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| Open AccessSIKs control osteocyte responses to parathyroid hormone
Parathyroid hormone (PTH) is an endogenous hormone and osteoporosis therapeutic that suppresses sclerostin activity. Here the authors develop SIK inhibitors as potential therapeutic tools and use them to show that PTH-cAMP signalling in osteocytes inhibits SIK2 from driving Hdac4/5 nuclear shuttling to suppress sclerostin.
- Marc N. Wein
- , Yanke Liang
- & Henry M. Kronenberg
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Article
| Open AccessBoundaries steer the contraction of active gels
The actomyosin cytoskeleton consists of a contractile array but how it becomes organized is not clear. Here the authors reconstitute a controllable contractile system to show that force balances at boundaries determine contraction dynamics, and spatial anisotropy leads to self-organization or aligned contractile fibres.
- Matthias Schuppler
- , Felix C. Keber
- & Andreas R. Bausch
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Article
| Open AccessMacrophage-derived extracellular vesicle-packaged WNTs rescue intestinal stem cells and enhance survival after radiation injury
The intestinal stroma secretes WNT ligands but the role of WNT in intestinal repair is unclear. Here, the authors show that when WNT synthesis is ablated from stromal macrophages, the intestine morphology is normal but hypersensitive to radiation injury, implicating macrophage-derived WNT in intestinal repair.
- Subhrajit Saha
- , Evelyn Aranda
- & Jeffrey W. Pollard
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Article
| Open AccessLWD–TCP complex activates the morning gene CCA1 in Arabidopsis
TheArabidopsisCCA1 transcription factor is a core regulator of the circadian clock. Here, the authors show that the LWD1 protein, in complex with the TCP20 or TCP22 transcription factors, acts as a co-activator of CCA1 expression contributing to elevated CCA1 expression at dawn.
- Jing-Fen Wu
- , Huang-Lung Tsai
- & Shu-Hsing Wu
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Article
| Open AccessSpecification of haematopoietic stem cell fate via modulation of mitochondrial activity
Haematopoietic stem cells rely on glycolysis for their energy demands but whether this affects their fate is unknown. Here, the authors show that forcing the cells to rely on glycolysis is important for self-renewal and that this involves a reduction in mitochondrial mass.
- Nicola Vannini
- , Mukul Girotra
- & Matthias P. Lutolf
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Article
| Open AccessPolarization of M2 macrophages requires Lamtor1 that integrates cytokine and amino-acid signals
The role of nutrient-sensing pathways in regulation of innate immune response is unexplored. Here the authors show that IL-4 activates the amino-acid sensing pathway in macrophages and leads to polarization of anti-inflammatory M2 macrophages via the transcription factor liver X receptor.
- Tetsuya Kimura
- , Shigeyuki Nada
- & Atsushi Kumanogoh
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Article
| Open AccessTiam1/Rac1 complex controls Il17a transcription and autoimmunity
Tiam1 is a guanine nucleotide exchange factor for the Rho-family GTPase Rac1. Here, the authors show that nuclear Tiam1 and Rac1 bind to RORγt on the IL-17 promoter, activating its transcription, and that inhibiting Tiam1/Rac1 is beneficial in a mouse model of autoimmunity.
- Ahmed T. Kurdi
- , Ribal Bassil
- & Wassim Elyaman
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Article
| Open AccessCoordinated integrin activation by actin-dependent force during T-cell migration
The role of force in activating integrin cell adhesion receptors is not known. Here the authors develop fluorescent tension sensors for αL and β2 integrins and show that in migrating T cells force is transduced across the β2 integrin, and that this correlates with an active conformational state.
- Pontus Nordenfelt
- , Hunter L. Elliott
- & Timothy A. Springer
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Article
| Open AccessActomyosin-dependent dynamic spatial patterns of cytoskeletal components drive mesoscale podosome organization
Podosomes are adhesive cytoskeletal structures found in several cell types, but whether or how they are interconnected is not known. Here the authors demonstrate mesoscale connectivity of podosome clusters by imaging directional flow patterns of podosome components vinculin, talin and F-actin.
- Marjolein B. M. Meddens
- , Elvis Pandzic
- & Alessandra Cambi
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Article
| Open AccessSeparating mitochondrial protein assembly and endoplasmic reticulum tethering by selective coupling of Mdm10
The protein Mdm10 is known to be present in the endoplasmic reticulum-mitochondria encounter structure (ERMES) and in mitochondrial sorting and assembly machinery (SAM). Here, the authors examine how this protein interacts with SAM and EMRES, showing that the SAM-mediated protein machinery is independent of ERMES.
