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| Open AccessSpliceosome component Usp39 contributes to hepatic lipid homeostasis through the regulation of autophagy
Non-alcoholic fatty liver disease affects 25% of people worldwide. Here the authors report that spliceosome component Usp39 deletion in mice leads to spontaneous steatosis and impaired autophagy through the regulation of alternative splicing.
- Donghai Cui
- , Zixiang Wang
- & Zhaojian Liu
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Article
| Open AccessIntegrative analysis reveals a conserved role for the amyloid precursor protein in proteostasis during aging
The normal function of amyloid precursor protein (APP) implicated in Alzheimer’s disease is unclear. Here, authors use multi-omics to reveal the fly APP’s role in regulating proteostasis and validate using vertebrate and In-vivo tauopathy models.
- Vanitha Nithianandam
- , Hassan Bukhari
- & Mel B. Feany
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Article
| Open AccessDNAJB6 mutants display toxic gain of function through unregulated interaction with Hsp70 chaperones
Here the authors characterize DNAJB6 mutants found in LGMDD1 patients. They show that these mutants retain aggregation-prevention activity, but have impaired regulation of Hsp70 binding, uncontrollably recruiting Hsp70s, depleting the chaperone levels and disrupting proteostasis.
- Meital Abayev-Avraham
- , Yehuda Salzberg
- & Rina Rosenzweig
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Article
| Open AccessGlycoengineered keratinocyte library reveals essential functions of specific glycans for all stages of HSV-1 infection
Here authors generate a glycoengineered keratinocyte library delineating human glycosylation pathways. The use of this library reveals that each stage of the HSV-1 infectious cycle is sensitive to alterations in the cellular glycan landscape, identifying critical biosynthetic steps that could be exploited for targeting HSV-1.
- Ieva Bagdonaite
- , Irina N. Marinova
- & Hans H. Wandall
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Article
| Open AccessARF1 prevents aberrant type I interferon induction by regulating STING activation and recycling
Self-derived DNA may trigger interferon-driven autoinflammation mediated by the cGAS-STING axis. Here, the authors find that mutations in the GTPase ARF1 cause an interferonopathy by promoting aberrant mitochondrial DNA release and impairing STING recycling.
- Maximilian Hirschenberger
- , Alice Lepelley
- & Konstantin M. J. Sparrer
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Article
| Open AccessFollicle-stimulating hormone orchestrates glucose-stimulated insulin secretion of pancreatic islets
Follicle-stimulating hormone (FSH) is involved in mammalian reproduction, but several studies have suggested a role of FSH and its receptor in extragonadal tissue. Here, the authors show that FSH orchestrates glucose-stimulated insulin secretion (GSIS) via its receptor on pancreatic β-cells, with pre-menopausal FSH levels dose-dependently promoting GSIS and postmenopausal FSH levels inhibiting this effect.
- Yi Cheng
- , Hong Zhu
- & He-Feng Huang
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Article
| Open AccessHepatocyte FBXW7-dependent activity of nutrient-sensing nuclear receptors controls systemic energy homeostasis and NASH progression in male mice
NASH, nonalcoholic steatohepatitis, a severe fatty liver disease with no cure, can manifest through loss-of-function of the E3 ligase FBXW7. Here, the authors show an underpinning of dysregulated ERRα and PPARα nuclear receptor activity, thus highlighting potential new avenues for antiNASH therapy.
- Hui Xia
- , Catherine R. Dufour
- & Vincent Giguère
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Article
| Open AccessCancer-associated fibroblasts actively compress cancer cells and modulate mechanotransduction
Cancer-associated fibroblasts (CAFs) can produce ECM and form a physical barrier around the tumour. Here, the authors show in transgenic mouse models and in vitro systems that CAFs are able to actively compress cancer cells using actomyosin contractility and this leads to a modulation of cancer cell mechanosensing and tumour reorganisation.
- Jorge Barbazan
- , Carlos Pérez-González
- & Danijela Matic Vignjevic
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Article
| Open AccessCyclic fasting bolsters cholesterol biosynthesis inhibitors’ anticancer activity
Nutritional stress induced by short-term dietary restriction has been shown to alter the activity of some anti-tumour drugs. Here, the authors demonstrate that periodic fasting enhances the anti-tumour effect of cholesterol biosynthesis inhibitors via decreased AKT-STAT3 signaling and oxidative phosphorylation.
- Amr Khalifa
- , Ana Guijarro
- & Alessio Nencioni
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Article
| Open AccessHIV-1 diverts cortical actin for particle assembly and release
HIV-1 assembles and buds from the host cell membrane of infected T lymphocytes. Here, Dibsy et al. characterise the role of cortical actin, viral Gag and host factor Arpin in virion assembly and release.
