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| Open AccessThe Hippo pathway links adipocyte plasticity to adipose tissue fibrosis
Adipose tissue fibrosis is connected to obesity-related metabolic dysfunction. Qiu and colleagues discover that the Hippo pathway acts as a molecular switch in the initiation and development of adipose tissue fibrosis upon TGFβ stimulation.
- Hongyu Shen
- , Xun Huang
- & Yifu Qiu
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Article
| Open AccessOptineurin links Hace1-dependent Rac ubiquitylation to integrin-mediated mechanotransduction to control bacterial invasion and cell division
Uropathogenic strains of Escherichia coli (UPEC) are a leading cause of urinary tract infections (UTIs) and invasion involves Rho GTPase members, notably Rac1, to drive actin cytoskeleton rearrangement leading to engulfment. Here, Petracchini et al. provide evidence of an ECM stiffnessmodulated role of Optineurin (OPTN), which regulates HACE1-dependant Rac1 activity and thus controls integrinmediated mechanotransduction and bacterial invasion.
- Serena Petracchini
- , Daniel Hamaoui
- & Amel Mettouchi
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Article
| Open AccessAirway basal cells show a dedifferentiated KRT17highPhenotype and promote fibrosis in idiopathic pulmonary fibrosis
The functional role of airway basal cells has not been comprehensively studied in idiopathic pulmonary fibrosis (IPF). Here, the authors show that airway basal cells of IPF patients display a distinct phenotype, are profibrotic if transplanted to mice and that fibrosis can be ameliorated by Src iinhibitors.
- Benedikt Jaeger
- , Jonas Christian Schupp
- & Antje Prasse
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Article
| Open AccessSpecificity of TGF-β1 signal designated by LRRC33 and integrin αVβ8
Microenvironment localization and activation of L-TGF-β1 determine its specific function. Here, the authors elucidated the underlying mechanisms of specific presentation of L-TGF-β1 on the surface of myeloid lineage cells designated by LRRC33, and its activation by integrin αVβ8.
- Zelin Duan
- , Xuezhen Lin
- & Zhe Zhang
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Article
| Open AccessNanoscale segregation of channel and barrier claudins enables paracellular ion flux
Meshworks of claudin polymers control the paracellular transport and barrier properties of epithelial tight junctions. Here, the authors show different claudin nanoscale organization principles, finding that claudin segregation enables barrier formation and paracellular ion flux across tight junctions.
- Hannes Gonschior
- , Christopher Schmied
- & Martin Lehmann
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Article
| Open AccessIntrinsic cell rheology drives junction maturation
How intrinsic cell properties such as stiffness contribute to cell-cell junction stabilization is not well described. Here they show that higher levels of intrinsic cell mechanics at the cortex, cytoskeleton and nucleus of neighboring cells promote junctional maturation.
- K. Sri-Ranjan
- , J. L. Sanchez-Alonso
- & Vania M. M. Braga
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Article
| Open AccessMannose ameliorates experimental colitis by protecting intestinal barrier integrity
New potential therapies for inflammatory bowel disease are needed as not all patients respond to or maintain a response to conventional therapies. Here the authors report that mannose supplementation ameliorates experimental colitis in male mice, potentially via effects on intestinal epithelium lysosomal integrity.
- Lijun Dong
- , Jingwen Xie
- & Daming Zuo
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Article
| Open AccessAnionic nanoplastic exposure induces endothelial leakiness
In this study, the authors report that anionic nanoplastics can harness the paracellular space of endothelial cells and puncture blood vasculature ex vivo and in vivo, thereby entailing new environmental and health implications.
- Wei Wei
- , Yuhuan Li
- & Pu Chun Ke
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Article
| Open AccessAfadin couples RAS GTPases to the polarity rheostat Scribble
Goudreault et al. investigate the role of Afadin downstream of RAS GTPases, substantiating this cell adhesion protein as a true RAS effector that couples its activation to cell polarity through the Scribble protein.
- Marilyn Goudreault
- , Valérie Gagné
- & Matthew J. Smith
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Article
| Open AccessActin nano-architecture of phagocytic podosomes
Podosomes are actin structures important in multiple cell functions. Here, the authors use iPALM microscopy to reveal an “hourglass” shape of the podosome actin core, a protruding “knob” at the bottom of the core, and two actin networks extending from it.