- Lars Ellenrieder
- , Łukasz Opaliński
- & Thomas Becker
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Article
| Open AccessBimodal antagonism of PKA signalling by ARHGAP36
Protein kinase A (PKA) is a key mediator of cyclic AMP signalling. Here, Eccles et al. show that ARHGAP36 antagonizes PKA by acting as a kinase inhibitor and targeting the catalytic subunit for endolysosomal degradation, thus reducing sensitivity of cells to cAMP and promoting Hedgehog signalling.
- Rebecca L. Eccles
- , Maciej T. Czajkowski
- & Oliver Rocks
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Article
| Open AccessInsulin and TOR signal in parallel through FOXO and S6K to promote epithelial wound healing
The TOR and insulin/IGF signalling (IIS) network are central responses to wound healing. Here the authors develop a technique of live imaging of laser-induced epidermal wounds to flies and show that TOR and IIS are independently required for wound healing, which may have implications for diabetic wound healing and its treatment.
- Parisa Kakanj
- , Bernard Moussian
- & Maria Leptin
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Article
| Open AccessARD1-mediated Hsp70 acetylation balances stress-induced protein refolding and degradation
The chaperone Hsp70 has a dual role, promoting both protein refolding and protein degradation. Seo and Park et al. show that Hsp70 acetylation enhances protein refolding after stress, and that subsequent deacetylation progressively promotes ubiquitin ligase binding and protein degradation.
- Ji Hae Seo
- , Ji-Hyeon Park
- & Kyu-Won Kim
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Article
| Open AccessSpatiotemporal control of cell–cell reversible interactions using molecular engineering
Reversible manipulation of cell-cell interactions has potential applications in basic research and cell-based therapy. Here the authors control cell-cell adhesion in vitrowith light, by modifying the surface sugars of cells to display β-cyclodextrin, which recognises one isoform of light-isomerizable azobenzene linkers.
- Peng Shi
- , Enguo Ju
- & Xiaogang Qu
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Article
| Open AccessDifferential hepatic distribution of insulin receptor substrates causes selective insulin resistance in diabetes and obesity
Type 2 diabetes and obesity are associated with increased hepatic gluconeogenesis and lipogenesis, known as selective insulin resistance. Here Kubota et al. explain selective insulin resistance in the liver with the zonal distribution and selective insulin-mediated regulation of Irs1 and Irs2.
- Naoto Kubota
- , Tetsuya Kubota
- & Takashi Kadowaki
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Article
| Open AccessA regulatory circuit of miR-125b/miR-20b and Wnt signalling controls glioblastoma phenotypes through FZD6-modulated pathways
Glioblastoma (GBM) is classified as proneural (PN), neural, mesenchymal (MES) and classical GBM. Here the authors show that Wnt signalling, miR-125b and miR-20b establish a regulatory circuitry including FZD6 which distinguishes PN from the MES subtype.
- Tianzhi Huang
- , Angel A. Alvarez
- & Shi-Yuan Cheng
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Article
| Open AccessSUMOylated NKAP is essential for chromosome alignment by anchoring CENP-E to kinetochores
The kinetochore-bound motor CENP-E plays a critical role in chromosome alignment. Here, the authors show that NF-κB activating protein (NKAP) dynamically localises to kinetochores, is SUMOylated during mitosis, and this modification is required for NKAP to bind CENP-E and localise CENP-E to the kinetochore.
- Teng Li
- , Liang Chen
- & Qing Xia
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Article
| Open AccessA plasma membrane microdomain compartmentalizes ephrin-generated cAMP signals to prune developing retinal axon arbors
It is unclear what role cholesterol-enriched domains of the plasma membrane play in mediating the development of neuronal circuits. Here, the authors show that such domains localize ephrin-A-induced cAMP signals, causing the pruning of retinal ganglion cell axons.
- Stefania Averaimo
- , Ahlem Assali
- & Xavier Nicol
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Article
| Open AccessDynamic actin cycling through mitochondrial subpopulations locally regulates the fission–fusion balance within mitochondrial networks
Mitochondria are dynamic organelles that can undergo fission and fusion. Here the authors identify a novel pathway in which actin dynamically assembles in an Arp2/3- and formin-dependent manner around a subset of cellular mitochondria, promoting localized Drp1-dependent fission and impeding fusion.
- Andrew S. Moore
- , Yvette C. Wong
- & Erika L. F. Holzbaur
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Article
| Open AccessAntagonistic roles of Drosophila Tctp and Brahma in chromatin remodelling and stabilizing repeated sequences
Genome stability is important for normal cellular function. Here, Hong and Choi show that translationally controlled tumour protein (TCTP) in Drosophilaregulates pericentromeric chromatin remodelling and transcription via negatively regulating a chromatin remodeler Brahma.