- Rayane Dibsy
- , Erwan Bremaud
- & Delphine Muriaux
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Article
| Open AccessRemodeling the cellular stress response for enhanced genetic code expansion in mammalian cells
Genetic code expansion (GCE) is a protein engineering tool that enables programmed and site-specific installation of noncanonical amino acids into proteins. Here, authors show that cellular stress remodelling boosts GCE in mammalian cells including GCE realized by orthogonally translating organelles.
- Mikhail E. Sushkin
- , Christine Koehler
- & Edward A. Lemke
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Article
| Open AccessHomodimer-mediated phosphorylation of C/EBPα-p42 S16 modulates acute myeloid leukaemia differentiation through liquid-liquid phase separation
CCAAT/enhancer binding protein α (C/EBPα) regulates myeloid differentiation, and its dysregulation contributes to acute myeloid leukaemia progress. Here the authors show that homodimer-mediated phosphorylation of C/EBPα-p42 modulates acute myeloid leukaemia cell differentiation by liquid-liquid phase separation.
- Dongmei Wang
- , Tao Sun
- & Chunyan Ji
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Article
| Open AccessDIAPH1-MFN2 interaction regulates mitochondria-SR/ER contact and modulates ischemic/hypoxic stress
Proximity between mitochondria and endoplasmic reticulum regulates mitochondria fitness and is adversely affected by tissue ischemia. This work reveals that Diaphanous1-Mitofusin2 interaction regulates this proximity and impairs recovery in ischemia.
- Gautham Yepuri
- , Lisa M. Ramirez
- & Ravichandran Ramasamy
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Article
| Open AccessNanobody-based VSR7 tracing shows clathrin-dependent TGN to Golgi recycling
Nanobody-epitope interaction-based analysis of the Arabidopsis VACUOLAR SORTING RECEPTOR7 (VSR7) suggests immobilization-based ligand transport to the TGN/EE and ends due to acidity-driven ligand release and clathrin-dependent receptor recycling.
- Xiaoyu Shao
- , Hao Xu
- & Peter Pimpl
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Article
| Open AccessAn apical Phe-His pair defines the Orai1-coupling site and its occlusion within STIM1
The intermembrane complexes mediating calcium signals are crucial but poorly understood. Here the authors identify a Phe-His pair in the calcium-sensing STIM1 protein that controls both activation and pairing of STIM1 with Orai channels to generate calcium signals
- Yandong Zhou
- , Michelle R. Jennette
- & Donald L. Gill
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Article
| Open AccessFarnesoid X receptor activation by bile acids suppresses lipid peroxidation and ferroptosis
Ferroptosis is a regulated form of cell death occurring upon lipid peroxidation. Here, the authors discovered that activation of the Farnesoid X receptor by bile acids suppresses ferroptosis through upregulation of anti-ferroptotic genes.
- Juliane Tschuck
- , Lea Theilacker
- & Kamyar Hadian
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Article
| Open AccessA phosphoinositide switch mediates exocyst recruitment to multivesicular endosomes for exosome secretion
The molecular mechanism by which exosomes are released from cells is unclear. Here the authors report that a phosphatidylinositide conversion couples the recruitment of the octameric exocyst complex to multivesicular endosomes for exosome secretion.
- Di-Ao Liu
- , Kai Tao
- & Wei Guo
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Article
| Open AccessThe Lin28b/Wnt5a axis drives pancreas cancer through crosstalk between cancer associated fibroblasts and tumor epithelium
Crosstalk between tumor cells and the microenvironment is essential for tumor progression. Here, the authors show Pancreatic ductal adenocarcinoma (PDAC) epithelial cells with high level of Lin28b secrete Wnt5a to upregulate Lin28b expression in cancer-associated fibroblasts, which in turn promote growth of PDAC cells via production of PCSK9.
- Zhaoqi Shu
- , Minghe Fan
- & Ying Zhao
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Article
| Open AccessStructural titration reveals Ca2+-dependent conformational landscape of the IP3 receptor
Inositol 1,4,5-trisphosphate receptors (IP3Rs) are intracellular Ca2+ channels that produce Ca2+ oscillations in response to GPCR and RTK activation. Here, Paknejad et al. resolve the conformational landscape of IP3Rs that gives rise to the biphasic dependence on Ca2+ for channel activity.
