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| 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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| 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
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Article
| Open AccessLate gene therapy limits the restoration of retinal function in a mouse model of retinitis pigmentosa
Is there a critical period to deliver gene therapies in photoreceptor degeneration? Using a mouse model of retinitis pigmentosa, the authors show that once 70% of rods are lost, gene replacement fails to restore normal retinal output.
- Miranda L. Scalabrino
- , Mishek Thapa
- & Greg D. Field
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Article
| Open AccessGRAF1 integrates PINK1-Parkin signaling and actin dynamics to mediate cardiac mitochondrial homeostasis
Cytoskeletal remodeling is known to facilitate mitophagy, but the mechanism is not fully understood. Here, the authors show that damaged mitochondria recruit a RhoA GTPase activating protein that promotes their capture and encasement by autophagosomes.
- Qiang Zhu
- , Matthew E. Combs
- & Joan M. Taylor
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Article
| Open AccessRAAS-deficient organoids indicate delayed angiogenesis as a possible cause for autosomal recessive renal tubular dysgenesis
Autosomal Recessive Renal Tubular Dysgenesis (AR-RTD) arises from mutations in Angiotensin II sensing genes, but how they impact the kidney was unclear. This study reveals that delayed angiogenesis at a critical developmental window underlies AR-RTD.
- Naomi Pode-Shakked
- , Megan Slack
- & Raphael Kopan
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Article
| Open AccessSenescence-associated 13-HODE production promotes age-related liver steatosis by directly inhibiting catalase activity
Polyunsaturated fatty acid-derived bioactive lipids play critical roles as signalling molecules in metabolic processes. Here, the author show 13-HODE produced by senescent hepatocytes and macrophages activates SREBP1 by directly inhibiting CAT activity and promotes age-related steatosis.
- Jinjie Duan
- , Wenhui Dong
- & Chunjiong Wang
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Article
| Open AccessA class of secreted mammalian peptides with potential to expand cell-cell communication
The cells of our bodies use chemical signals to talk with each other. Here the authors describe a class of signaling molecules called “capped peptides” that may mediate cell-cell communication. Unlike other peptides, capped peptides have unique chemical modifications which make them potentially more active and stable.
- Amanda L. Wiggenhorn
- , Hind Z. Abuzaid
- & Jonathan Z. Long
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| Open AccessA naturally occurring polyacetylene isolated from carrots promotes health and delays signatures of aging
Ameliorating or preventing signatures of aging in humans using natural compounds is an exciting area of research. Here the authors isolate a previously unknown phytochemical from carrots which activates defence mechanisms against oxidative stress and extends lifespan in worms, and improves glucose metabolism, promotes exercise capacity, and protects from frailty at higher age in mice.
- Carolin Thomas
- , Reto Erni
- & Michael Ristow
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Article
| Open AccessFunctional and analytical recapitulation of osteoclast biology on demineralized bone paper
Here, authors report demineralized bone paper-based in vitro osteogenic culture and assay platforms that replicate essential bone tissue complexity, osteoclast processes, and drug responses with high fidelity and predictive power.
- Yongkuk Park
- , Tadatoshi Sato
- & Jungwoo Lee
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Article
| Open AccessSEMA6A drives GnRH neuron-dependent puberty onset by tuning median eminence vascular permeability
Pubertal timing in mammals depends on the function of GnRH neurons that innervate the median eminence (ME) of the hypothalamus. Here, the authors show that Semaphorin 6A regulates GnRH innervation and puberty onset by tuning vascular permeability at the ME.
- Antonella Lettieri
- , Roberto Oleari
- & Anna Cariboni
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Article
| Open AccessEarly-adult methionine restriction reduces methionine sulfoxide and extends lifespan in Drosophila
Dietary methionine restriction extends lifespans in many organisms. Here, the authors show in Drosophila that methionine restriction in early adulthood can increase lifespan and that the beneficial effect of the dietary manipulation declines with age.
- Hina Kosakamoto
- , Fumiaki Obata
- & Masayuki Miura
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Article
| Open AccessThe AMPK-Sirtuin 1-YAP axis is regulated by fluid flow intensity and controls autophagy flux in kidney epithelial cells
Urinary flow is sensed by renal cells but its intensity is dysregulated in renal diseases. Here, the authors report that physiological flow inhibits YAP to promote autophagy, while pathological flow leads to YAP activation and autophagy inhibition.