- J. Cody Herron
- , Shiqiong Hu
- & Klaus M. Hahn
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Article
| Open AccessA critical role of the mechanosensor PIEZO1 in glucose-induced insulin secretion in pancreatic β-cells
Insulin secretion depends on action potential firing in pancreatic islet beta-cells, but the underlying mechanism is unclear. Here, the authors show that activation of the mechanosensor ion channel PIEZO1 plays a central role in beta-cell electrical activity and insulin release.
- Yingying Ye
- , Mohammad Barghouth
- & Erik Renström
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Article
| Open AccessNeuropilin 1 and its inhibitory ligand mini-tryptophanyl-tRNA synthetase inversely regulate VE-cadherin turnover and vascular permeability
Functional vascular tree formation is a key step in many contexts, such as cancer, and Neuropilin1 (NRP1) has been associated with adhesion receptor endocytic turnover. Here, authors show NRP1 and its mini-WARS ligand play a role in reducing endothelial permeability.
- Noemi Gioelli
- , Lisa J. Neilson
- & Guido Serini
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Article
| Open AccessSpatially resolved proteomic map shows that extracellular matrix regulates epidermal growth
Ling Leng et al. construct a hierarchical skin proteome map and identify an extracellular matrix glycoprotein TGFBI, which is located in basement membrane and could enhance the growth and function of epidermal stem cells and promote wound healing.
- Jun Li
- , Jie Ma
- & Ling Leng
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Article
| Open AccessDiscovery of archaeal fusexins homologous to eukaryotic HAP2/GCS1 gamete fusion proteins
Sexual reproduction in eukaryotes involves gamete fusion, mediated by fusogenic proteins. Here, the authors identify fusogenic protein homologs encoded within mobile genetic elements in archaeal genomes, solve the crystal structure of one of the proteins, and show that its ectopic expression can fuse mammalian cells, suggesting potential roles in cell-cell fusion and gene exchange.
- David Moi
- , Shunsuke Nishio
- & Benjamin Podbilewicz
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Article
| Open AccessMyotonic dystrophy RNA toxicity alters morphology, adhesion and migration of mouse and human astrocytes
Myotonic dystrophy type 1 (DM1) is characterized by debilitating neurological symptoms. Dinca et al. demonstrate the pronounced impact of DM1 on the morphology and RNA metabolism of astrocytes. Their findings suggest astroglial pathology in DM1 brain dysfunction.
- Diana M. Dincã
- , Louison Lallemant
- & Mário Gomes-Pereira
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Article
| Open AccessTight junction channel regulation by interclaudin interference
Tight junctions are formed by claudin proteins that can be classified as pore- or barrier-forming. Here, Shashikanth et al. report a third function, termed interclaudin interference, in which one claudin inhibits pore function of another claudin by disrupting its polymeric complexes.
- Nitesh Shashikanth
- , Marion M. France
- & Jerrold R. Turner
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Article
| Open AccessCell surface glycan engineering reveals that matriglycan alone can recapitulate dystroglycan binding and function
Matriglycan, a repeating disaccharide on α-dystroglycan, is the receptor for Lassa virus and specific extracellular matrix proteins. Here, the authors demonstrate that matriglycan, in a length-dependent tunable manner, is both necessary and sufficient for protein binding and viral infection.
- M. Osman Sheikh
- , Chantelle J. Capicciotti
- & Geert-Jan Boons
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Article
| Open AccessInhibition of negative feedback for persistent epithelial cell–cell junction contraction by p21-activated kinase 3
Actin and myosin operate at cell–cell junctions during junctional shortening. Here the authors show that prolonged actomyosin contractility can compromise junctional shortening, and that Pak3 is required for attenuation of abnormal active protrusive structure and thus keeps junction contraction, appropriate E-cadherin distribution, and junction shortening in Drosophila.
- Hiroyuki Uechi
- , Kazuki Fukushima
- & Erina Kuranaga
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Article
| Open AccessMechanically active integrins target lytic secretion at the immune synapse to facilitate cellular cytotoxicity
Cytotoxic response is mediated by delivery of lytic molecules at the effector cell/target cell junction site, termed the immunological synapse. Here the authors find, using single cell biophysical measurements, that the during this process the αLβ2 integrin, LFA-1, helps focus lytic granule release via talin-dependent, pulling force-mediated spatial guidance.
- Mitchell S. Wang
- , Yuesong Hu
- & Morgan Huse
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Article
| Open AccessCharacterisation of a nucleo-adhesome
Cell adhesion proteins have been described at sites away from the cell surface, including in the nucleus. Here, the authors report the scale of nuclear localisation of adhesion proteins, establishing a nucleo-adhesome and showing that nuclear adhesion proteins can cooperate to control transcription.
