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| Open AccessCytosolic ROS production by NADPH oxidase 2 regulates muscle glucose uptake during exercise
Reactive oxygen species (ROS) stimulate GLUT4-mediated glucose transport following contraction of isolated muscle, but it is not clear if this occurs in vivo. Here, the authors show in human volunteers that exercise induces ROS increase in muscle and, using loss of-function animal models, they demonstrate that NOX2 is a major ROS source required to stimulate glucose uptake during exercise.
- Carlos Henríquez-Olguin
- , Jonas R. Knudsen
- & Thomas E. Jensen
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Article
| Open AccessHIF1α inhibition facilitates Leflunomide-AHR-CRP signaling to attenuate bone erosion in CRP-aberrant rheumatoid arthritis
Leflunomide is used for the treatment of rheumatoid arthritis. Here, the authors show that effectiveness is limited in patients with higher levels of serum c-reactive protein (CRP). Using animal models, they show that higher CRP induces HIF1a expression, which in turn interferes with Leflunomide signalling, and that effectiveness of the drug is restored when HIF1a is pharmacologically inhibited.
- Chao Liang
- , Jie Li
- & Aiping Lu
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Article
| Open AccessFirst-in-human trial of blood–brain barrier opening in amyotrophic lateral sclerosis using MR-guided focused ultrasound
MR-focused ultrasound can be used to transiently open the blood-brain barrier (BBB). Here, the authors report the results of a first-in-human trial on four patients with amyotrophic lateral sclerosis (ALS), showing that the procedure reversibly permeabilised the BBB in the motor cortex without complications, and suggest that the procedure could in the future be used to increase drug delivery in ALS patients.
- Agessandro Abrahao
- , Ying Meng
- & Lorne Zinman
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Article
| Open AccessThe hidden structure of human enamel
Enamel is the hardest tissue in the body and has been widely studied, yet aspects of its structure remain unclear. Here, the authors report on a study of the orientation and alignment of enamel crystals and challenge previous assumptions.
- Elia Beniash
- , Cayla A. Stifler
- & Pupa U. P. A. Gilbert
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Article
| Open AccessDepletion of HuR in murine skeletal muscle enhances exercise endurance and prevents cancer-induced muscle atrophy
HuR is an RNA-binding protein that regulates myotube differentiation in vitro. Here, the authors show that the muscle-specific ablation of HuR in mice leads to enhanced endurance capacity and an increase in oxidative fibres by destabilising PGC1α-mRNA, and show that the mice are protected against cancer cachexia
- Brenda Janice Sánchez
- , Anne-Marie K. Tremblay
- & Imed-Eddine Gallouzi
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Perspective
| Open AccessA systems biology approach towards understanding and treating non-neovascular age-related macular degeneration
No effective therapies exist for dry age-related macular degeneration. In this perspective, the authors propose that research should emphasize system biology approaches that integrate various ‘omics’ data into mathematical models to establish pathogenic mechanisms on which to design novel treatments, and identify biomarkers that predict disease progression and therapeutic response.
- James T. Handa
- , Cathy Bowes Rickman
- & Lindsay A. Farrer
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Article
| Open AccessmTORC1 and PKB/Akt control the muscle response to denervation by regulating autophagy and HDAC4
Denervation leads to muscle atrophy and neuromuscular endplate remodeling. Here, the authors show that a balanced activation of mTORC1 contributes to the dynamic regulation of autophagic flux in denervated muscle and that activation of PKB/Akt promotes the nuclear import of HDAC4, which is essential for endplate maintenance upon nerve injury
- Perrine Castets
- , Nathalie Rion
- & Markus A. Rüegg
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Article
| Open AccessA zwitterionic near-infrared fluorophore for real-time ureter identification during laparoscopic abdominopelvic surgery
Iatrogenic injury of the ureters is a feared complication of laparoscopic abdominal surgery. Here the authors present the NIR fluorophore ZW800-1 as an intraoperative imaging agent for ureter mapping, showing its safety, pharmacokinetic properties, and efficacy in healthy volunteers and patients undergoing abdominopelvic surgery.