- Sung-Tae Hong
- & Kwang-Wook Choi
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Article
| Open AccessConfocal reference free traction force microscopy
Traction force microscopy is an effective method of measuring forces between cells and their environment, but requires removing the cells to obtain a reference image. Here the authors use nanodrip printing of quantum dots into compliant substrates to provide a regular array of fiducial spots, removing the need for a reference image.
- Martin Bergert
- , Tobias Lendenmann
- & Aldo Ferrari
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Article
| Open AccessEnrichment of hydroxylated C24- and C26-acyl-chain sphingolipids mediates PIN2 apical sorting at trans-Golgi network subdomains
Sphingolipids in the trans-Golgi network have been implicated in polar trafficking. Here Wattelet-Boyer et al. show that hydroxylated C24- and C26-acyl-chain sphingolipids are enriched in trans-Golgi network subdomains that are critical for polar sorting of the PIN2 auxin carrier in plant cells.
- Valérie Wattelet-Boyer
- , Lysiane Brocard
- & Yohann Boutté
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Article
| Open Access14-3-3ζ regulates the mitochondrial respiratory reserve linked to platelet phosphatidylserine exposure and procoagulant function
Platelets express negatively charged phosphatidylserine (PS) on their plasma membrane when propagating coagulation within a developing thrombus. Here the authors show that an adaptor protein 14-3-3 regulates mitochondrial function and PS exposure and thus platelet procoagulant activity, promising a new therapy to reduce thrombosis.
- Simone M. Schoenwaelder
- , Roxane Darbousset
- & Shaun P. Jackson
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Article
| Open AccessPlatelet clearance via shear-induced unfolding of a membrane mechanoreceptor
The platelets detect and respond to shear stress generated by blood flow. Here the authors show that the binding of the soluble von Willebrand factor to its receptor GPIba under physiological shear stress induces receptor's domain unfolding on the platelet and signalling into the platelet, leading to platelets clearance.
- Wei Deng
- , Yan Xu
- & Renhao Li
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Article
| Open AccessThe RNA-binding protein vigilin regulates VLDL secretion through modulation of Apob mRNA translation
RNA-binding proteins (RBP) are an emerging group of post-translational regulators. Here the authors show that the RBP vigilin regulates translation of mRNA encoding for proatherogenic proteins—apoB, apoC-III and fibronectin—representing a potential therapeutic target in cardiovascular diseases.
- Mehrpouya B. Mobin
- , Stefanie Gerstberger
- & Markus Stoffel
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Article
| Open AccessThe tobacco-specific carcinogen-operated calcium channel promotes lung tumorigenesis via IGF2 exocytosis in lung epithelial cells
The binding of tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) to nicotinic acetylcholine receptors (nAChRs) induces calcium signalling. Here the authors show that NKK-induced calcium influx in airway epithelial cells triggers IGF2 secretion and tumourigenesis.
- Hye-Jin Boo
- , Hye-Young Min
- & Ho-Young Lee
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Article
| Open AccessFMRP regulates an ethanol-dependent shift in GABABR function and expression with rapid antidepressant properties
Alcohol is thought to lead to neuroadaptive changes, although the underlying molecular mechanisms are unclear. Here, the authors find ethanol treatment alters GABAB-receptor expression via fragile-X mental retardation protein in mice, leading to antidepressant-like behaviours.
- Sarah A. Wolfe
- , Emily R. Workman
- & Kimberly F. Raab-Graham
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Article
| Open AccessTransport of a kinesin-cargo pair along microtubules into dendritic spines undergoing synaptic plasticity
Transport of cargo into dendritic spines is required for synaptic plasticity. McVicker et al.describe a method of activity-dependent transport of a kinesin KIF1A and its cargo synaptotagmin-IV along microtubules that are transiently polymerized into dendritic spines.
- Derrick P. McVicker
- , Adam M. Awe
- & Erik W. Dent
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Article
| Open AccessA bead-based western for high-throughput cellular signal transduction analyses
Dissecting cellular signalling requires the analysis of large numbers of proteins. Here the authors describe DigiWest, a high-throughput protein detection method that combines the concept of western and widely-used bead array systems that allows rapid quantification of hundreds of specific proteins.
