by repressing p21
How excitatory neurons (EN) acquire senescence is unclear. Here, the authors show that GDF11 in ENs slows EN senescence, brain ageing, cognitive decline and maintains lifespan, revealing a mechanism underlying EN senescence and brain ageing.
- Di-Xian Wang
- , Zhao-Jun Dong
- & Jing-Wei Zhao
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Article
| Open AccessDeciphering a critical role of uterine epithelial SHP2 in parturition initiation at single cell resolution
The mechanism of parturition initiation remains elusive. Here, authors show that epithelium is an underestimated site for parturition initiation via epithelial PGF2a regulated by SHP2-COX1/COX2.
- Meng Liu
- , Mengjun Ji
- & Wenbo Deng
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Article
| Open AccessMechanical loading and hyperosmolarity as a daily resetting cue for skeletal circadian clocks
The 24-hour circadian clocks in cartilage and intervertebral disc play key roles in regulating tissue physiology, yet how they are reset on a daily basis remains elusive. Here the authors show that daily patterns of mechanical loading and associated changes in osmolarity provide a tissue-type specific entrainment time cue for these skeletal clocks.
- Michal Dudek
- , Dharshika R. J. Pathiranage
- & Qing-Jun Meng
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Article
| Open AccessFNIP1 abrogation promotes functional revascularization of ischemic skeletal muscle by driving macrophage recruitment
Functional revascularization is vital to the recovery of blood flow. Here, Sun et al. show that myofiber FNIP1 is a negative regulator of muscle functional angiogenesis and revascularization after ischemia by controlling macrophage recruitment.
- Zongchao Sun
- , Likun Yang
- & Zhenji Gan
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Article
| Open AccessElevator-like movements of prestin mediate outer hair cell electromotility
Probing the molecular dynamics of the membrane motor, prestin, with biophysical measures and MD simulations, Kuwabara et al. find that an elevator-like domain movement across the membrane produces the unique piezoelectric behavior.
- Makoto F. Kuwabara
- , Bassam G. Haddad
- & Dominik Oliver
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Article
| Open AccessTranscriptional repression of beige fat innervation via a YAP/TAZ-S100B axis
Sympathetic innervation is essential for the development of functional beige fat that maintains metabolic homeostasis. Qiu and colleagues discover that YAP/TAZ can act as a brake on the beige fat innervation by blocking PRDM16-C/EBPβ-mediated S100b expression.
- Xun Huang
- , Xinmeng Li
- & Yifu Qiu
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Article
| Open AccessSpliceosome component Usp39 contributes to hepatic lipid homeostasis through the regulation of autophagy
Non-alcoholic fatty liver disease affects 25% of people worldwide. Here the authors report that spliceosome component Usp39 deletion in mice leads to spontaneous steatosis and impaired autophagy through the regulation of alternative splicing.
- Donghai Cui
- , Zixiang Wang
- & Zhaojian Liu
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Article
| Open AccessStructure of a membrane-bound menaquinol:organohalide oxidoreductase
The structure of a bacterial membrane protein complex involved in the bioremediation of tetrachloroethene, a major chlorinated organic pollutant, was determined. It elucidates the path of electrons from menaquinol to the active site of the enzyme.
- Lorenzo Cimmino
- , Américo G. Duarte
- & Julien Maillard
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Article
| Open AccessThe lncRNA Sweetheart regulates compensatory cardiac hypertrophy after myocardial injury in murine males
LncRNAs take part in fine-tuning gene regulatory networks in development, homeostasis, and disease settings. Here, the authors show that the lncRNA Sweetheart has an important role in cardiomyocytes after myocardial injury to act together with NKX2-5 in adapting gene programs after myocardial stress.
- Sandra Rogala
- , Tamer Ali
- & Phillip Grote
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Article
| Open AccessHepatocyte FBXW7-dependent activity of nutrient-sensing nuclear receptors controls systemic energy homeostasis and NASH progression in male mice
NASH, nonalcoholic steatohepatitis, a severe fatty liver disease with no cure, can manifest through loss-of-function of the E3 ligase FBXW7. Here, the authors show an underpinning of dysregulated ERRα and PPARα nuclear receptor activity, thus highlighting potential new avenues for antiNASH therapy.