- Kim S. de Valk
- , Henricus J. Handgraaf
- & Alexander L. Vahrmeijer
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Article
| Open AccessBioinspired extracellular vesicles embedded with black phosphorus for molecular recognition-guided biomineralization
Bone regeneration is of interest for treating a wide range of medical conditions. Here, the authors report on bioinspired matrix vesicles loaded with black phosphorus nanosheets and cell-specific aptamers for bone regeneration and demonstrate bone defect repair in vivo.
- Yingqian Wang
- , Xiaoxia Hu
- & Quan Yuan
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Article
| Open AccessMacrophage hypoxia signaling regulates cardiac fibrosis via Oncostatin M
Fibrosis is a hallmark of several cardiac pathologies and its underlying mechanisms are still poorly defined. Here the authors show that macrophage hypoxia signaling following transverse aortic constriction in mice suppresses the activation of cardiac fibroblasts by secreting oncostatin M.
- Hajime Abe
- , Norihiko Takeda
- & Issei Komuro
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Article
| Open AccessTargeting a therapeutic LIF transgene to muscle via the immune system ameliorates muscular dystrophy
A number of therapeutic agents aimed at reducing pathology in Duchenne muscular dystrophy have been developed, but may have off-target effects when delivered systemically. Here, the authors express the therapeutic LIF transgene in leukocytes, and show this results in targeting to inflamed dystrophic muscle and reduced fibrosis by suppressing type 2 immunity.
- Steven S. Welc
- , Ivan Flores
- & James G. Tidball
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Article
| Open AccessA 3,2-Hydroxypyridinone-based Decorporation Agent that Removes Uranium from Bones In Vivo
In vivo decorporation of U(VI) from bones is an unsolved challenge because of the formation of stable uranium phosphate complexes. Here, the authors develop a hydroxypyridonone-based ligand with strong uranium complexation and low cytotoxicity. They find this ligand effectively removes uranium from kidney and bones in mice, and is suitable for oral administration.
- Xiaomei Wang
- , Xing Dai
- & Shuao Wang
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Article
| Open AccessDRP1-mediated mitochondrial shape controls calcium homeostasis and muscle mass
Muscle loss is associated with altered expression of proteins involved in mitochondrial homeostasis, but whether this is causative remains unclear. Here, the authors show that genetic ablation of the pro-fission protein DRP1 leads to accumulation of abnormal mitochondria that induce muscle atrophy by altering Ca2+ homeostasis and cellular stress responses.
- Giulia Favaro
- , Vanina Romanello
- & Marco Sandri
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Article
| Open AccessPreclinical safety study of a combined therapeutic bone wound dressing for osteoarticular regeneration
Arthroplasty is the main clinical option for the treatment of osteoarticular lesions, but has limited efficacy. Here, the authors use a wound dressing with autologous mesenchymal stromal cells, functionalised for local BMP2 delivery, and show feasibility and safety in standardised preclinical tests in animal models, suggesting suitability for use in clinical trials.
- Laetitia Keller
- , Luc Pijnenburg
- & Nadia Benkirane-Jessel
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Article
| Open AccessLiver-target nanotechnology facilitates berberine to ameliorate cardio-metabolic diseases
Berberine has lipid-lowering effects and other metabolic benefits, but it presents with poor bioavailability. Here the authors conjugate berberine to liver-targeting nanoparticles, and show increased accumulation of berberine in the liver, improved metabolic profiles and reduced atherosclerotic plaques in mice.
- Hui-Hui Guo
- , Chen-Lin Feng
- & Jian-Dong Jiang
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Article
| Open AccessImmunoregulation of macrophages by dynamic ligand presentation via ligand–cation coordination
Control of macrophage adhesion and phenotype is important to biomaterial applications. Here, the authors report on the use of bisphosphonate coated gold nanoparticles by magnesium coordination for the controlled adhesion and polarisation of macrophages in vitro and in vivo and controlled cell release.