- Adam Byron
- , Billie G. C. Griffith
- & Margaret C. Frame
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Article
| Open AccessTopography-induced large-scale antiparallel collective migration in vascular endothelium
The physical environment dictates the emergence of specific patterns of collective cell migration. Here, authors show that unconfined endothelial monolayers on microgroove substrates exhibit an original pattern of antiparallel cell streams.
- Claire Leclech
- , David Gonzalez-Rodriguez
- & Abdul I. Barakat
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Article
| Open AccessPlasma membrane phosphatidylinositol (4,5)-bisphosphate is critical for determination of epithelial characteristics
Epithelial cells provide cell-cell adhesion to maintain the integrity of multicellular organisms. Here the authors show that phospholipid phosphatidylinositol (4,5)-bisphosphate is critical for the maintenance of epithelial characteristics.
- Kaori Kanemaru
- , Makoto Shimozawa
- & Yoshikazu Nakamura
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Article
| Open AccessMechanism of integrin activation by talin and its cooperation with kindlin
The authors report here that talin and kindlin, the two key integrin binders and activators, are bridged by paxillin to induce microclustering of integrins to potently bind to multivalent extracellular ligand and trigger rapid cell attachment.
- Fan Lu
- , Liang Zhu
- & Jun Qin
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Article
| Open AccessGeneric self-stabilization mechanism for biomolecular adhesions under load
Cellular adhesions have the remarkable property that they adapt their stability to the applied mechanical load. Here, authors describe a generic physical mechanism that explains self-stabilization of idealized adhesion systems under shear.
- Andrea Braeutigam
- , Ahmet Nihat Simsek
- & Benedikt Sabass
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Article
| Open AccessA loss-of-adhesion CRISPR-Cas9 screening platform to identify cell adhesion-regulatory proteins and signaling pathways
Targeting integrin-mediated retention of malignant B cells in their protective microenvironment is an efficacious treatment for lymphoma and leukemia. Here, the authors present an unbiased loss-of-adhesion CRISPR screening method, identifying therapeutic targets for these B-cell malignancies.
- Martin F. M. de Rooij
- , Yvonne J. Thus
- & Marcel Spaargaren
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Article
| Open AccessMicrovascular stabilization via blood-brain barrier regulation prevents seizure activity
The mechanisms underlying epilepsy development are not well understood. Here the authors show that loss of a key component of the so called blood-brain barrier drives seizures in mice and is also lost in humans with treatment resistant epilepsy
- Chris Greene
- , Nicole Hanley
- & Matthew Campbell
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Article
| Open AccessPI3Kγ stimulates a high molecular weight form of myosin light chain kinase to promote myeloid cell adhesion and tumor inflammation
Myeloid cell recruitment during tumor inflammation depends on the VCAM-1 receptor integrin α4β1. Here the authors show that a high molecular weight form of myosin light chain kinase, MLCK210, is required for myeloid cell integrin α4β1 activation and adhesion and that MLCK210 inhibition reduces tumor growth and inflammation in preclinical cancer models.
- Michael C. Schmid
- , Sang Won Kang
- & Judith A. Varner
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Article
| Open AccessLoss of CLDN5 in podocytes deregulates WIF1 to activate WNT signaling and contributes to kidney disease
Claudin-5 is a tight junction integral membrane protein, but it is also expressed in mature podocytes which lack tight junctions. Here the authors report that podocyte claudin-5 regulates WNT signaling activity by modulating WIF1 expression, and its downregulation contributes to kidney disease progression in mice.
- Hui Sun
- , Hui Li
- & Yongfeng Gong
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Article
| Open AccessGpr125 is a unifying hallmark of multiple mammary progenitors coupled to tumor latency
Gpr125 has emerged as a specific marker of mammary stem cells and basal progenitors. Here they show that Gpr125 cells congregate at ductal tips during morphogenesis and amass at tumor margins, and that high Gpr125 predicts early tumor onset and poor outcome in basal breast cancer.
- Elena Spina
- , Julia Simundza
- & Pamela Cowin
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Article
| Open Accessα-catenin switches between a slip and an asymmetric catch bond with F-actin to cooperatively regulate cell junction fluidity
By using laser tweezers, the authors show that a single α-catenin molecule does not resist force on F-actin. However, clustering of multiple molecules and force applied toward F-actin pointed end engage a molecular switch in α-catenin, which unfolds and strongly binds F-actin.