- Hui Xia
- , Catherine R. Dufour
- & Vincent Giguère
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Article
| Open AccessGenome-wide association analysis of plasma lipidome identifies 495 genetic associations
The human plasma lipidome captures risk for cardiometabolic diseases. Here, the authors perform univariate and multivariate genome-wide analyses of 179 lipid species in 7174 Finnish individuals, revealing genetic links between diseases and lipid species beyond the standard lipids HDL-Cholesterol, LDL-Cholesterol, Triglycerides, and total Cholesterol.
- Linda Ottensmann
- , Rubina Tabassum
- & Matti Pirinen
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Article
| Open AccessDIAPH1-MFN2 interaction regulates mitochondria-SR/ER contact and modulates ischemic/hypoxic stress
Proximity between mitochondria and endoplasmic reticulum regulates mitochondria fitness and is adversely affected by tissue ischemia. This work reveals that Diaphanous1-Mitofusin2 interaction regulates this proximity and impairs recovery in ischemia.
- Gautham Yepuri
- , Lisa M. Ramirez
- & Ravichandran Ramasamy
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Article
| Open AccessMaternal thyroid hormone receptor β activation in mice sparks brown fat thermogenesis in the offspring
Maternal thyroid hormone is important for fetal development. Here, the authors show that hyperthyroidism during pregnancy can program the offsprings’ glucose sensitivity and response to cold via activation of maternal thyroid hormone receptor β in a sex dependent manner
- Rebecca Oelkrug
- , Lisbeth Harder
- & Jens Mittag
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Article
| Open AccessLipocalin 2 regulates mitochondrial phospholipidome remodeling, dynamics, and function in brown adipose tissue in male mice
Mitochondrial function is essential for energy metabolism in brown adipocytes. Here, the authors show that LCN2 plays a critical role as a phosphatidic acid binding protein in phospholipid acyl chain remodeling and mitochondrial bioenergetics, influencing signaling pathway activation.
- Hongming Su
- , Hong Guo
- & Xiaoli Chen
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Article
| Open AccessMetabolic regulation of proteome stability via N-terminal acetylation controls male germline stem cell differentiation and reproduction
How cellular metabolism is connected to differentiation remains poorly understood. Here the authors report a regulatory cascade in which circulating citrate regulates sperm production by controlling protein stability via a specific protein post-translational modification.
- Charlotte M. François
- , Thomas Pihl
- & Bruno Hudry
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Article
| Open AccessFSH and ApoE4 contribute to Alzheimer’s disease-like pathogenesis via C/EBPβ/δ-secretase in female mice
Follicle stimulating hormone (FSH) has been shown to Alzheimer’s disease like pathology in rodent models. Here the authors show using cellular and animal models that ApoE4 and FSH collectively act to trigger AD-like pathogenesis, by activating C/EBPβ/δ-secretase signalling.
- Jing Xiong
- , Seong Su Kang
- & Keqiang Ye
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Article
| Open AccessEndogenous renal adiponectin drives gluconeogenesis through enhancing pyruvate and fatty acid utilization
Adiponectin is a widely studied secretory protein produced by adipocytes. Here, the authors show that adiponectin is also expressed in the kidney where it is a major driver of fatty acid oxidation, from which the kidney derives energy for gluconeogenesis.
- Toshiharu Onodera
- , May-Yun Wang
- & Philipp E. Scherer
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Article
| Open AccessHuman thalamic low-frequency oscillations correlate with expected value and outcomes during reinforcement learning
The functional role of the human thalamus in reinforcement learning is debated. Here, using intra-thalamic recordings in humans, the authors report that thalamic low-frequency oscillations correlate with variables for learning from both reward and punishment.
- Antoine Collomb-Clerc
- , Maëlle C. M. Gueguen
- & Julien Bastin
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Article
| Open AccessPPTC7 maintains mitochondrial protein content by suppressing receptor-mediated mitophagy
The mitochondrial phosphatase PPTC7 has previously been linked to the maintenance of mitochondrial content, but the mechanisms underlying this phenotype remain unclear. Here, the authors demonstrate that loss of Pptc7 results in metabolic defects and further suggest that PPTC7 is a regulator of receptor-mediated mitophagy.
- Natalie M. Niemi
- , Lia R. Serrano
- & David J. Pagliarini
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Article
| Open AccessMYH10 activation rescues contractile defects in arrhythmogenic cardiomyopathy (ACM)
Arrhythmogenic cardiomyopathy is an untreatable heart muscle disease and a common cause of sudden cardiac death in young athletes. The authors show a link between actomyosin dysregulation and cardiac dysfunction by studying nonsense PKP2 mutants classified as pathogenic to identify a potential treatment.
