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| Open AccessAn organism-wide atlas of hormonal signaling based on the mouse lemur single-cell transcriptome
Endocrinologists have traditionally focused on studying one hormone or organ system at a time. Here the authors use transcriptomic data from the mouse lemur to globally characterize primate hormonal signaling, describing hormone sources and targets, identifying conserved and primate specific regulation, and elucidating principles of the network.
- Shixuan Liu
- , Camille Ezran
- & James E. Ferrell Jr.
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Article
| Open AccessmicroRNA-33 controls hunger signaling in hypothalamic AgRP neurons
AgRP neurons regulate feeding behavior by promoting signals of hunger. Here, the authors show that miR-33, represses the activity of AgRP neurons, and selective loss of miR-33 in AgRP neurons promotes obesity and metabolic dysfunction in mice.
- Nathan L. Price
- , Pablo Fernández-Tussy
- & Carlos Fernández-Hernando
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Article
| Open AccessA single-cell atlas of Drosophila trachea reveals glycosylation-mediated Notch signaling in cell fate specification
Studying Drosophila trachea development can inform the mechanisms of growth of all tubular structures. Here, the authors generate a transcriptomic cell atlas of the developing fly trachea and establish roles for Notch signaling, which may be disrupted by diet-induced glycosylation.
- Yue Li
- , Tianfeng Lu
- & Hai Huang
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Article
| Open AccessFunctional analysis of the human perivascular subarachnoid space
Functional implications of subarachnoid space anatomy remain unclear. Here, the authors show by human in vivo imaging that an intrathecal tracer propagates antegrade along the major cerebral arteries within a perivascular subarachnoid space facilitating tracer passage towards the brain.
- Per Kristian Eide
- & Geir Ringstad
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Article
| Open AccessALKBH5-mediated m6A modification of IL-11 drives macrophage-to-myofibroblast transition and pathological cardiac fibrosis in mice
Cardiac macrophage contributes to the onset of cardiac fibrosis, but the underneath mechanisms remain unclear. Here the authors show that mouse cardiac macrophages from circulating monocytes may trans-differentiate into myofibroblast under hypertensive conditions for fibrosis development, with an AKLBH5/IL11 molecular axis modulating this macrophage-to-myofibroblast transition.
- Tao Zhuang
- , Mei-Hua Chen
- & Cheng-Chao Ruan
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Article
| Open AccessNDUFS4 regulates cristae remodeling in diabetic kidney disease
Mitochondrial Ndufs4, a subunit of complex I, is a regulator of the electron transport chain. Here, the authors show that forced expression of Ndufs4 in podocytes improves the assembly of respiratory supercomplexes, maintains cristae integrity, and mitigates the progression of diabetic kidney disease
- Koki Mise
- , Jianyin Long
- & Farhad R. Danesh
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Article
| Open AccessA GREB1-steroid receptor feedforward mechanism governs differential GREB1 action in endometrial function and endometriosis
The endometrium is activated by the pregnancy hormones estrogen and progesterone to facilitate embryo implantation, and errors in endometrial responsiveness can lead to reduced fertility or endometriosis. Here they show that GREB1 interacts with hormone receptors in the endometrium, leading to normal or pathological consequences depending on the hormones involved.
- Sangappa B. Chadchan
- , Pooja Popli
- & Ramakrishna Kommagani
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Article
| Open AccessThe proteasome modulates endocytosis specifically in glomerular cells to promote kidney filtration
In the kidney, maintaining permeability of the filtration barrier is critical. Here, Sachs W. et al show that homeostasis of podocytes and glomerular endothelial cells relies on differing proteasome constitutions which orchestrate endocytic activity in addition to protein degradation.
- Wiebke Sachs
- , Lukas Blume
- & Catherine Meyer-Schwesinger
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Article
| Open AccessA spatial map of hepatic mitochondria uncovers functional heterogeneity shaped by nutrient-sensing signaling
Kang et al. reveal structural and functional differences in mitochondria across the hepatic lobule. Mitochondrial distinct phosphoproteome influences their functions highlighting how nutrient availability helps to shape mitochondria zonation.
- Sun Woo Sophie Kang
- , Rory P. Cunningham
- & Natalie Porat-Shliom
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Article
| Open AccessCellular reprogramming in vivo initiated by SOX4 pioneer factor activity
Upon physiological injury, hepatocytes transdifferentiate into biliary epithelial cells, a process involving molecular rewiring. Here, authors show that Sox4 organizes the early steps, acting as a pioneer factor to decommission hepatocyte enhancers and open chromatin around biliary genes.