- Heemin Kang
- , Boguang Yang
- & Liming Bian
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Article
| Open AccessExcessive mechanical loading promotes osteoarthritis through the gremlin-1–NF-κB pathway
Excessive mechanical stress promotes the development of osteoarthritis. Here Chang et al. identify gremlin-1 as a factor expressed in chondrocytes in response to mechanical stress, and contributing to osteoarthritis via activation of the NF-κB pathway.
- Song Ho Chang
- , Daisuke Mori
- & Taku Saito
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Article
| Open AccessZEB1 protects skeletal muscle from damage and is required for its regeneration
Following muscle damage, an inflammatory response is associated to activation of satellite cells, which drive muscle repair. Here, the authors show that upregulation of Zeb1 in macrophages and muscle fibres regulates inflammation, and also show a role for Zeb1 in maintenance of satellite cell quiescence.
- Laura Siles
- , Chiara Ninfali
- & Antonio Postigo
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Article
| Open AccessTG-interacting factor 1 (Tgif1)-deficiency attenuates bone remodeling and blunts the anabolic response to parathyroid hormone
Parathyroid hormone (PTH) is used to treat osteoporosis, but its therapeutic mechanism remains unclear. Here, the authors show that Tgif1 is a PTH target gene, and that its deletion impairs the function of osteoblasts and PTH-induced bone formation in mice.
- Hiroaki Saito
- , Andreas Gasser
- & Eric Hesse
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Article
| Open AccessNoninvasive sub-organ ultrasound stimulation for targeted neuromodulation
Stimulation of peripheral nerve activity may be used to treat metabolic and inflammatory disorders, but current approaches need implanted devices. Here, the authors present a non-invasive approach, and show that ultrasound-mediated stimulation can be targeted to specific sub-organ locations in preclinical models and alter the response of metabolic and inflammatory neural pathways.
- Victoria Cotero
- , Ying Fan
- & Christopher Puleo
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Article
| Open AccessSingle-cell analysis reveals fibroblast heterogeneity and myeloid-derived adipocyte progenitors in murine skin wounds
The diversity of fibroblasts contributing to wound healing is unclear. Here, the authors use single-cell RNA-sequencing to identify heterogeneity among murine fibroblasts in the wound and find that recruited myeloid cells contribute to adipocyte regeneration during healing.
- Christian F. Guerrero-Juarez
- , Priya H. Dedhia
- & Maksim V. Plikus
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Article
| Open AccessBMP9 stimulates joint regeneration at digit amputation wounds in mice
Mammalian joints have poor regenerative capacity following amputation. Here, the authors show that in mice, stimulation of the amputation wound with BMP2 and BMP9 stimulates regeneration of a synovial joint that includes bone, cartilage and a synovial cavity.
- Ling Yu
- , Lindsay A. Dawson
- & Ken Muneoka
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Article
| Open AccessTAZ couples Hippo/Wnt signalling and insulin sensitivity through Irs1 expression
Insulin resistance is associated with development of type 2 diabetes. Here the authors show that TAZ interacts with c-Jun and Tead4, inducing expression of the insulin receptor substrate 1 (IRS1) leading to increased glucose uptake in muscle, and that its activity is counteracted by statin administration.
- Jun-Ha Hwang
- , A Rum Kim
- & Jeong-Ho Hong
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Article
| Open AccessImproved TMC1 gene therapy restores hearing and balance in mice with genetic inner ear disorders
Mutations in the mechanotransduction channel component TMC1/2 cause deafness. Here, the authors use a synthetic AAV to replace TMC1 and 2 in the inner ear and show restoration of cochlear and vestibular function, of neuronal reponses in the auditory cortex and of hearing and balance in mice.