- Nieves García-Quintáns
- , Silvia Sacristán
- & Juan A. Bernal
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Article
| Open AccessPalmitoylation-driven PHF2 ubiquitination remodels lipid metabolism through the SREBP1c axis in hepatocellular carcinoma
Palmitoylation of proteins can have pathophysiological implications. Here, the authors show that palmitoylation enhances the proteasomal degradation of the histone demethylase PHF2, leading to increased lipogenesis and cell proliferation in an SREBP1c dependent manner and further show that PHF2 acts as an E3 ligase of SREBP1c, suppressing the growth of liver cancer cells.
- Do-Won Jeong
- , Jong-Wan Park
- & Yang-Sook Chun
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Article
| Open AccessFAM210A is essential for cold-induced mitochondrial remodeling in brown adipocytes
Mammalians rely on brown adipocytes to generate heat under cold exposure, this thermogenic function requires dynamic remodeling of the mitochondria. Here the authors identify a protein called FAM210A as a key regulator of cold-induced mitochondrial remodeling in brown adipocytes.
- Jiamin Qiu
- , Feng Yue
- & Shihuan Kuang
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Article
| Open AccessPredicting discrete-time bifurcations with deep learning
Critical transitions and qualitative changes of dynamics in cardiac, ecological, and economical systems, can be characterized by discrete-time bifurcations. The authors propose a deep learning framework that provides early warning signals for critical transitions in discrete-time experimental data.
- Thomas M. Bury
- , Daniel Dylewsky
- & Gil Bub
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Article
| Open AccessComprehensive assessment of physiological responses in women during the ESA dry immersion VIVALDI microgravity simulation
To consider the impact of sex on adaptation to space, the European Space Agency initiated VIVALDI dry immersion microgravity simulation in female subjects. Here, the authors show marked deconditioning with 5-day exposure, and propose comprehensive multi-system physiological assessment in 18 healthy women.
- Adrien Robin
- , Angelique Van Ombergen
- & Nastassia Navasiolava
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Article
| Open AccessFluorescent sensors for imaging of interstitial calcium
The study of interstitial calcium remains challenging due to scarce methodology. Here, authors present ultra-low affinity genetically encoded fluorescent biosensors for monitoring calcium in intercellular spaces in living tissues.
- Ariel A. Valiente-Gabioud
- , Inés Garteizgogeascoa Suñer
- & Oliver Griesbeck
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Article
| Open AccessThe proton channel OTOP1 is a sensor for the taste of ammonium chloride
Ammonium is detected by chemosensory systems of humans and other animals to guide avoidance or attractive behavior. Here, the authors show that the proton channel OTOP1 is activated by ammonium, is required for ammonium taste responses in mice, and identify a conserved residue involved in ammonium sensitivity.
- Ziyu Liang
- , Courtney E. Wilson
- & Emily R. Liman
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Article
| Open AccessMechanically induced pyroptosis enhances cardiosphere oxidative stress resistance and metabolism for myocardial infarction therapy
Therapeutic options for myocardial infarction therapy remain limited. Here the authors report the application of an optimized liquid crystal substrate in the mass production and effective preconditioning of cardiospheres, which could generate cardiospheres with improved cell bioactivity and resistance to oxidative stress for myocardial infarction therapy.
- Yingwei Wang
- , Qi Li
- & Zheng Wu
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Article
| Open AccessMulti-omics profiling reveals rhythmic liver function shaped by meal timing
Post-translational modifications (PTMs) couple feed-fast cycles to circadian clocks. Here, the authors systematically profile daily rhythms of the proteome, 4 PTMs and lipidome in mouse livers under TRF, providing a comprehensive resource detailing rhythmic liver functions shaped by meal timing.
- Rongfeng Huang
- , Jianghui Chen
- & Min-Dian Li
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Article
| Open AccessTMEM135 links peroxisomes to the regulation of brown fat mitochondrial fission and energy homeostasis
Mitochondrial dynamics affect the thermogenic capacity of brown adipose tissue. Here, the authors show that TMEM135 regulates thermogenesis and energy homeostasis by mediating mitochondrial fission in brown adipocytes.