- Takeshi Katsuda
- , Jonathan H. Sussman
- & Ben Z. Stanger
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Article
| Open AccessDirect contribution of the sensory cortex to the judgment of stimulus duration
The neural substrates of time perception are still unclear. Here, the authors show that as rats judged tactile stimuli, optogenetic manipulation of somatosensory cortex systematically altered perception of stimulus intensity and of duration, unveiling a multiplexed code.
- Sebastian Reinartz
- , Arash Fassihi
- & Mathew E. Diamond
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Article
| Open AccessReducing the metabolic burden of rRNA synthesis promotes healthy longevity in Caenorhabditis elegans
Synthesis of ribosomal RNA (rRNA) by Pol I sustains cell growth but is highly energy demanding. Here the authors show that curbing of Pol I activity lowers systemic energy utilization and delays metabolic aging by reducing triglyceride lipolysis and mitochondrial oxygen consumption.
- Samim Sharifi
- , Prerana Chaudhari
- & Maria Ermolaeva
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Article
| Open AccessRunx1+ vascular smooth muscle cells are essential for hematopoietic stem and progenitor cell development in vivo
Hematopoietic stem cells are supported by niche cells that help balance stem cell self-renewal and differentiation. Here they show that Runx1 deletion in the embryonic perivascular HSC niche impairs hematopoietic development in vivo and causes transcriptional changes in pericytes/vSMCs, endothelial cells and hematopoietic cells in the murine AGM.
- Zaniah N. Gonzalez Galofre
- , Alastair M. Kilpatrick
- & Mihaela Crisan
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Article
| Open AccessHigh resolution spatial profiling of kidney injury and repair using RNA hybridization-based in situ sequencing
Advancements in spatial transcriptomics technologies have enabled the analysis of gene expression at cellular resolution in situ. The authors applied direct RNA hybridization-based in situ sequencing (dRNA HybISS) and developed a computational tool, CellScopes, to study gene expression in mouse kidneys, identifying cellular changes and interactions during injury and repair.
- Haojia Wu
- , Eryn E. Dixon
- & Benjamin D. Humphreys
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Article
| Open AccessAdipocyte p53 coordinates the response to intermittent fasting by regulating adipose tissue immune cell landscape
Adipose tissue (AT) inflammation is strongly associated with obesity and constitutes an obesogenic memory upon weight loss. Here, the authors show that intermittent fasting leads to an adipocyte p53-signaling dependent emergence of lipid-associated macrophages in visceral AT of obese mice which limits the systemic fasting response.
- Isabel Reinisch
- , Helene Michenthaler
- & Andreas Prokesch
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Article
| Open AccessMultigenerational paternal obesity enhances the susceptibility to male subfertility in offspring via Wt1 N6-methyladenosine modification
The mechanisms through which multigenerational paternal obesity affects spermatogenesis in offspring remain poorly understood. Here, the authors show that it affects Wt1 m6A modifications, decreasing the fertility of offspring.
- Yong-Wei Xiong
- , Hua-Long Zhu
- & Hua Wang
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Article
| Open AccessPolar bear energetic and behavioral strategies on land with implications for surviving the ice-free period
Declining Arctic sea ice is increasing polar bear land use. Here, the authors follow 20 different polar bears on land over 3 years and measure daily energy expenditure finding that despite behavioural and diet plasticity the bears are at risk of starvation.
- Anthony M. Pagano
- , Karyn D. Rode
- & Charles T. Robbins
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Article
| Open AccessA common allele increases endometrial Wnt4 expression, with antagonistic implications for pregnancy, reproductive cancers, and endometriosis
Authors show that a common SNP upregulates endometrial Wnt4 expression and proimplantation genes in mouse proestrus and estrus. They suggest that this increases uterine permissiveness to embryo invasion, while decreasing resistance to invasion in reproductive cancers and endometriosis.
- Mihaela Pavličev
- , Caitlin E. McDonough-Goldstein
- & Louis Muglia
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Article
| Open AccessProtection against overfeeding-induced weight gain is preserved in obesity but does not require FGF21 or MC4R
Overfeeding triggers a mechanistically ill-defined compensatory response that counteracts weight gain. Here, the authors show that the defence against overfeeding is preserved in obesity, and that it is independent from FGF21 and MC4R.