- Navid Paknejad
- , Vinay Sapuru
- & Richard K. Hite
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Article
| Open AccessAntiviral responses in a Jamaican fruit bat intestinal organoid model of SARS-CoV-2 infection
Bats are natural reservoirs for several zoonotic viruses including SARS-CoV-2 thus there is a need to better define bat antiviral responses. Here, Hashimi et al. profile antiviral responses to SARS-CoV-2 in bat intestinal organoids finding that interferon and regenerative responses where induced.
- Marziah Hashimi
- , T. Andrew Sebrell
- & Diane Bimczok
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Article
| Open AccessMechanism of synergistic activation of Arp2/3 complex by cortactin and WASP-family proteins
Arp2/3 complex is activated by nucleation promoting factors (NPFs) to form actin branches that are stabilized by cortactin. Here, the authors show that NPFs and cortactin activate Arp2/3 complex synergistically by helping recruit the complex to F-actin and by stabilizing its active conformation
- Fred E. Fregoso
- , Malgorzata Boczkowska
- & Roberto Dominguez
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Article
| Open AccessA circular RNA activated by TGFβ promotes tumor metastasis through enhancing IGF2BP3-mediated PDPN mRNA stability
TGFbeta is known to promote cancer metastasis through the promotion of epithelial-mesenchymal transition (EMT). Here, the authors demonstrate that a TGFbeta induced circular RNA (circITGB6) promotes colorectal cancer metastasis via activation of the m6A reader protein, IGF2BP3, resulting in stabilization of an EMT-promoting gene, PDPN.
- Ke Li
- , Jiawei Guo
- & Yong Peng
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Article
| Open AccessDynamic interactions between E-cadherin and Ankyrin-G mediate epithelial cell polarity maintenance
The maintenance of cell polarity depends on adhesion complexes that tether to the cytoskeleton. Here the authors show the dynamic nature of E-cadherin–Ankyrin-G complex formation and investigate its functional role in epithelial cell polarity maintenance.
- Chao Kong
- , Xiaozhan Qu
- & Chao Wang
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Article
| Open AccessFolding correctors can restore CFTR posttranslational folding landscape by allosteric domain–domain coupling
The conformational biogenesis of multi-domain ABC-transporters is poorly understood. Here the authors show the critical role of dynamic allosteric coupling networks, its perturbation and restoration in CFTR folding, misfolding, and pharmacological rescue, respectively.
- Naoto Soya
- , Haijin Xu
- & Gergely L. Lukacs
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Article
| Open AccessProlonging somatic cell proliferation through constitutive hox gene expression in C. elegans
Somatic cells in C. elegans stop dividing after completing their normal lineage at the end of development. Here, Heinze et al. show that constitutive expression of a hox gene prolongs proliferation beyond the restriction imposed by the cell lineage.
- Svenia D. Heinze
- , Simon Berger
- & Alex Hajnal
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Article
| Open AccessFIGNL1 AAA+ ATPase remodels RAD51 and DMC1 filaments in pre-meiotic DNA replication and meiotic recombination
Assembly and disassembly of RAD51/DMC1 during homologous recombination are tightly regulated. Here, the authors show that the FIGNL1 ATPase limits non-productive assembly of RAD51/DMC1 on single-stranded and double-stranded DNAs during meiosis.
- Masaru Ito
- , Asako Furukohri
- & Akira Shinohara
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Article
| Open AccessSmall leucine-rich proteoglycans inhibit CNS regeneration by modifying the structural and mechanical properties of the lesion environment
The mechanical properties of central nervous system (CNS) scar tissue are considered to contribute to axon regeneration failure. Here, the authors identify members of the small leucine-rich proteoglycan family as modulators of the inhibitory viscoelastic response of CNS lesions.
- Julia Kolb
- , Vasiliki Tsata
- & Daniel Wehner
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Article
| Open AccessPhosphorylation-dependent pseudokinase domain dimerization drives full-length MLKL oligomerization
How the necroptosis executioner, MLKL, converts to a killer form has been mysterious. Here, authors show RIPK3-mediated phosphorylation of human MLKL is the cue for pseudokinase domain dimerization before assembly of pro-necroptotic MLKL tetramers.
- Yanxiang Meng
- , Sarah E. Garnish
- & James M. Murphy
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Article
| Open AccessSTRA8–RB interaction is required for timely entry of meiosis in mouse female germ cells
Female germ cells initiate meiosis within a limited time period in the fetal ovary. Here the authors show that the interaction between STRA8 and RB ensures precise timing of meiosis initiation and highlight the regulatory mechanisms underlying female-specific meiotic initiation in mice.