- Carl A. Nist-Lund
- , Bifeng Pan
- & Jeffrey R. Holt
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Article
| Open AccessHematopoietic PBX-interacting protein mediates cartilage degeneration during the pathogenesis of osteoarthritis
Osteoarthritis (OA) is associated with cartilage degeneration, and no effective therapy exists. Here, the authors show that the HPIP protein modulates OA progression by regulating Wnt signaling, and that its knockdown in joints via AAV-mediated gene silencing attentuates pathology.
- Quanbo Ji
- , Xiaojie Xu
- & Yan Wang
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Article
| Open AccessRNA-binding protein ZFP36L1 regulates osteoarthritis by modulating members of the heat shock protein 70 family
Osteoarthritis is characterised by degeneration of joint cartilage. Here the authors show that the RNA-binding protein ZFP36L1 is upregulated in chondrocytes of humans and mice with osteoarthritis, and that its knockdown in mouse joints protects chondrocytes against apoptosis by modulating the function of heat shock proteins.
- Young-Ok Son
- , Hyo-Eun Kim
- & Jang-Soo Chun
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Article
| Open AccessA region-resolved mucosa proteome of the human stomach
The human stomach is divided into seven anatomically distinct regions but their protein composition is largely unknown. Here, the authors present a region-resolved map of the healthy human stomach mucosa as well as mucosa proteomes of tumor and tumor nearby tissue from gastric cancer patients.
- Xiaotian Ni
- , Zhaoli Tan
- & Jun Qin
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Article
| Open AccessClosed-loop functional optogenetic stimulation
Optogenetics is a promising alternative approach for restoration of neuromuscular function. Here the authors establish a closed-loop functional optogenetic stimulation for the control of limb joint angle in murine models, which demonstrates improved control and less fatigue than electrical stimulation systems.
- Shriya S. Srinivasan
- , Benjamin E. Maimon
- & Hugh M. Herr
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Article
| Open AccessRobo signalling controls pancreatic progenitor identity by regulating Tead transcription factors
A role for Slit/Robo signalling in pancreas development has not been defined. Here, the authors generate Robo1/Robo2 knockout mice to identify both as needed for establishing initial pancreatic cell identity as well as for proliferation and survival of pancreatic progenitors.
- Sophie Escot
- , David Willnow
- & Francesca M. Spagnoli
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Article
| Open AccessROBO2 is a stroma suppressor gene in the pancreas and acts via TGF-β signalling
SLIT-ROBO alterations arise in pancreatic ductal adenocarcinoma (PDAC), but their role in the pancreas is unclear. Here, the authors use mouse models to show that loss of epithelial Robo2 activates the neighbouring stroma via TGF-β signalling; findings are relevant to PDAC patients, where ROBO expression correlates with survival outcomes.
- Andreia V. Pinho
- , Mathias Van Bulck
- & Ilse Rooman
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Article
| Open AccessThe Trithorax protein Ash1L promotes myoblast fusion by activating Cdon expression
Myoblast fusion in skeletal muscle is a complex process but how this is regulated is unclear. Here, the authors identify Ash1L, a histone methyltransferase, as modulating myoblast fusion via activation of the myogenesis gene Cdon, and observe decreased Ash1L expression in Duchenne muscular dystrophy.
- Ilaria Castiglioni
- , Roberta Caccia
- & Davide Gabellini
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Article
| Open AccessDisease-relevant transcriptional signatures identified in individual smooth muscle cells from healthy mouse vessels
Vascular smooth muscle cell (VSMC) accumulation is associated with cardiovascular disease. Here, the authors combine single-cell RNA sequencing with lineage labelling to profile VSMC heterogeneity in healthy mice. They show that upregulation of Sca1 in a rare VSMC subpopulation marks a cell phenotype that is prevalent in disease.