- Camilla Lund
- , Pablo Ranea-Robles
- & Christoffer Clemmensen
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| Open AccessThe impact of reproductive factors on the metabolic profile of females from menarche to menopause
Here, the authors explore the relation between age at menarche, parity and age at natural menopause with 249 metabolic traits in over 65,000 UK Biobank to explore whether reproductive factors are likely to impact females’ metabolic profile later in life.
- Gemma L. Clayton
- , Maria Carolina Borges
- & Deborah A. Lawlor
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Article
| Open AccessRelaxation of mitochondrial hyperfusion in the diabetic retina via N6-furfuryladenosine confers neuroprotection regardless of glycaemic status
Restoring mitochondrial function has emerged as a promising therapeutic strategy for diabetic retinopathy. Here, the authors show that mitochondrial hyperfusion blunts mitophagy during the disease process, and that rescuing this process pharmacologically confers retinal neuroprotection independent of an improved glycaemic status in type-1 diabetic mice.
- Aidan Anderson
- , Nada Alfahad
- & Jose R. Hombrebueno
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Article
| Open AccessIdentification of myeloid-derived growth factor as a mechanically-induced, growth-promoting angiocrine signal for human hepatocytes
After partial liver resection, the remaining liver blood vessels receive more blood flow and get mechanically stretched. Here the authors show that MYDGF is released from the stretched cells of these liver vessels, and that it is required and sufficient to promote liver regeneration and cell proliferation.
- Linda Große-Segerath
- , Paula Follert
- & Eckhard Lammert
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Article
| Open AccessResolvin T4 enhances macrophage cholesterol efflux to reduce vascular disease
Specialized pro-resolving mediators (SPM) are involved in the reprogramming of immune responses. Here the authors show that resolvin (RvT) 4 limits the progression of vascular disease in mouse models of arthritis exacerbated atherosclerotic inflammation.
- Mary E. Walker
- , Roberta De Matteis
- & Jesmond Dalli
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Article
| Open AccessSecretin-dependent signals in the ventromedial hypothalamus regulate energy metabolism and bone homeostasis in mice
The mechanism by which central secretin regulates metabolism is unclear. Here, the authors show that ventromedial hypothalamus-derived secretin maintains energy and bone homeostasis by controlling food intake and sympathetic nerve activity.
- Fengwei Zhang
- , Wei Qiao
- & Billy Kwok Chong Chow
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Article
| Open AccessThe liver and muscle secreted HFE2-protein maintains central nervous system blood vessel integrity
Blood vessel integrity is critical to maintain brain health. Here, the authors show that both the liver and the muscles secrete HFE2, a protein that promotes blood vessel integrity in healthy animals and in an animal model for multiple sclerosis.
- Xue Fan Wang
- , Robin Vigouroux
- & Philippe P. Monnier
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Article
| Open AccessArtesunate treats obesity in male mice and non-human primates through GDF15/GFRAL signalling axis
Obesity is a global health challenge with an ongoing need for new medical treatments. Here, the authors show that artesunate, an FDA-approved treatment for severe malaria, can be repurposed for the treatment of obesity via GDF15/GFRAL signaling axis without overt side effects in mice and non-human primates.
- Xuanming Guo
- , Pallavi Asthana
- & Hoi Leong Xavier Wong
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Article
| Open AccessUbiquitin ligase RNF20 coordinates sequential adipose thermogenesis with brown and beige fat-specific substrates
Upon cold exposure, two types of thermogenic fat cells, brown and beige adipocytes, are sequentially activated. Here, the authors show that E3 ubiquitin ligase RNF20 coordinates the sequential thermogenic activation through fat depot specific substrates.
- Yong Geun Jeon
- , Hahn Nahmgoong
- & Jae Bum Kim
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Article
| Open AccessEffect of aging on the human myometrium at single-cell resolution
Age-associated myometrial dysfunction can cause complications during pregnancy and labor. Here, the authors report that aging myometrium is characterized by diminished contractile capillary cells, altered gene expression, and disrupted cellular communication leading to impaired angiogenesis, increased fibrosis and inflammation.
- Paula Punzon-Jimenez
- , Alba Machado-Lopez
- & Aymara Mas
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Article
| Open AccessRescuing SERCA2 pump deficiency improves bone mechano-responsiveness in type 2 diabetes by shaping osteocyte calcium dynamics
Here, Shao et. al attribute the reduction in bone mechano-responsiveness seen in type 2 diabetes to abnormal osteocytic calcium dynamics. They identify reduced SERCA2 pump activity as a mediator of this process and show that rescuing SERCA2 significantly improves bone mechanical adaptation in this context.