- C. Arbore
- , M. Sergides
- & M. Capitanio
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Article
| Open AccessCell adhesion molecule KIRREL1 is a feedback regulator of Hippo signaling recruiting SAV1 to cell-cell contact sites
How cell-cell contact is sensed by Hippo pathway is poorly understood. Here, the authors show that KIRREL1 functions as a feedback regulator of the mammalian Hippo pathway by sensing cell-cell interaction and recruiting SAV1 to cell-cell contacts.
- Atanu Paul
- , Stefano Annunziato
- & Feng Cong
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Article
| Open AccessDual clathrin and integrin signaling systems regulate growth factor receptor activation
The integration and organization of growth factor signaling, adhesion, and endocytosis is poorly understood. Here the authors use light and electron microscopy to shed light on the role of flat clathrin lattices and cell adhesion in growth factor signaling.
- Marco A. Alfonzo-Méndez
- , Kem A. Sochacki
- & Justin W. Taraska
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Article
| Open AccessPPARα−ACOT12 axis is responsible for maintaining cartilage homeostasis through modulating de novo lipogenesis
Increasing evidence suggested that dysregulation in lipid metabolism is linked to OA pathogenesis, but the underlying regulatory mechanism is not well understood. Here, the authors show that PPARα-ACOT12 signalling regulates cartilage homeostasis by regulating de novo lipogenesis in mice.
- Sujeong Park
- , In-Jeoung Baek
- & Eun-Jung Jin
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Article
| Open AccessType-I collagen produced by distinct fibroblast lineages reveals specific function during embryogenesis and Osteogenesis Imperfecta
Collagen is the most abundant protein in the human body. Here, the authors show that different classes of fibroblasts produce collagen of unique functions with different impacts on embryo development and bone formation.
- Yang Chen
- , Sujuan Yang
- & Raghu Kalluri
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Article
| Open AccessTissue fluidity mediated by adherens junction dynamics promotes planar cell polarity-driven ommatidial rotation
Ommatidial rotation in the Drosophila eye is a regulated process and a Planar Cell Polarity (PCP) cell motility model. Here, the authors show that tissue fluidity via junctional remodeling, as regulated by the PCP effector kinase Nemo, is critical for this cell motility process.
- Nabila Founounou
- , Reza Farhadifar
- & Marek Mlodzik
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Article
| Open AccessDynamic mechanochemical feedback between curved membranes and BAR protein self-organization
Amphiphysin BAR proteins reshape membranes, but the dynamics of the process remained unexplored. Here, the authors show through experiment and modelling that reshaping depends on the initial template shape, occurs even at low initial curvature, and involves the coexistence of isotropic and nematic states.
- Anabel-Lise Le Roux
- , Caterina Tozzi
- & Pere Roca-Cusachs
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Article
| Open AccessAgrin-Matrix Metalloproteinase-12 axis confers a mechanically competent microenvironment in skin wound healing
Replenishing key extracellular matrix (ECM) proteins facilitate wound healing through unclear mechanisms. Here the authors report that injury-triggered Agrin, an ECM proteoglycan, tunes a mechanocompetent niche by engaging MMP-12, thereby enforcing efficient skin wound healing.
- Sayan Chakraborty
- , Divyaleka Sampath
- & Wanjin Hong
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Article
| Open AccessExtracellular LGALS3BP regulates neural progenitor position and relates to human cortical complexity
Basal progenitors are enriched in gyrencephalic species like humans contributing to neuronal expansion. Here the authors show that LGALS3BP de novo variants are related to reduced cortical complexity and area in humans and that LGALS3BP regulates neural progenitor position in organoids, human fetal tissue and mice.
- Christina Kyrousi
- , Adam C. O’Neill
- & Silvia Cappello
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Article
| Open AccessMechanics-driven nuclear localization of YAP can be reversed by N-cadherin ligation in mesenchymal stem cells
Mesenchymal stem cells adopt differentiation pathways based upon mechanical cues in their environment which change throughout development. Here the authors develop a material and culture system to modify and measure the degree to which cells retain cumulative effects of mechanosensing to explore how cells erase the memory of some cues while locking in memory of others.