- Donghua Hu
- , Min Tan
- & Irfan J. Lodhi
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Article
| Open AccessIctogenesis proceeds through discrete phases in hippocampal CA1 seizures in mice
Predicting seizure onsets may allow for seizure prevention in patients. Here, authors show two distinct phases that always preceded temporal lobe seizures in mice, with activity confined within these two phases failing to progress into a seizure.
- John-Sebastian Mueller
- , Fabio C. Tescarollo
- & Hai Sun
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Article
| Open AccessBAP1 promotes osteoclast function by metabolic reprogramming
Here, the authors demonstrate that BRCA1-associated protein 1 (Bap1) regulates osteoclast’s capacity to degrade bone. Reprogramming of epigenetic-metabolic axis upon Bap1 loss inhibits bone degradation, preserving bone mass, making it a potential therapeutic target for osteoporosis.
- Nidhi Rohatgi
- , Wei Zou
- & Steven L. Teitelbaum
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Article
| Open AccessHigh-dimensional topographic organization of visual features in the primate temporal lobe
The functional organisation of the inferotemporal cortex is not well understood. Here, the authors construct a multi-dimensional space of visual features using deep neural networks, and show the spatial organisation of feature preference in both human and monkey inferotemporal cortex.
- Mengna Yao
- , Bincheng Wen
- & Le Chang
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Article
| Open AccessIncreasing associative plasticity in temporo-occipital back-projections improves visual perception of emotions
Temporo-occipital areas are involved in perceiving emotional faces. Here, the authors show that strengthening back-projections from temporal to occipital areas enhances visual cortex’s response to face stimuli and perception of emotions from them.
- Sara Borgomaneri
- , Marco Zanon
- & Alessio Avenanti
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Article
| Open AccessSRC and TKS5 mediated podosome formation in fibroblasts promotes extracellular matrix invasion and pulmonary fibrosis
The activation and accumulation of lung fibroblasts resulting in aberrant deposition of extracellular matrix components is a pathogenic hallmark of idiopathic pulmonary fibrosis. Here, the authors show that the formation of podosomes in lung fibroblasts stimulates extracellular matrix invasion in a mouse model of the disease, suggesting that pharmacological targeting of podosome formation or organization might be a therapeutic option.
- Ilianna Barbayianni
- , Paraskevi Kanellopoulou
- & Vassilis Aidinis
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Article
| Open AccessDeficiency of endothelial sirtuin1 in mice stimulates skeletal muscle insulin sensitivity by modifying the secretome
Endothelial Sirtuin1 downregulation in metabolic disorders causes vascular dysfunction and inflammation. Here, the authors show that deficiency of endothelial Sirtuin1, while having deleterious effects on the vasculature, stimulates skeletal muscle insulin sensitivity and improves glucose disposal.
- Qiuxia Li
- , Quanjiang Zhang
- & Kaikobad Irani
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Article
| Open AccessCD44 connects autophagy decline and ageing in the vascular endothelium
Mechanisms underlying the connection between autophagy decline and vascular endothelial cell (VEC) ageing remain unclear. Here, the authors identify a key role for CD44 in controlling autophagy and ageing in VECs, and this function is conserved in nematodes.
- Lu Zhang
- , Peichang Yang
- & Shiwei Ma
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Article
| Open AccessPeroxisomal compartmentalization of amino acid biosynthesis reactions imposes an upper limit on compartment size
Compartmentalization is thought to modulate metabolic flux by spatially segregating enzymes and their coupled reactants. Here, the authors show that peroxisomal compartmentalization of amino acid synthesis imposes an upper limit on compartment size.
- Ying Gu
- , Sara Alam
- & Snezhana Oliferenko
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Article
| Open AccessCold-activated brown fat-derived extracellular vesicle-miR-378a-3p stimulates hepatic gluconeogenesis in male mice
During cold exposure, activated brown adipose tissue takes up a large amount of circulating glucose to fuel thermogenesis. Here, the authors show that cold stress enhances the packaging of miR-378a-3p into BAT-derived EVs, which are delivered to the liver and consequently stimulates gluconeogenesis.
- Jinhong Xu
- , Le Cui
- & Xiaohong Jiang
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Article
| Open AccessMKP1 promotes nonalcoholic steatohepatitis by suppressing AMPK activity through LKB1 nuclear retention
Nonalcoholic steatohepatitis (NASH) is a devastating type of liver disease that is caused by hepatocellular death which triggers liver inflammation and fibrosis. Here, the authors show that MAP kinase phosphatase-1 promotes hepatocellular death thus, driving the development of NASH.