- Xi Shao
- , Yulan Tian
- & Da Jing
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Article
| Open AccessA renal clearable fluorogenic probe for in vivo β-galactosidase activity detection during aging and senolysis
In vivo detection of cell senescence remains a challenge in aging research. This work introduces a novel fluorogenic probe for β-Gal activity that is excreted in urine, providing a simple diagnosis method to estimate the systemic load of senescent cells during aging and senolytic interventions.
- Sara Rojas-Vázquez
- , Beatriz Lozano-Torres
- & Ramón Martínez-Máñez
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Article
| Open AccessMolecular quantitative trait loci in reproductive tissues impact male fertility in cattle
Investigating the genetics of male fertility requires comprehensive genotype and phenotype data. Here, the authors characterize the transcriptional complexity of bovine male reproductive tissues to identify loci associated with male fertility.
- Xena Marie Mapel
- , Naveen Kumar Kadri
- & Hubert Pausch
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Article
| Open AccessDNMT3A clonal hematopoiesis-driver mutations induce cardiac fibrosis by paracrine activation of fibroblasts
This study uncovers a critical link between DNMT3A-driven CHIP and heart failure and, in particular, it shows that DNMT3A inactivation in monocytes boosts the release of HB-EGF, which activates fibroblasts inducing diffuse fibrosis in the heart.
- Mariana Shumliakivska
- , Guillermo Luxán
- & Stefanie Dimmeler
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Article
| Open AccessUpregulated hepatic lipogenesis from dietary sugars in response to low palmitate feeding supplies brain palmitate
The origin of brain palmitic acid (PAM) has been debated. Here, by using natural abundance carbon isotope ratios and RNA sequencing the authors show that the majority of brain PAM is maintained by hepatic PAM synthesis from dietary sugars during development and is upregulated in mice fed low PAM.
- Mackenzie E. Smith
- , Chuck T. Chen
- & Richard P. Bazinet
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Article
| Open AccessThe Piezo channel is a mechano-sensitive complex component in the mammalian inner ear hair cell
The identity of hair cells’ mechanoelectrical transduction (MET) channel-complex components is unknown. Here, the authors used multiple biochemical, genetic, and functional approaches to show that mouse hair cells utilize Piezo1 and Piezo2 isoforms as part of the MET-complex component.
- Jeong Han Lee
- , Maria C. Perez-Flores
- & Ebenezer N. Yamoah
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Article
| Open AccessAmyloid beta 42 alters cardiac metabolism and impairs cardiac function in male mice with obesity
Epidemiological evidence has identified associations among obesity, Alzheimer’s disease, and cardiovascular disease. Here, the authors report that adipose tissue releases amyloid beta 42 (Aβ42) and that antagonizing Aβ42 protects cardiac function in obesity murine models.
- Liam G. Hall
- , Juliane K. Czeczor
- & Sean L. McGee
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Article
| Open AccessThe neural origin for asymmetric coding of surface color in the primate visual cortex
Whether end-spectral bias for red and blue in the visual cortex inherits from the pre-cortical stage or emerges within V1 remains incompletely understood. Here, the authors revealed a feedforward mechanism of end-spectral bias which is mainly transmitted through parvocellular pathway.
- Yujie Wu
- , Minghui Zhao
- & Dajun Xing
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Article
| Open AccessDiabetic sensory neuropathy and insulin resistance are induced by loss of UCHL1 in Drosophila
The mechanisms underlying diabetic neuropathy remain elusive. Here, the authors identify that UCHL1 deubiquitinase positively regulates insulin signaling and its loss leads to axonal degeneration of sensory neurons.
- Daewon Lee
- , Eunju Yoon
- & Jongkyeong Chung
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Article
| Open AccessMicroglia govern the extinction of acute stress-induced anxiety-like behaviors in male mice
Stress-related anxiety can gradually become extinct but the underlying mechanisms are unclear. Here, the authors show that microglial engulfment of dendritic spines promotes the extinction of acute stress-induced anxiety-like behaviors in mice.
- Danyang Chen
- , Qianqian Lou
- & Yan Jin
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Article
| Open AccessMuscle abnormalities worsen after post-exertional malaise in long COVID
In this longitudinal, case-controlled, cohort design study, authors show that post-exertional malaise is associated with severe exercise-induced myopathy, local and systemic metabolic disturbances and infiltration of amyloid-containing deposits in skeletal muscles of patients with long COVID.