- Ryuki Shimada
- , Yuzuru Kato
- & Kei-ichiro Ishiguro
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Article
| Open AccessVisualization of accessible cholesterol using a GRAM domain-based biosensor
Regulated cholesterol transport is essential for the maintenance of cellular cholesterol distribution and homeostasis, but tools to monitor this process are limited. Here, the authors develop a genetically encoded cholesterol biosensor and demonstrate its use for visualising cellular cholesterol distribution in various live cells in real time.
- Dylan Hong Zheng Koh
- , Tomoki Naito
- & Yasunori Saheki
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Article
| Open AccessThe mitochondrial fusion protein OPA1 is dispensable in the liver and its absence induces mitohormesis to protect liver from drug-induced injury
The role of the mitochondrial fusion protein OPA1 in liver function is unknown. Here, authors showed that OPA1 is dispensable in the liver, and that the mitohormesis induced by OPA1 deletion prevents liver injury and contributes to liver resiliency.
- Hakjoo Lee
- , Tae Jin Lee
- & Yisang Yoon
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Article
| Open AccessProfiling of the Helicobacter pylori redox switch HP1021 regulon using a multi-omics approach
Helicobacter pylori adapted to the harsh conditions of the human stomach using a handful of regulatory proteins. Here, the authors identify H. pylori processes controlled by the HP1021 response regulator under optimal growth and oxidative stress.
- Mateusz Noszka
- , Agnieszka Strzałka
- & Anna Zawilak-Pawlik
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Article
| Open AccessSynapsin condensation controls synaptic vesicle sequestering and dynamics
Brain functioning critically relies on coordinated neurotransmitter release by synaptic vesicles (SVs) at synapses. This study shows that synapsin/SVs condensation is sufficient to guarantee reliable confinement and motility of SVs at synapses in vivo.
- Christian Hoffmann
- , Jakob Rentsch
- & Dragomir Milovanovic
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Article
| Open AccessHierarchical organization and assembly of the archaeal cell sheath from an amyloid-like protein
Cellular cryoET reveals how an amyloid-like protein of the prototypical archaeon, Methanospirillum hungatei, oligomerizes into a ring containing a giant 2700-strand β sheet, and how rings stack into hoops and into the cylindrical sheath of the cell.
- Hui Wang
- , Jiayan Zhang
- & Z. Hong Zhou
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Article
| Open AccessHow myosin VI traps its off-state, is activated and dimerizes
Canon et al. offer insights into the auto-inhibition and activation of the minus-end directed motor myosin VI. The work highlights how differential relief of auto-inhibition allows for fine control of myosin VI activity in vivo.
- Louise Canon
- , Carlos Kikuti
- & Anne Houdusse
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Article
| Open Access3D chromatin interactions involving Drosophila insulators are infrequent but preferential and arise before TADs and transcription
In Drosophila, insulators may be involved in the organization of Topological Associated Domains, but the mechanism of action is a still a matter of investigation. Here the authors investigate the role of insulators in the 3D organization of the Drosophila genome by combining bioinformatics analysis and Hi-M, an imaging-based methods developed to detect the 3D positions of multiple genomic loci in single cells.
- Olivier Messina
- , Flavien Raynal
- & Marcelo Nollmann
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Article
| Open AccessPalmitoyltransferase DHHC9 and acyl protein thioesterase APT1 modulate renal fibrosis through regulating β-catenin palmitoylation
The role and mechanisms for protein palmitoylation in renal fibrosis remain unclear. Here, the authors show that DHHC9 and APT1 catalysed β-catenin S-palmitoylation on Cys300 contributes to renal fibrosis, which may provide a new therapeutic strategy for chronic kidney diseases.
- Mengru Gu
- , Hanlu Jiang
- & Chunsun Dai
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Article
| Open AccessStructural insights into the agonists binding and receptor selectivity of human histamine H4 receptor
Histamine receptor H4R is implicated in chronic inflammatory diseases, such as asthma, arthritis, and atopic dermatitis. Here, the authors determined the first cryo-EM structure of the histamine H4 receptor, providing valuable structural insights for the design of drugs targeting H4R in chronic inflammatory diseases.
- Dohyun Im
- , Jun-ichi Kishikawa
- & So Iwata
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Article
| Open AccessThe transcription factor Zeb1 controls homeostasis and function of type 1 conventional dendritic cells
Type 1 conventional dendritic cells (cDC1) play a pivotal role in the cross-presentation of antigens, enabling efficient CD8 + T cell response. Here authors show that the transcription factor Zeb1 essentially regulates this process via facilitating the reactive-oxygen-species-dependent rupture of phagosomal membrane to allow antigen export to the cytoplasm.