- Fridolin Treindl
- , Benjamin Ruprecht
- & Markus F. Templin
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Article
| Open AccessGDF11 decreases bone mass by stimulating osteoclastogenesis and inhibiting osteoblast differentiation
GDF11 is related to myostatin yet has no known role in postnatal bone turnover. Here the authors show that recombinant GDF11 injection causes bone loss and impairs healing by driving osteoclastogenesis while inhibiting osteoblast differentiation, plus they show that anti-GDF11 Ab can inhibit bone loss in ovariectomy and ageing mouse models.
- Weiqing Liu
- , Liyan Zhou
- & Quan Yuan
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Article
| Open AccessMale-killing symbiont damages host’s dosage-compensated sex chromosome to induce embryonic apoptosis
Symbiotic bacteria are able to interfere with host reproduction in ways that are detrimental to the host organism. Here the authors show that Spiroplasma induces DNA damage on the male X chromosome in Drosophila, causing sex-specific apoptosis.
- Toshiyuki Harumoto
- , Hisashi Anbutsu
- & Takema Fukatsu
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Article
| Open AccessDephosphorylated parafibromin is a transcriptional coactivator of the Wnt/Hedgehog/Notch pathways
Normal epithelial intestine organisation requires Wnt and Hedgehog signalling activity. Here, the authors show that parafibromin can activate both pathways in a mutually exclusive manner and is important for intestinal homeostasis.
- Ippei Kikuchi
- , Atsushi Takahashi-Kanemitsu
- & Masanori Hatakeyama
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Article
| Open AccessPRMT1-mediated methylation of MICU1 determines the UCP2/3 dependency of mitochondrial Ca2+ uptake in immortalized cells
MICU1 is a regulatory subunit of mitochondrial Ca2+ channels that shields mitochondria from Ca2+ overload. Here the authors show that MICU1 methylation by PRMT1 reduces Ca2+ sensitivity, which is normalized by UCP2/3, re-establishing mitochondrial Ca2+uptake activity.
- Corina T. Madreiter-Sokolowski
- , Christiane Klec
- & Wolfgang F. Graier
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Article
| Open AccessCortical dynamics during cell motility are regulated by CRL3KLHL21 E3 ubiquitin ligase
Although focal adhesions (FAs) and microtubules (MTs) are known to associate, the underlying regulation of this dynamic interaction is not understood. Here the authors discover that the CRL3KLHL21E3 ubiquitin ligase localises to FAs and ubiquitinates the MT plus-tip binding protein EB1, thereby promoting MT and FA dynamics and cell migration.
- Thibault Courtheoux
- , Radoslav I. Enchev
- & Matthias Peter
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Article
| Open AccessDysferlin-mediated phosphatidylserine sorting engages macrophages in sarcolemma repair
Sarcolemma lesions are sealed by a repair patch of lipids and proteins that prevents cell death and myopathy. Here the authors show that the "eat-me" signal phosphatidylserine is sorted from adjacent sarcolemma to the repair patch in a Dysferlin dependent process in zebrafish and human cells.
- Volker Middel
- , Lu Zhou
- & Uwe Strähle
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Article
| Open AccessN-glycosylation enables high lateral mobility of GPI-anchored proteins at a molecular crowding threshold
How molecular crowding affects membrane protein diffusion and function is not known. Here the authors measure diffusion of variant surface glycoprotein on trypanosomes and discover a molecular crowding threshold that limits diffusion, and find that N-linked glycans help to prevent retarding intermolecular interactions.
- Andreas J. W. Hartel
- , Marius Glogger
- & Markus Engstler
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Article
| Open AccessLocal microRNA delivery targets Palladin and prevents metastatic breast cancer
MicroRNAs represent potential therapeutic targets to control metastasis progression. Here the authors show that miR-96 and miR-182 regulate invasion via Palladin and demonstrate that local delivery of miR-96 and miR-182 may serve as a potential anti-metastatic drug in breast cancer.
- Avital Gilam
- , João Conde
- & Noam Shomron
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Article
| Open AccessCDK1 phosphorylates WRN at collapsed replication forks
End-resection of double strand DNA breaks is essential for pathway choice between non-homologous end-joining and homologous recombination. Here the authors show that phosphorylation of WRN helicase by CDK1 is essential for resection at replication-related breaks.
- Valentina Palermo
- , Sara Rinalducci
- & Pietro Pichierri
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Article
| Open AccessA FRET biosensor reveals spatiotemporal activation and functions of aurora kinase A in living cells
Alterations in aurora kinase A (AURKA) activity can result in mitotic errors and have been associated with cancer progression. Here the authors develop a FRET biosensor which functionally replaces AURKA in cells, and show that its activation in the G1 phase is required to maintain microtubule stability.