- Bin Qiu
- , Ahmed Lawan
- & Anton M. Bennett
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Article
| Open AccessControl of intracellular pH and bicarbonate by CO2 diffusion into human sperm
Bicarbonate (HCO3−) is critical in sperm for stimulation of cAMP synthesis during fertilization, though there is dispute over how HCO3− is transported into sperm. Here the authors use limit-of-detection LC/MS to characterize sperm protein expression and show that HCO3− is produced from CO2 diffusion into sperm rather than active transport.
- Elena Grahn
- , Svenja V. Kaufmann
- & U.Benjamin Kaupp
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Article
| Open AccessThe interplay between dietary fatty acids and gut microbiota influences host metabolism and hepatic steatosis
Here, Schoeler et al. investigate how interaction between dietary lipids and the gut microbiota affect hepatic steatosis and host metabolism, showing that dietary lipids impact the gut microbiota composition independent on fiber intake in humans and mice.
- Marc Schoeler
- , Sandrine Ellero-Simatos
- & Robert Caesar
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Article
| Open AccessPurinergic signaling mediates neuroglial interactions to modulate sighs
Sighs are augmented breaths necessary to maintain normal breathing. Here, the authors show that sighs are generated within the preBötzinger complex by emergent network properties that involve neuroglial interactions mediated by purinergic signaling as well as intrinsic and extrinsic modulatory inputs.
- Liza J. Severs
- , Nicholas E. Bush
- & Jan-Marino Ramirez
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Article
| Open AccessHepatic SREBP signaling requires SPRING to govern systemic lipid metabolism in mice and humans
Hendrix et al show that absence of hepatic Spring dramatically lowers levels of lipids in the liver and plasma in mice, and protects from development of diet-induced steatosis. In line, genetic variation in SPRING is associated with lipid levels in humans.
- Sebastian Hendrix
- , Jenina Kingma
- & Noam Zelcer
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Article
| Open AccessImpaired Plakophilin-2 in obesity breaks cell cycle dynamics to breed adipocyte senescence
Plakophilin-2 is a key component of desmosomes required to maintain cardiac tissue cohesion. Here the authors uncover a previously unknown defect in cell cycle and adipocyte senescence due to impaired Plakophilin-2 in subjects with obesity.
- Aina Lluch
- , Jessica Latorre
- & Francisco J. Ortega
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Article
| Open AccessSYPL1 defines a vesicular pathway essential for sperm cytoplasmic droplet formation and male fertility
The cytoplasmic droplet is an elusive structure of mammalian sperm. Here, the authors uncover a key gene that defines a vesicular pathway essential for cytoplasmic droplet formation and male fertility.
- Jiali Liu
- , Louis Hermo
- & Chen Chen
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Article
| Open AccessBat teeth illuminate the diversification of mammalian tooth classes
Despite their key role in the evolution of mammals, the origin and diversification of tooth classes (incisors, canines, premolars and molars) remain relatively obscure. Here the authors use integrative approaches to explain the independent evolution and rapid diversification of two tooth classes, premolar and molars, in noctilionoid bats.
- Alexa Sadier
- , Neal Anthwal
- & Karen E. Sears
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Article
| Open AccessEndothelial ERα promotes glucose tolerance by enhancing endothelial insulin transport to skeletal muscle
Estrogen has anti-diabetic effects via estrogen receptor alpha (ERα). Here, authors show that via coupled nuclear and non-nuclear actions, ERα in endothelial cells promotes insulin transport to skeletal muscle to foster normal glucose homeostasis.
- Anastasia Sacharidou
- , Ken Chambliss
- & Philip W. Shaul
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Matters Arising
| Open AccessReply to: Fluid signal suppression characteristics of 3D-FLAIR with a T2 selective inversion pulse in the skull base
- Mehmet Sait Albayram
- , Garrett Smith
- & Onder Albayram
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Article
| Open AccessREPTOR and CREBRF encode key regulators of muscle energy metabolism
Obesity and cancer-induced cachexia are linked to an impairment in the ability of muscle to use glucose or lipids interchangeably as energy substrates. Here, the authors propose that Drosophila REPTOR and its mammalian ortholog CREBRF act as key transcriptional regulators of fuel choice in muscle.
- Pedro Saavedra
- , Phillip A. Dumesic
- & Norbert Perrimon