- Lina Dobnikar
- , Annabel L. Taylor
- & Helle F. Jørgensen
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Article
| Open AccessLRH-1 mitigates intestinal inflammatory disease by maintaining epithelial homeostasis and cell survival
Inflammatory bowel disease is characterised by epithelial dysfunction. Here the authors show that loss of the nuclear receptor LRH-1 leads to epithelial disruption by altering Notch signaling in mouse intestinal organoids, and that LRH-1 overexpression ameliorates immune-mediated colitis in a mouse model.
- James R. Bayrer
- , Hongtao Wang
- & Holly A. Ingraham
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Article
| Open AccessA missense variant in SLC39A8 is associated with severe idiopathic scoliosis
The majority of scoliosis is considered idiopathic with onset in adolescence (AIS) and has a genetic contribution. Here, the authors perform an exome wide association study of data from 457 severe AIS cases and 987 controls, and find a missense variant in SLC39A8 is associated with AIS.
- Gabe Haller
- , Kevin McCall
- & Christina A. Gurnett
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Article
| Open AccessLineage dynamics of murine pancreatic development at single-cell resolution
Coordinated proliferation and differentiation of diverse cell populations drive pancreatic epithelial and mesenchymal development. Here, the authors profile cell type dynamics in the developing mouse pancreas using single-cell RNA sequencing, identifying mesenchymal subtypes and undescribed endocrine progenitors.
- Lauren E. Byrnes
- , Daniel M. Wong
- & Julie B. Sneddon
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Article
| Open AccessThe gut microbiota promotes hepatic fatty acid desaturation and elongation in mice
The role of the gut microbiota in hepatic lipid metabolism is controversial and incompletely understood. Here the authors perform multi-omics analyses of altered lipid metabolic processes in germ-free and specific pathogen-free mice, revealing how the gut microbiota affects hepatic fatty acid desaturation and elongation.
- Alida Kindt
- , Gerhard Liebisch
- & Josef Ecker
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Article
| Open AccessDynamics of cellular states of fibro-adipogenic progenitors during myogenesis and muscular dystrophy
Fibro-adipogenic progenitors (FAPs) resident in skeletal muscle are involved in both regeneration and maladaptive processes. Here, the authors identify subpopulations of FAPs with biological activities implicated in physiological muscle repair that are altered in pathological conditions such as muscular dystrophies.
- Barbora Malecova
- , Sole Gatto
- & Pier Lorenzo Puri
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Article
| Open AccessNecroptosis mediates myofibre death in dystrophin-deficient mice
Muscular dystrophies are characterised by extensive myofibre cell death. Here Morgan et al. show that RIPK3-mediated necroptosis contributes to myofibre cell death in Duchenne muscular dystrophy, and that RIPK3 deletion protects dystrophic mice against myofibre degeneration.
- Jennifer E. Morgan
- , Alexandre Prola
- & Maximilien Bencze
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Article
| Open AccessJNK regulates muscle remodeling via myostatin/SMAD inhibition
Endurance and resistance exercise have different effects on skeletal muscle phenotype. Using mouse models and human subjects, the authors show that JNK/Smad2 signaling acts as molecular switch that when activated by resistance exercise leads to hypertrophy, and when inhibited promotes endurance adaptations in muscle.
- Sarah J. Lessard
- , Tara L. MacDonald
- & Laurie J. Goodyear
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Article
| Open AccessMale germ cells support long-term propagation of Zika virus
Zika virus (ZIKV) can persist for months in semen and sperm. Here, the authors show that germ cells, compared to other cell types in the reproductive tract, are most susceptible to ZIKV and produce high levels of progeny virus, which coincides with decreased expression of the interferon-stimulated gene Ifi44l.
- Christopher L. Robinson
- , Angie C. N. Chong
- & Shuibing Chen
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Article
| Open AccessProfiling human breast epithelial cells using single cell RNA sequencing identifies cell diversity
Epithelial subpopulations are present in the human breast but how these differentiate or form is unclear. Here, the authors use single-cell RNA sequencing of primary human breast epithelial cells to define previously undescribed luminal, basal epithelial subpopulations and ZEB1-positive basal cells.