- Giulia Bertolin
- , Florian Sizaire
- & Marc Tramier
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Article
| Open AccessThe oncometabolite 2-hydroxyglutarate activates the mTOR signalling pathway
Oncogenic mutations of isocitrate dehydrogenases 1 and 2 result in the production of the oncometabolite R-2-hydroxyglutarate. Here the authors show that the oncometabolite promotes mTOR activation in a PTEN/PI3K-independent manner by regulating DEPTOR stability via inhibition of KDM4A activity.
- Mélissa Carbonneau
- , Laurence M. Gagné
- & Frédérick A. Mallette
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Article
| Open AccessAnks1a regulates COPII-mediated anterograde transport of receptor tyrosine kinases critical for tumorigenesis
EphA2/ErbB2 complex is important in promoting breast cancer but the mechanism by which these receptor tyrosine kinases are exported from the endoplasmic reticulum is unknown. Here the authors show that Anks1a acts as a cargo adaptor in sorting EphA2 into COPII vesicles, thus modulating the surface level of EphA2.
- Haeryung Lee
- , Hyuna Noh
- & Soochul Park
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Article
| Open AccessStructural insights into the interaction and disease mechanism of neurodegenerative disease-associated optineurin and TBK1 proteins
Mutations in optineurin that cause defects in the interaction with TBK1 are associated with neurodegenerative diseases. Here, the authors report the structure of this complex, and outline a general binding mode for these proteins.
- Faxiang Li
- , Xingqiao Xie
- & Lifeng Pan
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Article
| Open AccessHigh cell-surface density of HER2 deforms cell membranes
HER2 is frequently overexpressed in breast cancer in association with increased metastatic potential. Here, the authors show that HER2 overexpression causes deformation of cell membranes in a signalling-independent manner that contributes to the disease phenotype by disrupting epithelial features.
- Inhee Chung
- , Mike Reichelt
- & Mark X. Sliwkowski
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Article
| Open AccessSuper-resolution microscopy reveals a preformed NEMO lattice structure that is collapsed in incontinentia pigmenti
NEMO is a member of the IKK complex that binds ubiquitin, involved in NF-κB signalling and proposed to form higher order structures. Here the authors use super-resolution microscopy to detect the presence of NEMO lattices in cells, that are modified by NF-κB treatment and abrogated by mutations affecting NEMO ubiquitin binding.
- Janine Scholefield
- , Ricardo Henriques
- & Musa M. Mhlanga
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Article
| Open AccessORP4L is essential for T-cell acute lymphoblastic leukemia cell survival
Lymphocytic leukaemia cells are characterized by high respiratory rates. Here, the authors report that the oxysterol-binding protein ORPL4 sustains mitochondrial respiration in T-cell acute lymphoblastic leukaemia cells by regulating Ca2+release from the endoplasmic reticulum.
- Wenbin Zhong
- , Qing Yi
- & Daoguang Yan
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Article
| Open AccessKinetics and specificity of paternal mitochondrial elimination in Caenorhabditis elegans
Autophagy mediates the degradation of paternal mitochondria after fertilization in C. elegansto ensure that mitochondria are inherited maternally. Here the authors show that mitochondrial dynamics is critical for the selectivity and kinetics of paternal mitochondrial elimination.
- Yang Wang
- , Yi Zhang
- & Ding Xue
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Article
| Open AccessInsulin post-transcriptionally modulates Bmal1 protein to affect the hepatic circadian clock
The effect of the liver clock is modified by food entrainment via Bmal1/Clock core machinery. Here the authors show that insulin promotes postprandial Akt-dependent phosphorylation of Bmal1, resulting in association with 14-3-3 and Bmal1 shuttling out of the nucleus, thereby disrupting Bmal1 transcriptional effects on the clock.
- Fabin Dang
- , Xiujie Sun
- & Yi Liu
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Article
| Open AccessNeutrophil recruitment limited by high-affinity bent β2 integrin binding ligand in cis
Integrin β2 attachment regulates inflammation via effects on neutrophil rolling and extravasation through sequential integrin extension then headpiece opening. Here the authors show an alternative open headpiece prior to extension stabilized in cisby ICAM-1 that limits neutrophil adhesion.
- Zhichao Fan
- , Sara McArdle
- & Klaus Ley
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Article
| Open AccessActin dynamics provides membrane tension to merge fusing vesicles into the plasma membrane
As vesicles fuse to the plasma membrane, they form intermediate Ω-shaped structures followed by either closure of the pore or full merging with the plasma membrane. Here Wen et al. show that dynamic actin assembly provides membrane tension to promote Ω merging in neuroendocrine cells and synapses.
- Peter J. Wen
- , Staffan Grenklo
- & Ling-Gang Wu
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