- Aurore Claude-Taupin
- , Pierre Isnard
- & Nicolas Dupont
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Article
| Open AccessChoroidal and retinal thinning in chronic kidney disease independently associate with eGFR decline and are modifiable with treatment
In patients with CKD, there is an unmet need for biomarkers that reliably track kidney injury. Here, in a series of prospective studies, the authors show that retinal OCT metrics reflect kidney injury, are modified by treatments for kidney disease and can predict future decline of kidney function.
- Tariq E. Farrah
- , Dan Pugh
- & Neeraj Dhaun
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Article
| Open AccessPhox2b-expressing neurons contribute to breathing problems in Kcnq2 loss- and gain-of-function encephalopathy models
Kcnq2 disfunction can cause developmental and epileptic encephalopathy (DEE). Here, authors show loss or gain of Kcnq2 function in Phox2b-expressing neurons disrupts breathing, thus identifying these cells as a likely basis for DEE breathing problems.
- J. Soto-Perez
- , C. M. Cleary
- & D. K. Mulkey
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Matters Arising
| Open AccessHow carvedilol does not activate β2-adrenoceptors
- Robert J. Lefkowitz
- , Howard A. Rockman
- & Milton Packer
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Article
| Open AccessSkeletal muscle-secreted DLPC orchestrates systemic energy homeostasis by enhancing adipose browning
MyoD is a transcription factor expressed in skeletal muscle that plays a critical role in determining myogenic cell fate. Here, Hu et al. reveal a metabolic role of MyoD in orchestrating systemic energy homeostasis by mediating muscle-fat crosstalk through the muscle-secreted lipokine DLPC.
- Xiaodi Hu
- , Mingwei Sun
- & Dahai Zhu
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Article
| Open AccessDbh+ catecholaminergic cardiomyocytes contribute to the structure and function of the cardiac conduction system in murine heart
Catecholaminergic transmitters are critical signalling effectors known to be released by sympathetic nerves and adrenomedullary endocrine cells in response to physiological stress. In this paper, the authors demonstrate a uniquely distributed group of catecholaminergic cardiomyocytes with key regulatory roles in cardiac excitation conduction.
- Tianyi Sun
- , Alexander Grassam-Rowe
- & Ming Lei
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Article
| Open AccessMicroRNA-mediated attenuation of branched-chain amino acid catabolism promotes ferroptosis in chronic kidney disease
Cisplatin, a chemotherapy drug, can cause long-lasting kidney injury. The authors explore miRNA:mRNA interactions in cisplatin-injured kidneys and find that such a cisplatin inducible miRNA as miR-429-3p suppresses the catabolism of branched-chain amino acids, leading to stimulation of ferroptotic cell death.
- Hisakatsu Sone
- , Tae Jin Lee
- & Sang-Ho Kwon
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Article
| Open AccessModulation of insulin secretion by RBFOX2-mediated alternative splicing
Insulin secretion from the pancreatic beta cell is a tightly regulated process that is vital for maintaining blood glucose homeostasis. Here, the authors show that the RNA binding protein RBFOX2 is a regulator of insulin secretion through the alternative splicing of genes required for insulin granule docking and exocytosis.
- Nicole D. Moss
- , Kristen L. Wells
- & Lori Sussel
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Article
| Open AccessA synaptic corollary discharge signal suppresses midbrain visual processing during saccade-like locomotion
How the visual system differentiates between external motion and sensory input arising from self-motion is poorly understood. Here, the authors investigate how motor-related synaptic signals impact neural activity in a key visual center during locomotion.
- Mir Ahsan Ali
- , Katharina Lischka
- & Johann H. Bollmann
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| Open AccessMid-old cells are a potential target for anti-aging interventions in the elderly
In this study, the authors introduce the concept of a unique cellular subtype within the organic stroma, which does not conform to a typical young or senescent but is significantly associated with age-related organic dysfunction among the elderly.
- Young Hwa Kim
- , Young-Kyoung Lee
- & Tae Jun Park
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Article
| Open AccessA distinct Acyl-CoA binding protein (ACBP6) shapes tissue plasticity during nutrient adaptation in Drosophila
Plasticity in tissue function and morphology is shaped by adaptive responses to nutrient changes. Here, the authors found that a putative calibration of acyl-CoA and acetyl-CoA metabolism through ACBP6 is crucial for Drosophila intestine’s proliferative homeostasis in response to nutrient changes.
- Xiaotong Li
- & Jason Karpac