- Brent Appelman
- , Braeden T. Charlton
- & Rob C. I. Wüst
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Article
| Open Access15-Lipoxygenase promotes resolution of inflammation in lymphedema by controlling Treg cell function through IFN-β
Specialised pro-resolving lipid mediators can reduce inflammatory responses and may be active in lymphedema. Here the authors show that in a mouse model 15-LO derived lipid mediators are reduced during inflammation and that a lack of the 15-LO producing enzyme aggravated disease and addition of 15-LO enzyme or Treg cells reduced disease.
- A. Zamora
- , M. Nougué
- & B. Garmy-Susini
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Article
| Open AccessSurplus fatty acid synthesis increases oxidative stress in adipocytes and induces lipodystrophy
The physiological significance of low fatty acid synthesis in adipocytes remains unclear. Here, the authors show a protective role of this phenomenon by demonstrating that overproduction of fatty acids increases ROS production and results in adipocyte necroptosis and lipodystrophy.
- Li Weng
- , Wen-Shuai Tang
- & Tong-Jin Zhao
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Article
| Open AccessSelective blockade of Cav1.2 (α1C) versus Cav1.3 (α1D) L-type calcium channels by the black mamba toxin calciseptine
L-type voltage-gated calcium channels are involved in multiple physiological functions. Here the authors identify calciseptine, a toxin purified from black mamba venom, as a selective inhibitor of Cav1.2 L-type Ca2+ channels.
- Pietro Mesirca
- , Jean Chemin
- & Joël Nargeot
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Article
| Open AccessApoL6 associates with lipid droplets and disrupts Perilipin1-HSL interaction to inhibit lipolysis
Lipolysis in adipose tissue releases fatty acids during fasting. Here, authors show that ApoL6, a lipid droplet-associated protein, is specifically expressed in adipocytes upon feeding to inhibit lipolysis by directly interacting with Perilipin 1 to competitively inhibit Perilipin 1-HSL interaction.
- Yuhui Wang
- , Hai P. Nguyen
- & Hei S. Sul
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Article
| Open AccessSpatiotemporal signaling underlies progressive vascular rarefaction in myocardial infarction
Enhancing vascularization to improve cardiac disease outcomes is a therapeutic approach with limited success. Here, the authors show that cardiac repair is governed by spatiotemporally regulated programs and underline the signaling mechanisms driving vascular deterioration.
- Lin Wei Tung
- , Elena Groppa
- & Fabio Rossi
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Article
| Open AccessHypothalamic CRH neurons represent physiological memory of positive and negative experience
How physiological memories are encoded is not fully understood. Here the authors show how physiological memories of aversive and appetitive experience are represented by corticotropin-releasing hormone synthesizing neurons in the paraventricular nucleus of the hypothalamus and demonstrate that behavioral readouts may not accurately reflect physiological changes invoked by the memory of salient experiences.
- Tamás Füzesi
- , Neilen P. Rasiah
- & Jaideep S. Bains
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Article
| Open AccessMtfp1 ablation enhances mitochondrial respiration and protects against hepatic steatosis
Excessive lipid accumulation in hepatocytes causes fatty liver disease and liver failure. Here the authors show that ablation of Mitochondrial Fission Process 1 in hepatocytes in mice protects fatty liver disease and dysfunction caused by high fat diet.
- Cecilia Patitucci
- , Juan Diego Hernández-Camacho
- & Timothy Wai
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Article
| Open AccessVoltage sensors of a Na+ channel dissociate from the pore domain and form inter-channel dimers in the resting state
It is believed that voltage sensor domains (VSD) of voltage-gated Na+ channels are always attached to the channel. Here, authors find that VSDs detach from the channel to form inter-channel dimers.
- Ayumi Sumino
- , Takashi Sumikama
- & Katsumasa Irie
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Article
| Open AccessFunctional-metabolic coupling in distinct renal cell types coordinates organ-wide physiology and delays premature ageing
Spatially resolved metabolism in complex tissues is vital but poorly understood. Here, the authors establish the Drosophila renal system as a paradigm for linking mechanistic analysis of metabolism at single-cell resolution to organ-wide physiology.
- Jack Holcombe
- & Helen Weavers
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Article
| Open AccessSphingosine-1-phosphate suppresses GLUT activity through PP2A and counteracts hyperglycemia in diabetic red blood cells
Red blood cells (RBC) carry the majority of sphingosine-1-phosphate (S1P). Here, the authors show that RBC dynamically regulate S1P levels in response to metabolic stress and employ them to regulate glucose uptake, glycolysis and the pentose phosphate pathway as protection against lipid peroxidation.
- Nadine Thomas
- , Nathalie H. Schröder
- & Bodo Levkau