- Yan Wang
- , Quan Zhang
- & Nengming Xiao
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Article
| Open AccessLactylation of METTL16 promotes cuproptosis via m6A-modification on FDX1 mRNA in gastric cancer
Cuproptosis regulation in tumors is unclear. Here the authors find that copper promotes METTL16 lactylation, inducing cuproptosis via stabilizing FDX1 in gastric cancer. Targeting lactyl-METTL16 and cuproptosis offers a potential feasible strategy for cancer therapy.
- Lianhui Sun
- , Yuan Zhang
- & Chen Huang
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Article
| Open AccessLactate dehydrogenase D is a general dehydrogenase for D-2-hydroxyacids and is associated with D-lactic acidosis
Currently the structure and biological function of Lactate Dehydrogenase D (LDHD) are unclear. Here the authors report the structure of LDHD bound with various ligands and show that LDHD is a general dehydrogenase for D-2-hydroxyacids with small to moderate-size hydrophobic moieties and investigate loss-of-function mutations that play an important role in D-lactic acidosis.
- Shan Jin
- , Xingchen Chen
- & Jianping Ding
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Article
| Open AccessGut insulin action protects from hepatocarcinogenesis in diabetic mice comorbid with nonalcoholic steatohepatitis
Diabetes is known to increase the risk of nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). Here, the authors show in a mice model that insulin action in the gut may play a protective role in the development of NASH and HCC in diabetes.
- Kotaro Soeda
- , Takayoshi Sasako
- & Kohjiro Ueki
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Article
| Open AccessReprogramming of cis-regulatory networks during skeletal muscle atrophy in male mice
Skeletal muscle’s metabolic status has an impact on health and the prognosis of chronic diseases. Here the authors unveil an atlas of open chromatin regions in skeletal muscles using single-nucleus techniques on juvenile male mice, highlight regulatory dynamics between normal and denervated states, and pinpoint ELK4 as a pivotal factor in muscle atrophy.
- Hongchun Lin
- , Hui Peng
- & Zhaoyong Hu
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Article
| Open AccessUbiquitin ligase CHFR mediated degradation of VE-cadherin through ubiquitylation disrupts endothelial adherens junctions
Vascular endothelial cadherin (VE-cadherin), endothelial cell-cell adhesive protein maintains blood vessel barrier integrity and vascular homeostasis. Here, the authors show that infectious bacterial toxin activates ubiquitin ligase CHFR which in turn degrades VEcadherin via ubiquitylation in endothelial cells to cause vascular injury.
- Chinnaswamy Tiruppathi
- , Dong-Mei Wang
- & Asrar B. Malik
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Article
| Open AccessO-GlcNAcylation regulates neurofilament-light assembly and function and is perturbed by Charcot-Marie-Tooth disease mutations
The neurofilament cytoskeleton is critical for axon function and can be dysregulated in disease. Here, the authors show that intracellular glycosylation regulates a key neurofilament protein.
- Duc T. Huynh
- , Kalina N. Tsolova
- & Michael Boyce
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Article
| Open AccessGreen leaf volatile sensory calcium transduction in Arabidopsis
Plants sense volatiles emitted by injured neighboring plants and elicit defense responses to external threats. Here, the authors show that Arabidopsis leaves uptake two green leaf volatiles via stomata and trigger cytosolic Ca2+ defense signaling.
- Yuri Aratani
- , Takuya Uemura
- & Masatsugu Toyota
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Article
| Open AccessA human lung alveolus-on-a-chip model of acute radiation-induced lung injury
Acute exposure to radiation can lead to acute pneumonitis, fibrosis or death. Here the authors develop an alveolus-on chip model to study the molecular characteristics of radiation induced lung injury, better understand radiation induced lung disease and facilitate drug screening.
- Queeny Dasgupta
- , Amanda Jiang
- & Donald E. Ingber
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Article
| Open AccessMolecular landscape and functional characterization of centrosome amplification in ovarian cancer
The prevalence of centrosome amplification (CA) and the genomic landscape of chromosomal instability in high-grade serous ovarian carcinoma (HGSOC) remain to be explored. Here the authors suggest CA as a potential driver of tumour evolution and a biomarker for treatment response in HGSOC.
- Carolin M. Sauer
- , James A. Hall
- & James D. Brenton
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Article
| Open AccessRedundancy and the role of protein copy numbers in the cell polarization machinery of budding yeast
Cell polarization of budding yeast recovers reliably and reproducibly from loss of one of its key components. Here, the authors show how this robustness emerges from redundant self-organization mechanisms coexisting within the underlying protein network.
- Fridtjof Brauns
- , Leila Iñigo de la Cruz
- & Erwin Frey
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