- Quy H. Nguyen
- , Nicholas Pervolarakis
- & Kai Kessenbrock
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Article
| Open AccessDeficiency of PRKD2 triggers hyperinsulinemia and metabolic disorders
Hyperinsulinemia can precede the development of insulin resistance. Here the authors identify a PKD2 mutation that leads to hyperinsulinemia and insulin resistance in Rhesus monkey and show that PKD2 deficiency promotes beta cell insulin secretion by activating L-type Ca2+ channels.
- Yao Xiao
- , Can Wang
- & Xiuqin Zhang
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Article
| Open AccessLRRC8/VRAC anion channels enhance β-cell glucose sensing and insulin secretion
Insulin secretion by β-cells is stimulated by glucose and is dependent on the induction of β-cell membrane depolarization, mainly driven by the closure of KATP channels, which in turn promotes voltage-gated Ca2+ channel opening. Here the authors show that LRRC8 volume-regulated anion channels (VRACs) modulate glucose-stimulated calcium increase and insulin secretion.
- Till Stuhlmann
- , Rosa Planells-Cases
- & Thomas J. Jentsch
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Article
| Open AccessCD4+ T cells are activated in regional lymph nodes and migrate to skin to initiate lymphedema
CD4+ T cells are critical for the development of lymphedema. Here the authors show how these cells contribute to lymphedema and identify that the sphingosine-1-phosphate receptor modulator FTY720 can prevent lymphedema in a mouse tail injury model by blocking the release of CD4+ T cells from the lymph nodes to the skin.
- Gabriela D. García Nores
- , Catherine L. Ly
- & Babak J. Mehrara
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Article
| Open AccessDkk3 dependent transcriptional regulation controls age related skeletal muscle atrophy
Ageing is associated with muscle atrophy. Here, the authors show that the secreted glycoprotein Dickkopf 3 promotes muscle atrophy by inducing nuclear import of beta-catenin, its association with FoxO3 and the consequent activation of the atrophy-related genes Atrogin1 and MuRF1.
- Jie Yin
- , Lele Yang
- & Ping Hu
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Article
| Open AccessGauging force by tapping tendons
Mechanical forces exerted on tendons during locomotion cannot be readily measured without invasive methods. Here, the authors develop a non-invasive wearable device to track tendon loads by measuring shear wave propagation speed, and demonstrate its use during dynamic human movements.
- Jack A. Martin
- , Scott C. E. Brandon
- & Darryl G. Thelen
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Article
| Open AccessCathelicidins prime platelets to mediate arterial thrombosis and tissue inflammation
Cathelicidins are antimicrobial peptides that eliminate pathogens and contribute to the innate immune response. Here the authors show that neutrophil-derived LL-37/CRAMP induces platelet activation and promotes arterial thrombosis and thrombo-inflammation.
- Joachim Pircher
- , Thomas Czermak
- & Christian Schulz
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Article
| Open AccessLRH-1 agonism favours an immune-islet dialogue which protects against diabetes mellitus
Type 1 diabetes mellitus (T1DM) is characterized by beta cell loss because of an autoimmune attack. Here the authors show that an agonist for LRH-1/NR5A2, a nuclear receptor known to be protective against beta cell apoptosis, inhibits immune-mediated inflammation and hyperglycemia in T1DM mouse models.
- Nadia Cobo-Vuilleumier
- , Petra I. Lorenzo
- & Benoit R. Gauthier
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Article
| Open AccessHCN2 Rescues brain defects by enforcing endogenous voltage pre-patterns
The authors have previously shown that membrane voltage can influence embryonic patterning during development. Here, the authors computationally model how nicotine disrupts Xenopus embryogenesis by perturbing voltage gradients, and rescue nicotine-inducted defects with HCN2 channel expression.
- Vaibhav P. Pai
- , Alexis Pietak
- & Michael Levin