- Cheng Zhang
- , Hongyuan Zhu
- & Min Lin
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Article
| Open AccessPlexin-B2 orchestrates collective stem cell dynamics via actomyosin contractility, cytoskeletal tension and adhesion
Biomechanical mechanisms orchestrating stem cell dynamics in development remain unclear. Here the authors show that guidance receptor Plexin-B2 organizes actomyosin contractility, cytoskeletal tension and adhesion during multicellular development of human embryonic stem cells and neuroprogenitor cells.
- Chrystian Junqueira Alves
- , Rafael Dariolli
- & Roland H. Friedel
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Article
| Open AccessPhysical basis for the determination of lumen shape in a simple epithelium
The formation of a hollow lumen surrounded by cells is a key developmental process that sets the shape of tissues and organs. Here, the authors show how the combined influence of geometric constraints imposed by cell packing and osmotic pressure can generate the diverse range in lumen shapes observed in different tissues.
- Claudia G. Vasquez
- , Vipul T. Vachharajani
- & Alexander R. Dunn
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Article
| Open AccessDisrupting biological sensors of force promotes tissue regeneration in large organisms
Humans and other large mammals heal wounds by forming fibrotic scar tissue with diminished function. Here, the authors show that disrupting mechanotransduction through the focal adhesion kinase pathway in large animals accelerates healing, prevents fibrosis, and enhances skin regeneration.
- Kellen Chen
- , Sun Hyung Kwon
- & Geoffrey C. Gurtner
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Article
| Open AccessTurn-key mapping of cell receptor force orientation and magnitude using a commercial structured illumination microscope
The authors have recently developed molecular force microscopy (MFM) which uses fluorescence polarisation to measure cell-surface receptor force orientation. Here they show that structured illumination microscopes, which inherently use fluorescence polarisation, can be used for MFM in a turn-key manner.
- Aaron Blanchard
- , J. Dale Combs
- & Khalid Salaita
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Article
| Open AccessA connexin/ifi30 pathway bridges HSCs with their niche to dampen oxidative stress
Reactive oxygen species (ROS) are metabolic by-products which in excess can be toxic for hematopoietic stem and progenitor cells (HSPCs). Here the authors show that toxic ROS are transferred by expanding HSPCs to the zebrafish developmental niche via connexin Cx41.8, where Ifi30 promotes their detoxification.
- Pietro Cacialli
- , Christopher B. Mahony
- & Julien Y. Bertrand
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Article
| Open AccessSpecies-specific gamete recognition initiates fusion-driving trimer formation by conserved fusogen HAP2
HAP2 is essential for gamete fusion during fertilization and is conserved among eukaryotes. Here the authors show that species-specific adhesion between Chlamydomonas plus and minus gametes initiates HAP2 to undergo a fusogenic conformational change into homotrimers via a molecular mechanism akin to that of enveloped viruses.
- Jun Zhang
- , Jennifer F. Pinello
- & William J. Snell
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Article
| Open AccessThe force loading rate drives cell mechanosensing through both reinforcement and cytoskeletal softening
Cells sense mechanical forces from their environment, but the precise mechanical variable sensed by cells is unclear. Here, the authors show that cells can sense the rate of force application, known as the loading rate, with effects on YAP nuclear localization and cytoskeletal stiffness remodelling.
- Ion Andreu
- , Bryan Falcones
- & Pere Roca-Cusachs
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Article
| Open AccessStructural mechanism of laminin recognition by integrin
Recognition of laminin by integrin receptors mediates epithelial cell adhesion to basement membrane. Here, the structures of the α6β1 integrin alone and in complex with three-chain laminin-511 fragment reveal the laminin-integrin interface in molecular detail.
- Takao Arimori
- , Naoyuki Miyazaki
- & Junichi Takagi
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Article
| Open AccessReal-time imaging of cellular forces using optical interference
Studying dynamic processes in mechanobiology has been challenging due to lack of appropriate tools. Here, the authors present an interference-based method, illuminated via two rapidly alternating wavelengths, which enables real-time mapping of nanoscale forces with sub-second mechanical fluctuations.
- Andrew T. Meek
- , Nils M. Kronenberg
- & Malte C. Gather
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Article
| Open AccessMechanically activated ion channel Piezo1 modulates macrophage polarization and stiffness sensing
Macrophages perform diverse functions during immune responses, but the molecular mechanisms by which physical properties of the tissue regulate macrophage behavior remain unknown. Here the authors find that Piezo1 is a mechanosensor of stiffness, and that its activity modulates macrophage polarization responses.
- Hamza Atcha
- , Amit Jairaman
- & Wendy F. Liu